Influence of the Linker Length on the Cytotoxicity of Homobinuclear Ruthenium(II) and Gold(I) Complexes

Article

pubs.acs.org/IC

Inﬂuence of the Linker Length on the Cytotoxicity of Homobinuclear

Ruthenium(II) and Gold(I) Complexes

Lucinda K. Batchelor, Emilia Paunescu, Mylene Soudani, Rosario Scopelliti, and Paul J. Dyson*

̆ ̀

́ ́ ́

Institut des Sciences et Ingenierie Chimiques, Ecole Polytechnique Federale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland

*

S Supporting Information

ABSTRACT: Dinuclear metal complexes have emerged as a

promising class of anticancer compounds with the ability to

cross-link biomolecular targets. Here, we describe two novel

series of phosphine-linked dinuclear ruthenium(II) p-cymene

and gold(I) complexes, in which the length of the connecting

poly(ethylene glycol) chain has been systematically modiﬁed.

The impact of the multinuclearity, lipophilicity, and linker

length on the antiproliferative activity of the compounds on

tumorigenic (A2780 and A2780cisR) and nontumorigenic

(

HEK-293) cell lines was assessed. The dinuclear ruthenium-

II) complexes were considerably more cytotoxic than their

mononuclear counterparts, and a correlation between the

lipophilicity of the linker and the cytotoxicity was observed,

whereas the cytotoxicity of the gold(I) series is independent of these factors.

2

7−32

33,34

INTRODUCTION

drug.

Similar to RAPTA complexes,

auranoﬁn

■

preferentially binds to cysteine-rich proteins such as thioredox-

in reductase (TrX).

The clinical success of cisplatin resulted in considerable eﬀorts

35−37

being directed toward the development of other platinum-

1

Multinuclearity, i.e., covalently connecting two or more metal

centers via an appropriate linker, emerged as an approach to

introducing new modes of action to overcome resistance in

chemoresistant cancers. The trinuclear platinum compound

{trans-PtCl(NH ) } -μ-(trans-Pt(NH ) {H N(CH ) -

based therapeutics. However, the need to overcome the

adverse side eﬀects and intrinsic or acquired resistance to these

compounds led to the investigation of alternative metals for

their therapeutic potential. Ruthenium(III) complexes imida-

38

2

[

3

2

3

2

2 6

zolium [trans-tetrachloro(1H-imidazole)(S-dimethyl sulfoxide)-

4

+

3

NH } ] ] (BBR3464; Figure 1) can overcome cisplatin

2 2

ruthenate(III)] and indazolium trans-[tetrachlorobis(1H-

4

−6

resistance, and it exhibits a proﬁle of antitumor eﬃcacy distinct

from that of cisplatin in a number of preclinical models.

However, despite successfully passing phase I clinical trials,

BBR3464 failed a phase II evaluation, with only a minor

response observed in small lung cancer and gastric/gastro-

esophageal adenocarcinoma.

A growing number of multinuclear ruthenium(II) and

gold(I) complexes have also been reported. Interest in

homobimetallic ruthenium(II) complexes has focused on the

structure−reactivity investigations and the use of bioactive

bridging ligands such as thiosemicarbazones.

of the spacer length on in vitro anticancer activity has

previously been explored using bis(pyridinone)alkane linkers

η -p-cymene)Ru(O,O-C H O N(CH ) NC H O -O,O)Ru-

η -p-cymene) (RU1, with n = 3, 6, 12; Figure 1), where the

cytotoxicity correlates to the lipophilicity, which increases with

indazole)ruthanate(III)] (KP1019) and its sodium analogue

39

7

(

NKP1339) have completed phase I and I/II clinical trials.

Ruthenium(II) organometallic compounds have also attracted

attention because they exhibit a number of promising

pharmacological properties.

8

−10

For example, the so-called

40,41

11

6

RAPTA complexes (Figure 1), of the general formula [Ru(η -

arene)(PTA)X ] (PTA = 1,3,5-triaza-7-phosphaadamantane),

2

38

6

+

and the RAED complexes, [Ru(η -arene)(en)Cl] (en =

1

2

ethylenediamine), have been particularly well studied for

1

3

14

their anticancer properties. RAPTA-C and RAED-C,

where C = p-cymene) along with their derivatives exhibit an

array of promising in vitro and in vivo properties.

Interestingly, crystallographic studies on the nucleosome core

particle have shown that the choice of ligand strongly inﬂuences

the biomolecular target of ruthenium(II) arene complexes with

RAED-C preferentially binding to DNA and RAPTA-C binding

to the histone proteins.

complexes have been evaluated for anticancer properties and

4

2,43

The inﬂuence

(

9

,12,13,15−19

6

(

6

5

2

n

6

5

2

6

44

2

0,21

increasing linker length. Both proteins and DNA were

identiﬁed as possible targets for the dinuclear ruthenium(II)

complexes, which hydrolyze rapidly to form active diaqua

Mononuclear gold(I) phosphine

2

2−25

exhibit promising activity.

Auranoﬁn (1-thio-β-D-glucopyr-

anose-2,3,4,6-tetraacetato-S)(triethylphosphine)gold(I) (Figure

1

), which is used clinically for the treatment of rheumatoid

Received: May 3, 2017

2

5,26

arthritis,

is currently being repositioned as an anticancer

©

XXXX American Chemical Society

A

DOI: 10.1021/acs.inorgchem.7b01082

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Article

Figure 1. Selected examples of dinuclear complexes inspired by well-known monometallic drugs.

Scheme 1. Synthesis of the Diphosphine Ligands (1a−7a), Diruthenium(II) p-Cymene Complexes (1b−7b), Digold(I) Chloride

Intermediates (1c−7c), and Digold(I) β-D-Thioglucosetetraacetate Complexes (1d−7d), Where n = 1−6 and 8

4

5

species. Interestingly, the cytotoxicity of the complex with the

longest bridging ligand was attributed to the ability of the

complex to form both DNA−DNA and DNA−protein cross-

plexes led to complexes with a higher cytotoxicity than those of

48

related compounds with rigid phenyl spacers. Attempts were

made to investigate poly(ethylene glycol) (PEG) linkers;

however, the bis(nicotinate)/bis(isonicotinate) ligands were

4

6

links. A RAED-type binuclear complex, [(Ru(η -biphenyl)-

2+

49

Cl(en)) (CH ) ] , similarly bearing an alkyl linker, has been

unstable in solution. Homobinuclear ruthenium(II) com-

2

2 6

47

shown to form interstrand DNA cross-links. Flexible alkyl

spacers used in acylpyrazolonato-bridged ruthenium(II) com-

plexes linked by diﬀerent stereochemically conﬁgured 1,2-

diphenylethylenediamine spacers exhibit open and closed

B

DOI: 10.1021/acs.inorgchem.7b01082

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Scheme 2. Synthesis of Mononuclear Ruthenium(II) p-Cymene (8b and 9b) and Gold(I) (8d and 9d) Complexes

conformations. The dinuclear complexes are considerably more

cytotoxic than the monomers but did not display cancer cell

selectivity. Consequently, a strategy was subsequently

and 4-(dimethylamino)pyridine (DMAP), a basic catalyst.

Ligands 1a−7a were isolated by chromatographic puriﬁcation

5

0

in moderate yields (36−64%).

developed to generate dinuclear ruthenium(II) complexes

The diruthenium(II) p-cymene complexes 1b−7b were

obtained in high yield (96−98%) in a single step from the

51

directly in cancer cells.

Signiﬁcant eﬀorts have also been devoted to the development

6

reaction of the appropriate ligands 1a−7a with the [Ru(η -p-

52−58

of diphosphinegold(I) complexes.

However, little atten-

cymene)Cl ] dimer, under inert conditions in dry dichloro-

2

tion has been paid to the nature of the linker in homobinuclear

methane (CH Cl ; Scheme 1). The binuclear gold(I) β-D-

2 2

gold(I) complexes. A series of [(AuCl) (Ph P-(CH ) PPh )]

thioglucosetetraacetate complexes 1d−7d were prepared by

following a two-step strategy (Scheme 1). The intermediate

binuclear gold(I) chloride complexes, 1c−7c, were obtained in

good yield (95−98%) from direct reaction of the appropriate

2

2 n

2

(

where n = 1−6) complexes were prepared and evaluated in

vitro against murine B16 melanoma cells (AU1; Figure 1). The

cytotoxicity initially decreases with the linker length, n = 1 (6

μM) and 2 (8 μM), up to n = 3, where a plateau is reached (n =

I

diphosphine ligands 1a−7a with Au Cl(tht) (tht = tetrahy-

59

3

⁻⁶^,^I^C⁵0 = 2−3 μM). Alkyl linkers were also assessed in

drothiophene), freshly prepared following an adapted literature

7

0,71

phosphine-bridged dinuclear gold(I) alkynyl complexes linked

via (CH ) (where n = 1 and 4) groups. More recently,

procedure.

The subsequent reaction of 1c−7c with the β-D-

60

2

n

thioglucosetetraacetate ligand under basic conditions (K CO )

2

3

investigations into the lipophilicity have included the exchange

of hydrophobic PPh ligands with more lipophilic PEt ligands

in acetone or ethanol (EtOH)/water (H O) aﬀords the desired

2

71,72

3

gold(I) complexes 1d−7d in good yield (84−96%).

in dinuclear phosphinegold(I) sulfanylcarboxylate complexes

Mononuclear complexes were also prepared to provide a

structure−activity comparison between the binuclear com-

plexes and the parent drugs, RAPTA-C and auranoﬁn. The

mononuclear ruthenium(II) p-cymene (8b and 9b) and gold(I)

61

resulting in lower IC values against selected cell lines. Other

5

0

investigations include the optimization of TrX inhibition

62−64

bridging bis(N-heterocyclic carbene) ligands,

alkylnyl

6

0,65−67

68,69

ligands,

and thiocarbonates.

(

8d and 9d) complexes, containing 4-(diphenylphosphanyl)-

Because the use of alkyl chains produced a general

dependence between the linker length and cytotoxicity,

correlating with increasing lipophilicity, we decided to evaluate

the eﬀect of PEG chains. Herein, we report the synthesis,

structural characterization, and antiproliferative activity of two

series of dinuclear complexes based on ruthenium(II) and

gold(I) systems. The diruthenium(II) and digold(I) centers are

linked via PEG chains of varying length, while the basic

structures of the parent drugs RAPTA-C and auranoﬁn are

maintained. This strategy allows the inﬂuence of the linker

length on the cytotoxicity to be studied and compared to their

monometallic precursors.

benzoic acid and triphenylphosphine ligands, were prepared

6

from the direct reaction of phosphines with the [Ru(η -p-

I

cymene)Cl ] dimer and Au Cl(tht) precursors, respectively

2

(

Scheme 2).

1

31

13

All compounds were characterized by H, P, and C NMR

spectroscopy, mass spectrometry (MS), and elemental analysis.

31

In the P NMR spectra, the phosphine ligands 1a−7a produce

a singlet between −4.99 and −5.08 ppm. In the binuclear

complexes, the peaks shift to higher frequencies, with singlet

resonances observed at 24.94−25.00 ppm for 1b−7b, 33.01−

3

3.14 ppm for 1c−7c, and 38.71−38.79 ppm for 1d−7d,

conﬁrming coordination of the phosphorus centers to the metal

ions. The mononuclear complexes also give rise to singlets

observed in the same range as the binuclear species, i.e., at

24.18 ppm for 8b, 25.28 ppm for 9b, 33.19 ppm for 8c, 33.21

ppm for 9c, 38.83 ppm for 8d, and 38.82 ppm for 9d.

RESULTS AND DISCUSSION

■

Two series of homobinuclear ruthenium(II) p-cymene, 1b−7b,

and gold(I), 1d−7d, derivatives were prepared using the routes

shown in Scheme 1. Universal diphosphine ligands 1a−7a were

synthesized via an esteriﬁcation reaction between 4-

1

The H NMR spectra of the ligands 1a−7a and complexes

also show distinct diﬀerences. The multiplet corresponding to

eight protons ortho to the C−P bond on the phenyl rings shifts

(diphenylphosphanyl)benzoic acid and the appropriate ethyl-

ene glycol in the presence of N-ethyl-N′-[3-(dimethylamino)-

propyl]carbodiimide hydrochloride (EDCI), a coupling agent,

from 7.29−7.39 to 7.76−7.83 ppm (Δδ ≈ 0.4 ppm), with a

H

larger shift to 7.85−7.98 ppm (Δδ ≈ 0.6 ppm) observed for

H

C

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Article

the four ortho protons on the functionalized ring. Similarly, a

shift of Δδ ≈ 0.2 ppm to higher frequencies is observed, from

H

7

.29−7.39 ppm (1a−7a) to 7.45−7.60 ppm (1c−7c and 1d−

d), corresponding to the 12 protons ortho to the C−P bond

in the gold(I) complexes. Complex 8b possesses two multiplets

in the aromatic region: 7.77−7.85 ppm, corresponding to the

six phenyl protons ortho to the C−P bond, and 7.46−7.32

ppm, corresponding to the nine meta and para protons. In

1

contrast, the H NMR spectra of complexes 8c and 8d contain

only one aromatic multiplet that corresponds to all 15 protons

of the triphenylphosphine ligand (8c, 7.42−7.58 ppm; 8d,

7.42−7.59 ppm). Complex 9b possesses a multiplet at 7.97−

8.00 ppm corresponding to the four protons of the function-

alized ring, whereas in 9c and 9d, the multiplets corresponding

to the two protons ortho to the C−P bond are observed at

8

.05−8.19 ppm in 9c and 7.81−7.90 ppm in 9d.

Coordination of the ligands to the metal ions is denoted by

Figure 2. Solid-state structure of one of the four independent

molecules in 9b. Thermal ellipsoids are 50% equiprobability envelopes.

the peaks corresponding to the carbon atoms directly

connected to the phosphorus center shifting to lower

Hydrogen atoms and solvent molecules (CHCl

clarity.

3

) are omitted for

1

frequencies (with increased J coupling constants) in the

C,P

1

3

C NMR spectra. In the diruthenium(II) p-cymene complexes

1

Table 1. Comparison of Selected Bond Lengths (Å) and

73

1

b−7b, a shift of Δδ ≈ 4.9 ppm and coupling of Δ J ≈ 28

C

C,P

Angles (deg) in RAPTA-C and 9b

Hz were observed for the two C−P carbon atoms on the

1

functionalized ring and Δδ ≈ 3 ppm and Δ J ≈ 34 Hz for

a

b

C

C,P

RAPTA-C

9b

the peaks corresponding to the four C−P carbon atoms on the

phenyl rings. An analogous eﬀect was observed for the

6

Ru−η

Ru−P

1.692, 1.701

1.709, 1.723, 1.706, 1.714

2.296(2),

2.298(3)

2.363(2), 2.3691(19), 2.364(2),

2.3651(19)

digold(I) complexes, for 1c−7c, there is a shift of Δδ ≈ 9.6

C

1

ppm and a coupling of Δ J ≈ 45 Hz, corresponding to the

Ru−Cl_a_v_e

2.421, 2.426

2.420, 2.420, 2.425, 2.420

C,P

two C−P carbon atoms on the functionalized ring and a shift of

Cl−Ru−Cl

87.25(8),

88.97(9)

89.85(7), 88.52(7), 89.50(7), 87.51(6)

1

Δδ ≈ 8.5 ppm and Δ J ≈ 52 Hz representing the four C−P

C

C,P

P−Ru−Cl_a_v_e

85.26, 84.04

89.16, 88.78, 89.91, 89.35

carbon atoms on the phenyl rings. A comparable, but slightly

a

1

3

In the crystal of RAPTA-C, there are two independent molecules in

the asymmetric unit. In 9b, there are four independent complexes in

less pronounced, eﬀect is observed in the C NMR spectra of

b

1

d−7d, and in the mononuclear complexes, similar changes are

the asymmetric unit.

also observed.

The impact of increasing PEG chain length on the electronic

environment of the metal centers is negligible, with all coupling

constants and P peaks remaining consistently similar

throughout the series.

the carboxylic acid groups are observed, leading to the

formation of homodimeric assemblies (Figure S2 ).

The slow diﬀusion of tetrahydrofuran (THF) into a saturated

3

1

The most abundant peaks observed in the electrospray₊

solution of 9c in CDCl aﬀorded crystals suitable for X-ray

3

ionization MS (ESI-MS) spectra may be assigned to [M + H]

diﬀraction analysis (Figure 3). The bond parameters around the

gold(I) center in 9c are presented in Table 2 and compared

+

and [M + Na] ions for ligands 1a−9a, [M − Cl] ions for 1b−

+

−

74

9

b, [M + Na] ions for 1c−8c, [M − H] ions for 9c, [M −

+ +

with those of auranoﬁn. The Au−P bond distance in 9c

Cl] ions for 1d−7d, and [M + H] ions for 8d−9d.

[2.233(9) Å] is comparable to the value observed in auranoﬁn

The solid-state structures of 9b and 9c were established by

single-crystal X-ray diﬀraction analysis, conﬁrming the expected

molecular structures. Single crystals of 9b were grown via the

slow evaporation of chloroform from a concentrated solution

(Figure 2). 9b contains four independent molecules in each

asymmetric unit (Figure S1) compared to the two found for

7

3

RAPTA-C. Key bond parameters are compared with those of

RAPTA-C (Table 1) and, overall, the arrangement around the

ruthenium(II) center is remarkably similar to that of 9b,

adopting the familiar half-sandwich three-legged piano-stool

6

geometry. The mean Ru−η distance is longer in 9b (1.706−

1

.723 Å) than in RAPTA-C (1.692−1.701 Å), and the same

trend is observed for the Ru−P bond lengths [9b, 2.363(2)−

.3691(19) Å; RAPTA-C, 2.296(2)−2.298(3) Å]. The average

2

Ru−Cl bond lengths and Cl−Ru−Cl angles are similar for both

complexes; however, a diﬀerence is observed in the average P−

Ru−Cl angles, with those in 9b (88.78−89.91°) being

consistently larger than those in RAPTA-C (84.04−87.25°).

In the crystal of 9b, intermolecular hydrogen bonds between

Figure 3. Solid-state structure of 9c. Thermal ellipsoids are 50%

equiprobability envelopes. Hydrogen atoms are omitted for clarity.

D

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Table 2. Comparison of Selected Bond Lengths (Å) and

Angles (deg) in Auranoﬁn and 9c

chain length, values of which are 1.4−1.5 and 0.3−0.4,

respectively.

74

The cytotoxicity of the 1a−7a ligands and ruthenium(II) p-

cymene 1b−9b and gold(I) β-D-thioglucosetetraacetate 1d−9d

complexes was assessed against human ovarian carcinoma cell

lines, A2780 and A2780cisR, with the latter having acquired

resistance to cisplatin and nontumoral human embryonic

kidney (HEK-293) cells using the 3-(4,5-dimethyl-2-thiazolyl)-

auranoﬁn

9c

Au−P

Au−S

2.259

2.293

173.6

Au−P

Au−Cl

P−Au−Cl

2.233(9)

2.286(10)

178.07(3)

P−Au−S

(

2.259 Å). Despite the diﬀerent labile ligands, i.e., thiol versus

2

,5-diphenyl-2H-tetrazolium bromide (MTT) assay (Table 3).

chloride, the Au−Cl bond in 9c [2.286(10) Å] is similar in

length to the Au−S bond in auranoﬁn (2.293 Å). However, the

nature of the labile ligand inﬂuences the angle around the

gold(I) center; the P−Au−Cl [178.07(3)°] angle in 9c is larger

than the auranoﬁn P−Au−S angle (173.6°). The crystal

network in 9c reveals dimeric arrangements due to

intermolecular hydrogen-bonding interactions of the carboxylic

acid group (Figure S3 ).

The cytotoxicities of 4-(diphenylphosphanyl)benzoic acid,

triphenylphosphine, auranoﬁn, cisplatin, and RAPTA-C were

evaluated for comparison purposes. Elemental analysis indicates

that CH Cl and CDCl are present in some compounds;

therefore, their cytotoxicities were evaluated at IC₅₀concen-

tration, and they were found to be inactive.

2

3

All compounds were predissolved in dimethyl sulfoxide

(

DMSO), and their stability in this solvent was conﬁrmed via

The lipophilicity has previously been correlated to increasing

cytotoxicity in dinuclear ruthenium(II) complexes (RU1;

1

31

H and P NMR spectroscopy (Figures S4 −S7), before being

immediately diluted into the appropriate cell culture medium.

Further stability studies under pseudocell culture conditions of

4

5

Figure 1). Consequently, the partition coeﬃcients (log P)

75,76

of PEG chains and alkyl chains were calculated.

As

1

4

00 mM NaCl in H O and 5% DMSO were conducted on 2d,

d, and 6d complexes over 72 h. The stability was monitored

2

expected, the lipophilicity of the alkanes increases with

increasing chain length (Chart 1), a trend that is transferred

via ESI-MS(+) (Figures S8 −S10), and all complexes showed

good stability under these conditions.

Chart 1. Calculated Partition Coeﬃcients for Alkyl Chains

The original RAPTA series possess low cytotoxicities with

a

and PEG Chains as a Function of the Length

11

IC₅₀values of >200 μM against a range of cell lines. As

discussed above, the structures of 9b and RAPTA-C are

comparable, and the similarities are reﬂected in their

cytotoxicities, with IC₅₀values >200 μM determined against

all tested cell lines. However, the mononuclear ruthenium(II)

complex 8b, bearing a hydrophobic triphenylphosphine ligand,

is considerably more cytotoxic than 9b, with an IC of 42 ± 1

50

μM. A similar trend is present with 8d and 9d, with 9d being

ca. 14-fold more cytotoxic than 8d. The free ligands

triphenylphosphine and 4-(diphenylphosphanyl)benzoic acid

also present respective IC₅₀values of 85 ± 7 and >200 μM

against the A2780 cell line; the diﬀerences may be attributed to

the diﬀerences in the lipophilicity. However, the impact of

global charge may be of inﬂuence.

a

The calculated log P_a_l_k_y_lvalue of methane (n = 1) was omitted for

The diphosphine ligands 1a−7a are inactive at concen-

trations of up to 500 μM on the three cell lines. The dinuclear

complexes 1b−7b and 1d−7d are considerably more cytotoxic

than the mononuclear complexes 9b and 9d against all cell

lines. The complexes containing the mono(ethylene glycol)

linker (1b and 1d) are considerably less cytotoxic than the

complexes with longer linkers (2b−7b and 2d−7d). In

contrast, in a series of diruthenium(II) p-cymene complexes

with bridging bis(nicotinate)/bis(isonicotinate) ligands, only

the complex with the shortest mono(ethylene glycol) linker

possessed moderate activity against a range of cell lines

including the human melanoma (518A2) cell line (IC = 53 ±

clarity.

to diruthenium complexes bearing alkyl linkers of the structure

6

(

η -p-cymene)Ru(O,O-C H O N(CH ) NC H O -O,O)Ru-

6

5

2

n

6

5

2

6

45

η -p-cymene) (n = 3, 6, and 12). In contrast, PEG chains

have limited lipophilicity, with the hydrophobicity increasing

with the chain length up to hexakis(ethylene glycol), where a

plateau is reached. According to calculations, octakis(ethylene

glycol) is the most lipophilic with a log P value of −0.63, and

longer PEG chains become increasingly hydrophilic. The

plateau, consisting of PEG chains 6−9, have similar log P

^v^a^l^u^e^sⁱⁿ^t^h^e^r^aⁿ^g^e⁻⁰^.⁶²^t^o⁻⁰^.⁶⁷^.^L^o^g^Poctanol/H₂_Ovalues were

5

0

49

1

μM).

The diruthenium(II) p-cymene complexes 2b−7b exhibit

IC values in the low micromolar range against the A2780 cell

determined experimentally for 1b−7b and 1d−7d using the

50

77

shake-ﬂask method (Table 1). The log P values reside in the

lipophilic range for both series. Digold(I) β-D-thioglucosete-

traacetate complexes 1d−7d are more hydrophilic than their

ruthenium counterparts 1b−7b because of the presence of two

β-D-thioglucosetetraacetate ligands. For the shorter chain

lengths, 1b−4b and 1d−3d, the lipophilicity was shown to

increase with increasing chain length for both series. However,

for complexes bearing longer chain lengths, 5b−7b and 5d−7b,

the log P values remain essentially constant despite increasing

line. The cytotoxicity toward the cisplatin-resistant cell line

(A2780cisR) remains in the low micromolar range, with up to

2-fold loss in cytotoxicity compared to the A2780 cisplatin-

sensitive cell line for 3b and 5b. No selectivity was observed

toward the cancer cell lines, with the values obtained for the

nontumorigenic HEK-293 cell line being similar in magnitude.

The cytotoxicities of these dinuclear complexes are comparable

to those of previously investigated series including the series of

rigid RAPTA-type dinuclear complexes, linked via the

E

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Table 3. Calculated Log P Values and in Vitro Antiproliferative Activities of Compounds 1b−9b and 1d−9d against Human

Ovarian Carcinoma (A2780), Human Ovarian Carcinoma Cisplatin Resistant (A2780cisR), and Human Embryonic Kidney 293

a

(HEK-293) Cell Lines after 72 h of Exposure

compound

log P_o_c_t_a_n_o_l_/_H₂_O

A2780

A2780cisR

HEK-293

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

7

8

9

b

d

1.3 ± 0.1

1.6 ± 0.1

1.8 ± 0.3

1.4 ± 0.05

1.4 ± 0.02

1.5 ± 0.02

60 ± 2

10 ± 0.1

19.4 ± 0.3

11.3 ± 0.1

6.4 ± 0.7

7.3 ± 0.3

11.6 ± 0.9

42 ± 1

110 ± 3

11.0 ± 0.7

37.6 ± 1.6

14.6 ± 0.3

12.9 ± 3.7

10.5 ± 0.1

14.1 ± 7.7

35 ± 7

66 ± 1

12.2 ± 0.5

19.6 ± 1.1

14.7 ± 0.9

6.8 ± 0.2

9.1 ± 0.1

14.2 ± 0.3

47 ± 1

>200

0.4 ± 0.3

0.9 ± 0.1

0.7 ± 0.2

0.6 ± 0.1

0.3 ± 0.2

0.4 ± 0.3

0.3 ± 0.2

1.5 ± 0.1

0.22 ± 0.03

0.19 ± 0.02

0.22 ± 0.02

0.17 ± 0.01

0.25 ± 0.02

0.54 ± 0.07

6.9 ± 0.8

>200

4.7 ± 0.1

0.67 ± 0.02

0.91 ± 0.01

1.1 ± 0.1

1.4 ± 0.1

1.4 ± 0.04

1.4 ± 0.4

1 ± 0.1

3.3 ± 0.3

1.2 ± 0.1

1.4 ± 0.1

1.8 ± 0.2

11.7 ± 0.4

>200

12.0 ± 2

>200

(C H ) PC H CO H

6 5 2 6 4 2

P(C H )

5 3

85 ± 7

6

cisplatin

1.3 ± 0.2

>200

11 ± 1

>200

9 ± 1

>200

RAPTA-C

auranoﬁn

1.3 ± 0.5

1.5 ± 0.5

1.9 ± 0.6

a

Values are given as the mean ± standard deviation (μM).

6

59

functionalization of the η -arene, where the most active

complex has an IC of 3.7 ± 0.6 μM against the A2780 cell

line.

ca. 2 μM, again murine B16 melanoma cells. A trend was

observed in this alkyl-linked series with 3-fold (n = 1) and 4-

fold (n = 2) higher cytotoxicities for the more lipophilic

50

5

0

59

The relationship between the linker length and cytotoxicity

on the A2780 cell line shows increasing cytotoxicity with

increasing linker length between 3b and 5b, which correlates

with the increasing lipophilicity of the linkers. However, 2b

with the bis(ethylene glycol) linker is ca. 2-fold more cytotoxic

than 3b. The lipophilicity is essentially constant for compounds

complexes. The series is also signiﬁcantly more cytotoxic than

the phosphine-bridged dinuclear gold(I) alkynyl complexes

bearing alkyl linkers, where no correlation was observed

60

between the cytotoxicity and linker length.

CONCLUDING REMARKS

■

6

b and 7b, with the IC values being 7.3 ± 0.3 and 11.6 ± 0.9

50

The synthesis of two series of homobinuclear RAPTA-like

ruthenium(II) p-cymene complexes 1b−7b and auranoﬁn-like

gold(I) complexes 1d−7d, linked via diphosphine-modiﬁed

PEG chains of varying length, was successfully achieved. The

antiproliferative activity of these compounds was determined

against tumorigenic and nontumorigenic cell lines, and a

distinct increase the cytotoxicity was observed for both series

compared to the mononuclear precursors 9b and 9d. There is a

correlation between the lipophilicity and cytotoxicity of the

diruthenium(II) complexes, which reaches a plateau where the

lipophilicity no longer increases with the length of the PEG

chain, i.e., when n = 6. In contrast, the cytotoxicities of all of the

digold(I) complexes lie within a narrow range and are not

readily correlated to the linker length and associated

lipophilicity.

μM, respectively.

The digold(I) β-D-thioglucosetetraacetate complexes 1d−7d

are highly cytotoxic on all three tested cell lines, with IC₅₀

values in the low micromolar range. Compounds 2d−7d are

highly cytotoxic against A2780 cells (with IC values between

5

0

.17 and 0.25 μM), while being signiﬁcantly less active, up to 8-

fold, on the cisplatin-resistant A2780cisR cell line. The IC₅₀

values of 1d−7d on nontumorigenic HEK-293 cells are very

similar to those on A2780cisR cells. Interestingly, no major

diﬀerences are observed between the activities of the digold(I)

complexes 2d−7d and the mononuclear complex 8d,

containing the hydrophobic PPh ligand, whereas 9d, with

the more hydrophilic phosphine ligand, i.e.,

C H ) PC H CO H, is ca. 35-fold less cytotoxic in A2780

3

(

6 5 2 6 4 2

cells and ca. 10-fold less cytotoxic in A2780cisR and HEK-293

cells. With the exception of complexes 1d and 9d, the activities

are in the same order as those of auranoﬁn.

EXPERIMENTAL SECTION

■

Materials. RuCl ·3H O was purchased from Precious Metals

Online. All other chemical reagents were purchased from Aldrich, Alfa

Aesar, Acros, and TCI Chemicals and used without further

3

2

Complexes 2d−7d display a narrow range of IC₅₀values

between 0.17 ± 0.01 and 0.25 ± 0.02 μM and, thus, there is no

discernible correlation with the linker length and associated

lipophilicity. However, the series is signiﬁcantly more cytotoxic

than [(AuCl) (Ph P-(CH ) PPh )] (where n = 1−6), in which

6

78

70,71

puriﬁcation. [Ru(η -p-cymene)Cl ]

and AuCl(tht)

were pre-

2

pared following literature procedures. CH Cl was dried and degassed

using a PureSolv solvent puriﬁcation system (Innovative Technology

Inc.). Thin-layer chromatography was conducted on Merck 60 F254

2

2 n

2

the most active complexes (n = 3, 5, and 6) have IC values of

5

0

F

DOI: 10.1021/acs.inorgchem.7b01082

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

TLC silica-gel-coated aluminum sheets and veriﬁed by a UV lamp at

bis(ethylene glycol) (0.128 mL, 1.349 mmol, 1 equiv), EDCI (0.614 g,

3.203 mmol, 2.4 equiv), and DMAP (0.065 g, 0.532 mmol, 0.4 equiv)

were stirred for 24 h in CH Cl (50 mL). Yield: 0.328 g, 0.480 mmol,

2

54 nm and KMnO staining. Puriﬁcation of the ligands was achieved

4

via a manual chromatograph using silica gel (Silicycle R12030B) or a

Varian 971-FP ﬂash chromatography system using prepackaged silica

gel columns (Luknova).

2

36%. Elem anal. Calcd for C42

H

O P : C, 73.89; H, 5.32. Found: C,

36

5 2

1

73.56; H, 5.51. H NMR (CDCl

): δ

7.94−7.97 (4H, m, 4O(C

3

H

Instrumentation and Methods. H (400 MHz), ¹³C (101 MHz),

and ³¹P (162 MHz) NMR spectra were recorded on a Bruker Avance

II 400 spectrometer at 298 K. Chemical shifts are reported in parts per

1

3

4

O)(Ar)CCHCHCP, JH,H = 8.5 Hz, JH,H = 1.5 Hz), 7.29−7.39 (24H,

m, 4O(CO)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)-

CCHCHCH, 4P(Ar)CCHCHCH), 4.46−4.49 (4H, m, 2Ar(C

3

1

million and referenced to deuterated solvent residual peaks (CDCl :

2

CH

2

O), 3.82−3.87 (4H, m, 2Ar(CO)OCH

2

CH

2

O).

P

3

1

13

1

13

H, δ 7.26 ppm; C{ H}, δ 77.16 ppm). Coupling constants (J) are

3

): δ

P

−5.08 (2P). C NMR (CDCl

3

): δ

C

166.4 (2C,

reported in hertz. High-resolution ESI-MS spectra were obtained on a

Thermo-Finnigan LCQ Deca XP Plus quadropole ion-trap instrument

operated in positive-ion or negative-ion mode. Elemental analyses

were carried out by the microanalytical laboratory at EPFL using a

Thermo Scientiﬁc Flash 2000 organic elemental analyzer. UV−vis

spectra were recorded using a SpectroMax M5e multimode microplate

reader (using SoftMax Pro software, version 6.2.2). The diﬀraction

data of compounds 9b and 9c were measured at low temperature

1

C,P

2

=

11 Hz), 134.1 (8C, d, 8P(Ar)CCHCHCH, J = 20 Hz), 133.2

C,P

2

(

4C, d, 4O(CO)(Ar)CCHCHCP, ^JC,P = 19 Hz), 130.0 (2C,

2

O(CO)(Ar)CCHCHCP), 129.5 (4C, d, 4O(CO)(Ar)-

3

CCHCHCP, J = 6 Hz), 129.3 (4C, 4P(Ar)CCHCHCH), 128.8

C,P

3

(

8C, d, 8P(Ar)CCHCHCH, J = 7 Hz), 69.3 (2C, 2(Ar)(C

C,P

O)OCH CH O), 64.2 (2C, 2(Ar)(CO)OCH CH O). ESI-MS(+).

2

+

Calcd for C H O P : m/z 682.6925 ([M + H] ). Found: m/z

[

100(2) K] using Mo Kα radiation on a Bruker APEX II CCD

42 37

5 2

+

6

83.2112. Calcd for C H NaO P : 705.1931 ([M + Na] ). Found:

diﬀractometer equipped with a Kappa geometry goniometer. The data

42 36 5 2

7

9

80

m/z 705.1936.

sets were reduced by EvalCCD and then corrected for absorption.

8

1,82

Compound 3a. According to the general procedure, 4-

diphenylphosphanyl)benzoic acid (0.900 g, 2.938 mmol, 2.2 equiv),

The solutions and reﬁnements were performed by SHELX.

The

(

crystal structures were reﬁned using full-matrix least squares based on

2

tris(ethylene glycol) (0.179 mL, 1.340 mmol, 1 equiv), EDCI (0.614 g,

.203 mmol, 2.4 equiv), and DMAP (0.065 g, 0.532 mmol, 0.4 equiv)

were stirred for 24 h in CH Cl (50 mL). Yield: 0.446 g, 0.614 mmol,

F , with all non-hydrogen atoms anisotropically deﬁned. Hydrogen

3

atoms were placed in calculated positions by means of the “riding”

model. The log P values of PEG and alkyl linker compounds were

predicted using the Virtual Computational Chemistry Lab

2

4

6%. Elem anal. Calcd for C H O P : C, 72.72; H, 5.55. Found: C,

44 40 6 2

1

7

5,76

72.54; H, 5.58. H NMR (CDCl

O)(Ar)CCHCHCP, J = 8.4 Hz, J = 1.4 Hz), 7.29−7.38 (24H,

3

): δ

H

7.95−7.98 (4H, m, 4O(C

(

VCCLAB).

The experimental log P

values were

octanol/H

2

O

3

4

77

H,H

determined using the shake-ﬂask method, and the absorbance of

each fraction was recorded using a SpectroMax M5e multimode

microplate reader (using SoftMax Pro software, version 6.2.2). The

absorbance of the MTT assay 96-well plates was recorded using a

SpectroMax M5e multimode microplate reader (using SoftMax Pro

software, version 6.2.2).

m, 4O(CO)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)-

CCHCHCH, 4P(Ar)CCHCHCH), 4.43−4.45 (4H, m, 2Ar(C

O)OCH CH O), 3.79−3.82 (4H, m, 2Ar(CO)OCH CH O), 3.69

2

31

(

4H, s, 2Ar(CO)O(CH ) OCH ). P NMR (CDCl ): δ −5.07

2

3

P

13

2P). C NMR (CDCl ): δ 166.4 (2C, 2O(CO)(Ar)-

3 C

1

CCHCHCP), 144.3 (2C, d, 2O(CO)(Ar)CCHCHCP, J = 14

C,P

Synthesis. General Procedure for the Synthesis of the

1

Hz), 136.3 (4C, d, 4P(Ar)CCHCHCH, J = 11 Hz), 134.1 (8C, d,

C,P

Diphosphine Ligands 1a−7a. 4-(Diphenylphosphanyl)benzoic acid

2

8

P(Ar)CCHCHCH, J = 20 Hz), 133.3 (4C, d, 4O(CO)(Ar)-

C,P

(

2.2 equiv) and EDCI (2.4 equiv) were dissolved in CH Cl (50 mL)

2

CCHCHCP, J = 19 Hz), 130.1 (2C, 2O(CO)(Ar)CCHCHCP),

C,P

and stirred under N at room temperature (RT) for 15 min. The

3

2

129.5 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 6 Hz), 129.3 (4C,

C,P

appropriate ethylene glycol (1.0 equiv) and DMAP (0.4 equiv) were

added, and the mixture was further stirred for 24 h at RT. The reaction

3

4

P(Ar)CCHCHCH), 128.8 (8C, d, 8P(Ar)CCHCHCH, J = 7 Hz),

C,P

7

0.9 (2C, 2(Ar)(CO)O(CH ) OCH ), 69.4 (2C, 2(Ar)(C

2

mixture was washed with H O (150 mL), and the aqueous phase was

2

O)OCH CH O), 64.3 (2C, 2(Ar)(CO)OCH CH O). ESI-MS(+).

Calcd for C H O P : m/z 727.2378 ([M + Na] ). Found: m/z

44 41 6 2

7

2

reextracted with CH Cl₂(2 × 100 mL). The organic phase was

+

2

washed with brine (150 mL), dried over anhydrous sodium sulfate,

ﬁltered, and concentrated under reduced pressure. The treated

product was puriﬁed by ﬂash column chromatography using an

+

27.2383. Calcd for C H NaO P : m/z 749.2198 ([M + H] ).

44 40 5 2

Found: m/z 749.2202

Compound 4a. According to the general procedure, 4-

(diphenylphosphanyl)benzoic acid (0.900 g, 2.938 mmol, 2.2 equiv),

tetrakis(ethylene glycol) (0.231 mL, 1.338 mmol, 1 equiv), EDCI

adapted elution system of hexanes/ethyl acetate or CH Cl /methanol.

2

The product was recovered as a colorless viscous solid.

Compound 1a. According to the general procedure, 4-

diphenylphosphanyl)benzoic acid (0.900 g, 2.938 mmol, 2.2 equiv),

(

0.615 g, 3.203, 2.4 equiv), and DMAP (0.065 g, 0.532 mmol, 0.4

(

equiv) were stirred for 24 h in CH Cl (50 mL). Yield: 0.487 g, 0.632

2

mono(ethylene glycol) (0.075 mL, 1.345 mmol, 1 equiv), EDCI

0.614 g, 3.203 mmol, 2.4 equiv), and DMAP (0.065 g, 0.532 mmol,

mmol, 47%. Elem anal. Calcd for C H O P : C, 71.68; H, 5.75.

46 44 7 2

1

(

Found: C, 71.59, H, 5.83. H NMR (CDCl ): δ 7.95−8.00 (4H, m,

3

H

3

4

0

.4 equiv) were stirred for 24 h in CH Cl (50 mL). Yield: 0.216 g,

4O(CO)(Ar)CCHCHCP, J

= 8.2 Hz, J

= 1.6 Hz), 7.29−

2

H,H

.338 mmol, 25%. Elem anal. Calcd for C H O P : C, 75.23; H, 5.05.

7.38 (24H, m, 4O(CO)(Ar)CCHCHCP, 8P(Ar)CCHCHCH,

8P(Ar)CCHCHCH, 4P(Ar)CCHCHCH), 4.43−4.46 (4H, m,

2Ar(CO)OCH CH O), 3.77−3.80 (4H, m, 2Ar(CO)-

4

0

32

4 2

1

Found: C, 75.55; H, 5.23. H NMR (CDCl ): δ 7.97 (4H, m,

3

H

3

4

7

8

O(CO)(Ar)CCHCHCP, J

= 8.6 Hz, J

= 1.4 Hz), 7.29−

H,H

2

.40 (24H, m, 4O(CO)(Ar)CCHCHCP, 8P(Ar)CCHCHCH,

OCH CH O), 3.61−3.70 (8H, m, 2Ar(CO)O(CH ) O(CH ) ).

2

2 2

31

13

P(Ar)CCHCHCH, 4P(Ar)CCHCHCH), 4.64 (4H, s, Ar(C

P NMR (CDCl ): δ −5.06 (2P). C NMR (CDCl ): δ 166.4 (2C,

3 P 3 C

31

13

O)O(CH ) O). P NMR (CDCl ): δ −4.99 (2P). C NMR

2O(CO)(Ar)CCHCHCP), 144.3 (2C, d, 2O(CO)(Ar)-

CCHCHCP, J = 14 Hz), 136.3 (4C, d, 4P(Ar)CCHCHCH, J

C,P C,P

2

3

P

1

(

2

CDCl ): δ 166.3 (2C, 2O(CO)(Ar)CCHCHCP), 144.6 (2C, d,

3

C

1

2

O(CO)(Ar)CCHCHCP, J = 15 Hz), 136.3 (4C, d, 4P(Ar)

= 11 Hz), 134.1 (8C, d, 8P(Ar)CCHCHCH, J = 20 Hz), 133.3

C,P

1

2

CCHCHCH, J = 11 Hz), 134.2 (8C, d, 8P(Ar)CCHCHCH, J

=

C,P

(4C, d, 4O(CO)(Ar)CCHCHCP, J_C_,_P= 19 Hz), 130.2 (2C,

C,P

2

1

0 Hz), 133.3 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 19 Hz),

2O(CO)(Ar)CCHCHCP), 129.5 (4C, d, 4O(CO)(Ar)-

C,P

3

29.8 (2C, 2O(CO)(Ar)CCHCHCP), 129.5 (4C, d, 4O(C

CCHCHCP, J = 7 Hz), 129.3 (4C, 4P(Ar)CCHCHCH), 128.8

C,P

3

O)(Ar)CCHCHCP, J = 6 Hz), 129.3 (4C, 4P(Ar)CCHCHCH),

(8C, d, 8P(Ar)CCHCHCH, J = 7 Hz), 70.77, 70.79, 70.83 (4C,

C,P

3

1

28.8 (8C, d, 8P(Ar)CCHCHCH, J_C_,_P= 7 Hz), 63.0 (2C, 2(Ar)(C

2(Ar)(CO)O(CH ) OCH , 2(Ar)(CO)O(CH ) OCH CH ),

2

+

O)O(CH ) O). ESI-MS(+). Calcd: m/z 639.1854 ([M + H]

69.3 (2C, 2(Ar)(CO)OCH CH O), 64.3 (2C, 2(Ar)(CO)-

2

+

C H O P ). Found: m/z 639.1853.

OCH CH O). ESI-MS(+). Calcd for C H O P : m/z 771.2641

4

0

33

4

2

2 2 46 45 7 2

+

Compound 2a. According to the general procedure, 4-

diphenylphosphanyl)benzoic acid (0.900 g, 2.938 mmol, 2.2 equiv),

([M + H] ). Found: m/z 771.2630. Calcd for C H NaO P : m/z

793.2460 ([M + Na] ). Found: m/z 793.2451.

46 44 7 2

+

(

G

DOI: 10.1021/acs.inorgchem.7b01082

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

1

3

Compound 5a. According to the general procedure, 4-

−5.06 (2P). C NMR (CDCl ): δ_C166.4 (2C, 2O(CO)(Ar)-

3

1

(

diphenylphosphanyl)benzoic acid (0.800 g, 2.612 mmol, 2.2 equiv),

pentakis(ethylene glycol) (0.251 mL, 1.186 mmol, 1 equiv), EDCI

0.546 g, 2.848 mmol, 2.4 equiv), and DMAP (0.058 g, 0.475 mmol,

CCHCHCP), 144.4 (2C, d, 2O(CO)(Ar)CCHCHCP, J = 15

C,P

1

Hz), 136.5 (4C, d, 4P(Ar)CCHCHCH, J = 11 Hz), 134.1 (8C, d,

C,P

2

(

0

8P(Ar)CCHCHCH, J = 20 Hz), 133.3 (4C, d, 4O(CO)(Ar)-

C,P

2

.4 equiv) were stirred for 24 h in CH Cl (50 mL). Yield: 0.621 g,

CCHCHCP, J = 19 Hz), 130.1 (2C, 2O(CO)(Ar)CCHCHCP),

2

C,P

3

.762 mmol, 64%. Elem anal. Calcd for C H O P : C, 70.75; H, 5.94.

129.5 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 6 Hz), 129.3 (4C,

4

8

48

8

2

C,P

1

3

Found: C, 70.85, H, 6.04. H NMR (CDCl ): δ 7.96−7.99 (4H, m,

4P(Ar)CCHCHCH), 128.8 (8C, d, 8P(Ar)CCHCHCH, J = 7 Hz),

3

H

C,P

3

4

7

8

2

O(CO)(Ar)CCHCHCP, J

= 8.4 Hz, J

= 1.6 Hz), 7.28−

70.92, 70.88, 70.85, 70.81 (12C, 2(Ar)(CO)O(CH ) OCH ,

H,H

2

.37 (24H, m, 4O(CO)(Ar)CCHCHCP, 8P(Ar)CCHCHCH,

P(Ar)CCHCHCH, 4P(Ar)CCHCHCH), 4.44−4.46 (4H, m,

Ar(CO)OCH CH O), 3.79−3.81 (4H, m, 2Ar(CO)-

2(Ar)(CO)O(CH ) OCH CH , 2(Ar)(CO)O(CH ) O-

2

2 2

(CH ) OCH , 2(Ar)(CO)O(CH ) O(CH ) OCH CH , 2(Ar)-

2 2 2 2 2 2 2 2 2

(CO)O(CH ) O(CH ) O(CH ) OCH , 2(Ar)(CO)O-

2

OCH CH O), 3.65−3.68 (4H, m, 2Ar(CO)O(CH ) OCH CH ),

(CH ) O(CH ) O(CH ) OCH CH ), 69.4 (2C, 2(Ar)(CO)-

2

3

2

(

.61−3.64 (4H, m, 2Ar(CO)O(CH ) OCH CH ), 3.62 (4H, s,

OCH CH O), 64.7 (2C, 2(Ar)(CO)OCH CH O). ESI-MS(+).

Calcd for C H O P : m/z 947.3684 ([M + H] ). Found: m/z

54 61 11 2

2

3

1

+

Ar(CO)O(CH ) O(CH ) OCH ), P NMR (CDCl ): δ −5.08

2

3

P

1

3

+

2P). C NMR (CDCl ): δ 166.4 (2C, 2O(CO)(Ar)-

947.3671. Calcd for C H NaO P : m/z 969.3509 ([M + Na] ).

Found: m/z 969.3488.

General Procedure for the Synthesis of the Diruthenium

3

C

54 60 11 2

1

CCHCHCP), 144.3 (2C, d, 2O(CO)(Ar)CCHCHCP, J = 14

C,P

1

Hz), 136.3 (4C, d, 4P(Ar)CCHCHCH, J = 11 Hz), 134.1 (8C, d,

C,P

2

6

8

P(Ar)CCHCHCH, J = 20 Hz), 133.2 (4C, d, 4O(CO)(Ar)-

Complexes 1b−7b. [Ru(η -p-cymene)Cl]

appropriate ligand 1a−7a (1 equiv) in CH

for 42 h at RT under N

2

Cl

2

(1 equiv) and the

(12 mL) were stirred

C,P

2

CCHCHCP, J = 19 Hz), 130.1 (2C, 2O(CO)(Ar)CCHCHCP),

2

C,P

3

1

4

7

29.5 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 6 Hz), 129.1 (4C,

2

in the dark. The reaction evolution was

monitored by H and P NMR (CDCl ). The reaction mixture was

C,P

3

1

31

P(Ar)CCHCHCH), 128.8 (8C, d, 8P(Ar)CCHCHCH, J = 7 Hz),

3

C,P

0.80, 70.76, 70.73 (6C, 2(Ar)(CO)O(CH ) OCH , 2(Ar)(C

concentrated under reduced pressure and then further dried under

high vacuum to yield the product as a red solid.

Compound 1b. According to the general procedure, [Ru(η -p-

2

O)O(CH ) OCH CH , 2(Ar)(CO)O(CH ) O(CH ) OCH ), 69.3

2

6

(

2C, 2(Ar)(CO)OCH CH O), 64.3 (2C, 2(Ar)(CO)-

2

+

OCH CH O). ESI-MS(+). Calcd for C H O P : m/z 815.2897

[M + H] ). Found: m/z 815.2905. Calcd for C H NaO P : m/z

37.2722 ([M + Na] ). Found: m/z 837.2723.

Compound 6a. According to the general procedure, 4-

diphenylphosphanyl)benzoic acid (0.800 g, 2.612 mmol, 2.2 equiv),

hexakis(ethylene glycol) (0.298 mL, 1.190 mmol, 1 equiv), EDCI

0.546 g, 2.848 mmol, 2.4 equiv), and DMAP (0.058 g, 0.475 mmol,

cymene)Cl]

mmol, 1 equiv), and CH

product was isolated as a dark-red solid. Yield: 0.376 g, 0.301 mmol,

98%. Elem anal. Calcd for C60 Ru ·CH Cl : C, 54.84; H,

4.68. Found: C, 54.77; H, 4.93. CH originates from the reaction

2

Cl

2

(0.19 g, 0.307 mmol, 1 equiv), 1a (0.20 g, 0.307

2

48 49

8 2

+

(

8

2

Cl (12 mL) were stirred for 42 h at RT. The

2

48

8 2

+

H60Cl

O

4

P

4

2

(

2 2

Cl

1

solvent. H NMR (CDCl

): δ

7.88−7.97 (8H, m, 4O(C

3

H

(

0

O)(Ar)CCHCHCP, 4O(CO)(Ar)CCHCHCP), 7.77−7.82 (8H,

.4 equiv) were stirred for 24 h in CH Cl (50 mL). Yield: 0.341 g,

m, 8P(Ar)CCHCHCH), 7.34−7.44 (12H, m, 8P(Ar)CCHCHCH,

2

3

.397 mmol, 33%. Elem anal. Calcd for C H O P : C, 69.92; H, 6.10.

4P(Ar)CCHCHCH), 5.20 (4H, d, 4CH

3

(Ar)CCHCHC, JH,H = 6.1

5

0

52

9 2

1

3

Found: C, 70.04; H, 6.13. H NMR (CDCl ): δ 7.96−7.99 (4H, m,

Hz), 4.98 (4H, d, 4CH

2 A r ( C  O ) O C H C H

CCHCHCCH(CH

CCHCHC), 1.09 (12H, d, 2(Ar)CCHCHCCH(CH )

3 2

3

(Ar)CCHCHC, JH,H = 6.1 Hz), 4.58 (4H, s,

O ) , 2 . 8 3 ( 2 H , s e p t , 2 ( A r ) -

H,H = 7.2 Hz), 1.84 (6H, s, 2CH (Ar)-

, JH,H = 7.2

25.00 (2P). C NMR (CDCl ): δ 165.8

3

H

3

4

7

8

2

O(CO)(Ar)CCHCHCP, J

= 8.4 Hz, J

= 1.2 Hz), 7.28−

2

,

2

H,H

3

.39 (24H, m, 4O(CO)(Ar)CCHCHCP, 8P(Ar)CCHCHCH,

P(Ar)CCHCH-CH, 4P(Ar)CCHCHCH), 4.44−4.47 (4H, m,

Ar(CO)OCH CH O), 3.79−3.82 (4H, m, 2Ar(CO)-

)

3

2

J

3

Hz). ³¹P NMR (CDCl

): δ

13

2

3

P

3

C

OCH CH O), 3.66−3.69 (4H, m, 2Ar(CO)O(CH ) OCH CH ),

(2C, 2O(CO)(Ar)CCHCHCP), 139.7 (2C, d, 2O(CO)(Ar)-

2

1

3

.61−3.65 (4H, m, 2Ar(CO)O(CH ) OCH CH ), 3.58−3.62 (8H,

CCHCHCP,

J

C,P = 43 Hz), 134.4 (4C, d, 4O(CO)(Ar)-

2

3

1

2

m, 2Ar(CO)O(CH ) O(CH ) O(CH ) . P NMR (CDCl ): δ

CCHCHCP, JC,P = 9 Hz), 134.3 (8C, d, 8P(Ar)CCHCHCH, JC,P

2

3

P

1

5

.06 (2P). ¹³C NMR (CDCl ): δ 166.3 (2C, 2O(CO)(Ar)-

= 9 Hz), 133.3 (4C, d, 4P(Ar)CCHCHCH, JC,P = 45 Hz), 130.9 (2C,

3

C

1

4

CCHCHCP), 144.1 (2C, d, 2O(CO)(Ar)CCHCHCP, J = 14

d, 2O(CO)(Ar)CCHCHCP,

JC,P = 3 Hz), 130.6 (4C, d,

C,P

1

4

Hz), 136.1 (4C, d, 4P(Ar)CCHCHCH, J = 11 Hz), 133.9 (8C, d,

4P(Ar)CCHCHCH, JC,P = 2 Hz), 128.8 (4C, d, 4O(CO)(Ar)-

C,P

2

3

8

P(Ar)CCHCHCH, J = 20 Hz), 133.1 (4C, d, 4O(CO)(Ar)-

CCHCHCP, JC,P = 10 Hz), 128.3 (8C, d, 8P(Ar)CCHCHCH, JC,P

10 Hz), 111.46, 111.43 (2C, 2CH (Ar)CCHCHC), 96.4 (2C,

2CH (Ar)CCHCHC), 89.12, 89.09 (4C, 4CH (Ar)CCHCHC),

87.39, 87.34 (4C, 4CH

(Ar)CCHCHC), 63.0 (2C, 2(Ar)(C

O)OCH CH O), 30.4 (2C, 2(Ar)CHCHCCH(CH ), 21.9 (4C,

2(Ar)CHCHCCH(CH ) ), 17.9 (2C, 2CH (Ar)CCHCH). ESI-

=

C,P

2

CCHCHCP, J = 19 Hz), 130.0 (2C, 2O(CO)(Ar)CCHCHCP),

3

C,P

3

1

4

7

(

2

29.4 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 6 Hz), 129.1 (4C,

3

C,P

3

P(Ar)CCHCHCH), 128.7 (8C, d, 8P(Ar)CCHCHCH, J = 7 Hz),

3

C,P

0.70, 70.65, 70.63, 70.59 (8C, 2(Ar)(CO)O(CH ) OCH , 2(Ar)-

2

)

3 2

2

CO)O(CH ) OCH CH , 2(Ar)(CO)O(CH ) O(CH ) OCH ,

2

3

2

3

+

(Ar)(CO)O(CH ) O(CH ) OCH CH ), 69.2 (2C, 2(Ar)(C

MS(+). Calcd for C H Cl O P Ru : m/z 1180.1431 ([M −

2

60 60

2

4

2

+

O)OCH CH O), 64.2 (2C, 2(Ar)(CO)OCH CH O). ESI-MS(+).

2Cl] ). Found: m/z 1180.1499. Calcd for C H Cl O P Ru : m/z

2

60 60 3 4 2 2

+

Calcd for C H O P : m/z 859.3165 ([M + H] ). Found: m/z

59.3168. Calcd for C H NaO P : m/z 881.2984 ([M + Na] ).

1215.1119 ([M − Cl] ). Found: m/z 1215.1104. Calcd for

+ +

50

53

9 2

+

8

C H Cl NaO P Ru : m/z 1273.0706 ([M + Na] ). Found: m/z

60 60 4 4 2 2

5

0

52

9

2

Found: m/z 881.2988.

1273.0695. UV−vis: λ = 250 and 370 nm.

max

6

Compound 7a. According to the general procedure, 4-

Compound 2b. According to the general procedure, [Ru(η -p-

cymene)Cl] Cl (0.49 g, 0.808 mmol, 1 equiv), 2a (0.55 g, 0.808

(

diphenylphosphanyl)benzoic acid (0.800 g, 2.612 mmol, 2.2 equiv),

2

octakis(ethylene glycol) (0.440 g, 1.188 mmol, 1 equiv), EDCI (0.546

g, 2.848 mmol, 2.4 equiv), and DMAP (0.058 g, 0.475 mmol, 0.4

equiv) were stirred for 24 h in CH Cl (50 mL). Yield: 0.499 g, 0.527

mmol, 1 equiv), and CH Cl (12 mL) were stirred for 42 h at RT. The

2 2

product was isolated as a dark-red solid. Yield: 1.03 g, 0.791 mmol,

98%. Elem anal. Calcd for C H Cl O P Ru : C, 57.50; H, 4.98.

2

62 64

4

5

2

1

mmol, 45%. Elem anal. Calcd for C H O P : C, 68.49; H, 6.39.

Found: C, 57.76; H, 5.12. H NMR (CDCl ): δ 7.86−7.96 (8H, m,

5

4

60 11

2

3

H

1

Found: C, 68.16; H, 6.35. H NMR (CDCl ): δ 7.96−8.00 (4H, m,

4O(CO)(Ar)CCHCHCP, 4O(CO)(Ar)CCHCHCP), 7.78−

3

H

3

4

7

8

2

O(CO)(Ar)CCHCHCP, J

= 8.4 Hz, J

= 1.6 Hz), 7.29−

7.83 (8H, m, 8P(Ar)CCHCHCH), 7.36−7.44 (12H, m, 8P(Ar)-

H,H

.37 (24H, m, 4O(CO)(Ar)CCHCHCP, 8P(Ar)CCHCHCH,

P(Ar)CCHCHCH, 4P(Ar)CCHCHCH), 4.45−4.47 (4H, m,

Ar(CO)OCH CH O), 3.80−3.82 (4H, m, 2Ar(CO)-

CCHCHCH, 4P(Ar)CCHCHCH), 5.21 (4H, d, 4CH (Ar)-

3

CCHCHC, J = 6.2 Hz), 4.98 (4H, d, 4CH (Ar)CCHCHC, J

H,H

3

H,H

= 6.2 Hz), 4.45−4.42 (4H, m, 2Ar(CO)OCH CH O), 3.83−3.81

2

OCH CH O), 3.67−3.70 (4H, m, 2Ar(CO)O(CH ) OCH CH ),

(4H, m, 2Ar(CO)OCH CH O), 2.85 (2H, sept, 2(Ar)-

CCHCHCCH(CH ) , J = 6.9 Hz), 1.85 (6H, s, 2CH (Ar)-

3 2 H,H 3

2

3

.63−3.66 (4H, m, 2Ar(CO)O(CH ) OCH CH ), 3.60−3.62 (8H,

2

3

m, 2Ar(CO)O(CH ) O(CH ) O(CH ) , 3.61 (8H, s, 2Ar(C

CCHCHC), 1.09 (12H, d, 2(Ar)CCHCHCCH(CH ) , J

= 6.9

2

3

2

H,H

3

1

31

13

O)O(CH ) O(CH ) O(CH ) O(CH ) . P NMR (CDCl ): δ

Hz). P NMR (CDCl ): δ 24.95 (2P). C NMR (CDCl ): δ 166.1

3 P 3 C

2

3

P

H

DOI: 10.1021/acs.inorgchem.7b01082

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

CCHCHCP, ²J_C_,_P= 8 Hz), 134.4 (8C, d, 8P(Ar)CCHCHCH, J

2

(

2C, 2O(CO)(Ar)CCHCHCP), 139.5 (2C, d, 2O(CO)(Ar)-

C,P

1

CCHCHCP,

J

= 43 Hz), 134.5 (4C, d, 4O(CO)(Ar)-

= 9 Hz), 133.4 (4C, d, 4P(Ar)CCHCHCH, J = 45 Hz), 131.4 (2C,

C,P

2

4

CCHCHCP, J = 9 Hz), 134.4 (8C, d, 8P(Ar)CCHCHCH, J

=

d, 2O(CO)(Ar)CCHCHCP, J_C_,_P= 2 Hz), 130.7 (4C, d,

C,P

1

4

9 Hz), 133.4 (4C, d, 4P(Ar)CCHCHCH, J = 45 Hz), 131.3 (2C,

4P(Ar)CCHCHCH, J = 2 Hz), 128.8 (4C, d, 4O(CO)(Ar)-

C,P

4

3

d, 2O(CO)(Ar)CCHCHCP, J_C_,_P= 2 Hz), 130.7 (4C, d,

CCHCHCP, J = 10 Hz), 128.3 (8C, d, 8P(Ar)CCHCHCH, J

=

C,P

4

P(Ar)CCHCHCH, J = 2 Hz), 128.8 (4C, d, 4O(CO)(Ar)-

10 Hz), 111.54, 111.50 (2C, 2CH (Ar)CCHCHC), 96.4 (2C,

2CH (Ar)CCHCHC), 89.11, 89.09 (4C, 4CH (Ar)CCHCHC),

C,P

3

CCHCHCP, J = 10 Hz), 128.3 (8C, d, 8P(Ar)CCHCHCH, J

=

C,P

3

1

2

8

0 Hz), 111.59, 111.56 (2C, 2CH (Ar)CCHCHC), 96.4 (2C,

87.46, 87.40 (4C, 4CH (Ar)CCHCHC), 70.8, 70.4 (4C, 2(Ar)(C

3

CH (Ar)CCHCHC), 89.15, 89.12 (4C, 4CH (Ar)CCHCHC),

O)O(CH ) OCH , 2(Ar)(CO)O(CH ) OCH CH ), 69.2 (2C,

3

2

7.49, 87.43 (4C, 4CH (Ar)CCHCHC), 69.4 (2C, 2(Ar)(C

2(Ar)(CO)OCH CH O), 64.5 (2C, 2(Ar)(CO)OCH CH O),

3

2

O)OCH CH O), 64.5 (2C, 2(Ar)(CO)OCH CH O), 30.4 (2C,

30.4 (2C, 2(Ar)CHCHCCH(CH ) ), 22.0 (4C, 2(Ar)CHCHCCH-

2

3 2

2

1

(Ar)CHCHCCH(CH ) ), 22.0 (4C, 2(Ar)CHCHCCH(CH ) ),

(CH ) ), 17.9 (2C, 2CH (Ar)CCHCH). ESI-MS(+). Calcd for

3

2

3

2

3 2 3

2

+

7.9 (2C, 2CH (Ar)CCHCH). ESI-MS(+). Calcd for

C H Cl O P Ru : 1312.2206 ([M − 2Cl] ). Found: m/z

3

66 72

2

7

2

+

C H Cl O P Ru : m/z 1224.1693 ([M − 2Cl] ). Found: m/z

1312.2328. Calcd for C H Cl O P Ru : 1347.1900 ([M − Cl] ).

6

2

64

2

5

2

66 72

3

7

2

+

1

224.1804. Calcd for C H Cl O P Ru : m/z 1259.1382 ([M −

Found: m/z 1347.1923. Calcd for C H Cl NaO P Ru : 1405.1487

62

64

3

5

2

66 72 4 7 2 2

+

2

+

Cl] ). Found: m/z 1259.1396. Calcd for C H Cl NaO P Ru : m/z

([M + Na] ). Found: m/z 1405.1474. UV−vis: λ = 250 and 370

62

64

4

5

2

max

+

1

317.0962 ([M + Na] ). Found: m/z 1317.0995. UV−vis: λ_m_a_x= 250

nm.

6

and 370 nm.

Compound 5b. According to the general procedure, [Ru(η -p-

6

Compound 3b. According to the general procedure, [Ru(η -p-

cymene)Cl] Cl (0.15 g, 0.251 mmol, 1 equiv), 3a (0.18 g, 0.251

mmol, 1 equiv), and CH Cl (12 mL) were stirred for 42 h at RT. The

cymene)Cl] Cl (0.16 g, 0.269 mmol, 1 equiv), 5a (0.22 g, 0.269

2

mmol, 1 equiv), and CH Cl (12 mL) were stirred for 42 h at RT. The

2

product was isolated as a red solid. Yield: 0.38 g, 0.263 mmol, 98%.

1

product was isolated as a dark-red solid. Yield: 0.33 g, 0.246 mmol,

Elem anal. Calcd for C H Cl O P Ru · / CH Cl : C, 55.98; H, 5.28.

68

76

4

8

2

9

4

8%. Elem anal. Calcd for C H Cl O P Ru ·CH Cl : C, 54.82; H,

Found: C, 55.86; H, 5.34. CH Cl originates from the reaction solvent.

64

66

4

6

2

2 2

1

.95. Found: C, 54.75, H, 4.95. CH Cl originates from the reaction

H NMR (CDCl ): δ_H7.88−7.97 (8H, m, 4O(CO)(Ar)-

2

3

1

solvent. H NMR (CDCl ): δ 7.86−7.94 (8H, m, 4O(C

3

H

CCHCHCP, 4O(CO)(Ar)CCHCHCP), 7.77−7.81 (8H, m, 8P-

O)(Ar)CCHCHCP, 4O(CO)(Ar)CCHCHCP), 7.76−7.82 (8H,

(

Ar)CCHCHCH), 7.35−7.42 (12H, m, 8P(Ar)CCHCHCH, 4P(Ar)-

3

m, 8P(Ar)CCHCHCH), 7.34−7.46 (12H, m, 8P(Ar)CCHCHCH,

CCHCHCH), 5.20 (4H, d, 4CH (Ar)CCHCHC, J = 6.1 Hz), 4.96

3

H,H

3

4

P(Ar)CCHCHCH), 5.19 (4H, d, 4CH (Ar)CCHCHC, J

= 6.1

3

H,H

(4H, d, 4CH (Ar)CCHCHC, J

= 6.1 Hz), 4.42−4.39 (4H, m,

3

H,H

3

Hz), 4.96 (4H, d, 4CH (Ar)CCHCHC, J

= 6.1 Hz), 4.40−4.38

3

H,H

2Ar(CO)OCH CH O), 3.77−3.74 (4H, m, 2Ar(CO)-

2

(

4H, m, 2Ar(CO)OCH CH O), 3.77−3.74 (4H, m, 2Ar(C

2

OCH CH O), 3.65−3.56 (12H, m, 2Ar(CO)O(CH ) OCH CH ,

2 2 2 2 2 2

O)OCH CH O), 3.65 (4H, s, 2Ar(CO)O(CH ) OCH ), 2.83 (2H,

2 2 2 2 2

2Ar(CO)O(CH ) OCH CH , 2Ar(CO)O(CH ) O-

2

3

sept, 2(Ar)CCHCHCCH(CH ) ,

J

= 6.9 Hz), 1.83 (6H, s,

H,H

3

2

(CH ) OCH ), 2.83 (2H, sept, 2(Ar)CCHCHCCH(CH ) , J

=

2

3

2

H,H

2

CH (Ar)CCHCHC), 1.08 (12H, d, 2(Ar)CCHCHCCH(CH ) ,

3

2

6.9 Hz), 1.84 (6H, s, 2CH (Ar)CCHCHC), 1.09 (12H, d,

3

31

13

3

31

^JH,H = 6.9 Hz). P NMR (CDCl ): δ 24.94 (2P). C NMR

3

P

2(Ar)CCHCHCCH(CH ) , J = 6.9 Hz). P NMR (CDCl ): δ_P

3 2 H,H 3

24.96 (2P). ¹³C NMR (CDCl ): δ_C166.1 (2C, 2O(CO)(Ar)-

(

CDCl ): δ 166.0 (2C, 2O(CO)-(Ar)CCHCHCP), 139.4 (2C, d,

3

C

3

1

2

O(CO)(Ar)CCHCHCP, J = 44 Hz), 134.4 (4C, d, 4O(C

CCHCHCP), 139.4 (2C, d, 2O(CO)(Ar)CCHCHCP, J = 44

C,P

2

O)(Ar)CCHCHCP, J = 8 Hz), 134.3 (8C, d, 8P(Ar)CCHCHCH,

Hz), 134.5 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 7 Hz), 134.4

C,P

2

1

2

J_C_,_P= 9 Hz), 133.4 (4C, d, 4P(Ar)CCHCHCH, J = 45 Hz), 131.4

(8C, d, 8P(Ar)CCHCHCH, J = 9 Hz), 133.4 (4C, d, 4P(Ar)

C,P

1

(

2C, m, 2O(CO)(Ar)CCHCHCP), 130.7 (4C, m, 4P(Ar)-

CCHCHCH,₄J_C_,_P= 45 Hz), 131.4 (2C, d, 2O(CO)(Ar)

3

4

CCHCHCH), 128.8 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 10

CCHCHCP, J = 2 Hz), 130.7 (4C, d, 4P(Ar)CCHCHCH, J

C,P

3

Hz), 128.3 (8C, d, 8P(Ar)CCHCHCH, J = 10 Hz), 111.50, 111.47

= 2 Hz), 128.8 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 10 Hz),

C,P

3

(

2C, 2CH (Ar)CCHCHC), 96.4 (2C, 2CH (Ar)CCHCHC), 89.09,

128.3 (8C, d, 8P(Ar)CCHCHCH, J = 10 Hz), 111.56, 111.53 (2C,

3

C,P

8

9.07 (4C, 4CH (Ar)CCHCHC), 87.43, 87.38 (4C, 4CH (Ar)-

2CH (Ar)CCHCHC), 96.4 (2C, 2CH (Ar)CCHCHC), 89.09, 89.11

3

CCHCHC), 70.8 (2C, 2(Ar)(CO)O(CH ) OCH CH ), 69.3

(4C, 4CH (Ar)CCHCHC), 87.41, 87.46 (4C, 4CH (Ar)CCHCHC),

2

3

(

2C, 2(Ar)(CO)OCH CH O), 64.4 (2C, 2(Ar)(CO)-

70.8, 70.7 (6C, 2(Ar)(CO)O(CH ) OCH , 2(Ar)(CO)O-

2 2 2 2 2 2 2 2 2

2

OCH CH O), 30.4 (2C, 2(Ar)CHCHCCH(CH ) ), 22.0 (4C,

(CH ) OCH CH , 2(Ar)(CO)O(CH ) O(CH ) OCH ), 69.2

2

3

2

(Ar)CHCHCCH(CH ) ), 17.9 (2C, 2CH (Ar)CCHCH). ESI-

(2C, 2(Ar)(CO)OCH CH O), 64.5 (2C, 2(Ar)(CO)-

OCH CH O), 30.4 (2C, 2(Ar)CHCHCCH(CH ) ), 22.0 (4C,

2 2 3 2

3

2

3

2 2

+

MS(+). Calcd for C H Cl O P Ru : m/z 1303.1644 ([M − Cl] ).

Found: m/z 1303.1660. Calcd for C H Cl NaO P Ru : m/z

64

68

3

6

2

+

6

4

68

3

6

2

2(Ar)CHCHCCH(CH ) ), 17.9 (2C, 2CH (Ar)CCHCH). ESI-

3 2 3

+

2+

1

2

361.1224 ([M + Na] ). Found: m/z 1361.1219. UV−vis: λ

=

MS(+). Calcd for C H Cl O P Ru : m/z 1356.2583 ([M −

max

68 76

2

8

2

+

50 and 370 nm.

2Cl] ). Found: m/z 1356.2609. Calcd for C H Cl O P Ru : m/z

68 76 3 8 2 2

6

+

Compound 4b. According to the general procedure, [Ru(η -p-

1391.2168 ([M − Cl] ). Found: m/z 1391.2207. Calcd for

+ +

cymene)Cl] Cl (0.13 g, 0.205 mmol, 1 equiv), 4a (0.16 g, 0.205

C H Cl NaO P Ru : m/z 1449.1749 ([M + Na] ). Found: m/z

68 76 4 8 2 2

2

mmol, 1 equiv), and CH Cl (12 mL) were stirred for 42 h at RT. The

product was isolated as a red solid. Yield: 0.275 g, 0.199 mmol, 97%.

1449.1803. UV−vis: λ = 250 and 370 nm.

2

max

6

Compound 6b. According to the general procedure, [Ru(η -p-

cymene)Cl] Cl (0.16 g, 0.261 mmol, 1 equiv), 6a (0.22 g, 0.261

1

Elem anal. Calcd for C H Cl O P Ru · / CH Cl : C, 56.03; H, 5.06.

66

72

4

7

2

Found: C, 55.67; H, 5.16. CH Cl originates from the reaction solvent.

mmol, 1 equiv), and CH Cl (12 mL) were stirred for 42 h at RT. The

2

2 2

1

H NMR (CDCl ): δ 7.85−7.95 (8H, m, 4O(CO)(Ar)-

product was isolated as a red solid. Yield: 0.38 g, 0.256 mmol, 98%.

Elem anal. Calcd for C H Cl O P Ru : C, 57.14; H, 5.48. Found: C,

3

H

CCHCHCP, 4O(CO)(Ar)CCHCHCP), 7.76−7.81 (8H, m, 8P-

7

0

80

4

9

2

1

(

Ar)CCHCHCH), 7.34−7.42 (12H, m, 8P(Ar)CCHCHCH, 4P(Ar)-

57.05, H, 5.64. H NMR (CDCl ): δ 7.88−7.97 (8H, m, 4O(C

3

H

3

CCHCHCH), 5.19 (4H, d, 4CH (Ar)CCHCHC, J = 6.2 Hz), 4.96

O)(Ar)CCHCHCP, 4O(CO)(Ar)CCHCHCP), 7.78−7.83 (8H, m,

3

H,H

3

(

4H, d, 4CH (Ar)CCHCHC, J

= 6.2 Hz), 4.41−4.38 (4H, m,

8P(Ar)CCHCHCH), 7.36−7.45 (12H, m, 8P(Ar)CCHCHCH, 4P-

3

H,H

3

2

Ar(CO)OCH CH O), 3.75−3.73 (4H, m, 2Ar(CO)-

(Ar)CCHCHCH), 5.21 (4H, d, 4CH (Ar)CCHCHC, J = 6.2 Hz),

2

3

H,H

3

OCH CH O), 3.64−3.60 (8H, m, 2Ar(CO)O(CH ) OCH CH ,

4.97 (4H, d, 4CH (Ar)CCHCHC, J = 6.2 Hz), 4.44−4.41 (4H, m,

2

3

H,H

2

Ar(CO)O(CH ) OCH CH ), 2.83 (2H, sept, 2(Ar)-

2Ar(CO)OCH CH O), 3.79−3.77 (4H, m, 2Ar(CO)-

2

3

CCHCHCCH(CH ) ,

J

= 6.9 Hz), 1.83 (6H, s, 2CH (Ar)-

OCH CH O), 3.67−3.61 (16H, m, 2Ar(CO)O(CH ) OCH CH ,

3

2

H,H

3

2 2 2 2 2 2

3

CCHCHC), 1.08 (12H, d, 2(Ar)CCHCHCCH(CH ) , J

= 6.9

2Ar(CO)O(CH ) OCH CH , 2Ar(CO)O(CH ) O-

2 2 2 2 2 2 2 2 2

3

2

H,H

2 2 2 2 2 2

Hz). ³¹P NMR (CDCl ): δ 24.96 (2P). C NMR (CDCl ): δ 166.1

13

(CH ) OCH ), 2Ar(CO)O(CH ) O(CH ) OCH CH ), 2.85

3 2 H,H

3

P

3

C

3

(

2C, 2O(CO)(Ar)CCHCHCP), 139.4 (2C, d, 2O(CO)(Ar)-

(2H, sept, 2(Ar)CCHCHCCH(CH ) , J = 6.9 Hz), 1.86 (6H, s,

1

CCHCHCP,

J

= 44 Hz), 134.5 (4C, d, 4O(CO)(Ar)-

2CH (Ar)CCHCHC), 1.10 (12H, d, 2(Ar)CCHCHCCH(CH ) ,

C,P

3

2

I

DOI: 10.1021/acs.inorgchem.7b01082

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

³J_H_,_H= 6.9 Hz). ³¹P NMR (CDCl ): δ 24.96 (2P). ¹³C NMR

d, 6P(Ar)CCHCHCH, ²J_C_,_P= 9 Hz), 133.9 (3C, d, 3P(Ar)

3

P

1

4

(

2

CDCl ): δ 166.1 (2C, 2O(CO)(Ar)CCHCHCP), 139.4 (2C, d,

CCHCHCH, JC,P = 46 Hz), 130.3 (3C, d, 3P(Ar)CCHCHCH, JC,P

3

C

1

3

O(CO)(Ar)CCHCHCP, J = 44 Hz), 134.5 (4C, d, 4O(C

= 2 Hz), 128.1 (8C, d, 8P(Ar)CCHCHCH, JC,P = 10 Hz), 111.20,

C,P

2

O)(Ar)CCHCHCP, J = 7 Hz), 134.4 (8C, d, 8P(Ar)CCHCHCH,

111.17 (1C, CH

89.18, 89.15 (2C, 2CH

CCHCHC), 30.3 (1C, (Ar)CHCHCCH(CH ) ), 22.0 (2C, (Ar)-

3

(Ar)CCHCHC), 96.1 (1C, 2CH

3

(Ar)CCHCHC),

C,P

2

1

J_C_,_P= 9 Hz), 133.4 (4C, d, 4P(Ar)CCHCHCH, J = 45 Hz), 131.4

3

(Ar)CCHCHC), 87.28, 87.23 (2C, 2CH

3

(Ar)-

C,P

4

(

4

2C, d, 2O(CO)(Ar)CCHCHCP, J = 2 Hz), 130.7 (4C, d,

3 2

C,P

4

P(Ar)CCHCHCH, J = 2 Hz), 128.8 (4C, d, 4O(CO)(Ar)-

CHCHCCH(CH

Calcd for C28H29PRu : m/z 498.1050 ([M − 2Cl] ). Found: m/z

+ +

3 2 3

) ), 17.8 (1C, CH (Ar)CCHCH). ESI-MS(+).

C,P

3

2+

+

CCHCHCP, J = 10 Hz), 128.3 (8C, d, 8P(Ar)CCHCHCH, J

=

C,P

1

2

8

2

0 Hz), 111.61, 111.58 (2C, 2CH (Ar)CCHCHC), 96.4 (2C,

498.1009. Calcd for C28

Found: m/z 533.0772.

Compound 9b. According to the general procedure, [Ru(η -p-

H

29ClPRu : m/z 533.0739 ([M − Cl] ).

3

CH (Ar)CCHCHC), 89.13, 89.10 (4C, 4CH (Ar)CCHCHC),

3

6

7.49, 87.44 (4C, 4CH (Ar)CCHCHC), 70.82, 70.73, 70.67 (8C,

3

(Ar)(CO)O(CH ) OCH , 2(Ar)(CO)O(CH ) OCH CH , 2-

cymene)Cl]

(diphenylphosphanyl)benzoic acid (0.30 g, 0.980 mmol, 1 equiv),

and CH Cl (12 mL), were stirred for 42 h at RT. The product was

isolated as a dark-red solid. Yield: 0.59 g, 0.961 mmol, 98%. Elem anal.

2

Cl

2

(0.30 g, 0.980 mmol, 1 equiv), 4-

2

(

Ar)(CO)O(CH ) O(CH ) OCH , 2(Ar)(CO)O(CH ) O-

2

2 2

CH ) OCH CH ), 69.2 (2C, 2(Ar)(CO)OCH CH O), 64.5

2

2 2 2 2 2 2

2C, 2(Ar)(CO)OCH CH O), 30.4 (2C, 2(Ar)CHCHCCH-

2

1

CH ) ), 22.0 (4C, 2(Ar)CHCHCCH(CH ) ), 17.9 (2C, 2CH (Ar)-

Calcd for C29

52.73; H, 4.67. CHCl

NMR (CDCl ): δ

H

29Cl

2

O

2

PRu.· /

originates from the recrystallization process. H

3

2 3

CHCl : C, 52.71; H, 4.42. Found: C,

3

2

3

2

3

2

+

1

CCHCH). ESI-MS(+). Calcd for C H Cl O P Ru : m/z

1

7

0

80

2

9

2

+

400.2742 ([M − 2Cl] ). Found: m/z 1400.2695. Calcd for

3

H

−7.97−8.00 (4H, m, 2O(CO)(Ar)-

+

C H Cl O P Ru : m/z 1435.2430 ([M − Cl] ). Found: m/z

CCHCHCP), 7.78−7.84 (4H, m, 4P(Ar)CCHCHCH), 7.36−7.45

7

0

80

3

9

2

+

1

435.2384. Calcd for C H Cl NaO P Ru : m/z 1493.2016 ([M +

(6H, m, 4P(Ar)CCHCHCH, 2P(Ar)CCHCHCH), 5.22 (2H, d,

70

80

4

9

2

+

3

Na] ). Found: m/z 1493.2328. UV−vis: λ = 250 and 370 nm. ₆

2CH

CCHCHC,

CCHCHCCH(CH

CCHCHC), 1.10 (6H, d, (Ar)CCHCHCCH(CH

3

(Ar)CCHCHC,

J

H,H = 6.1 Hz), 4.99 (2H, d, 2CH

6.1 Hz), 2.84 (1H, sept, (Ar)-

(Ar)-

3

(Ar)-

max

3

Compound 7b. According to the general procedure, [Ru(η -p-

cymene)Cl] Cl (0.18 g, 0.299 mmol, 1 equiv), 7a (0.28 g, 0.299

J

H , H

=

)

,

³JH,H = 6.9 Hz), 1.85 (3H, s, CH

2

3

2

3

mmol 1 equiv), and CH Cl (12 mL) were stirred for 42 h at RT. The

3

)

2

,

J

H,H = 6.9

2

Hz). ³¹P NMR (CDCl

): δ 25.27 (1P). C NMR (CDCl ): δ 171.1

3 P 3 C

13

product was isolated as a red solid. Yield: 0.45 g, 0.287 mmol, 96%.

Elem anal. Calcd for C H Cl O P Ru : C, 57.00; H, 5.69. Found: C,

(1C, O(CO)(Ar)CCHCHCP), 140.4 (1C, d, O(CO)(Ar)-

7

4

88

4

11

2

1

5

6.95; H, 5.90. H NMR (CDCl ): δ 7.88−7.98 (8H, m, 4O(C

CCHCHCP,

J

C,P = 43 Hz), 134.5 (2C, d, 2O(CO)(Ar)-

3

H

2

O)(Ar)CCHCHCP, 4O(CO)(Ar)CCHCHCP), 7.77−7.83 (8H, m,

CCHCHCP, JC,P = 11 Hz), 134.4 (4C, d, 4P(Ar)CCHCHCH, JC,P

= 10 Hz), 133.3 (2C, d, 2P(Ar)CCHCHCH, JC,P = 45 Hz), 130.7

1

8

(

4

2

P(Ar)CCHCHCH), 7.36−7.45 (12H, m, 8P(Ar)CCHCHCH, 4P-

3

4

Ar)CCHCHCH), 5.21 (4H, d, 4CH (Ar)CCHCHC, J = 6.2 Hz),

(2C, d, 2P(Ar)CCHCHCH, JC,P = 1 Hz), 130.5 (1C, d, O(C

3

H,H

3

4

.98 (4H, d, 4CH (Ar)CCHCHC, J = 6.2 Hz), 4.44−4.42 (4H, m,

O)(Ar)CCHCHCP, JC,P = 2 Hz), 129.3 (2C, d, 2O(CO)(Ar)-

3

H,H

3

Ar(CO)OCH CH O), 3.79−3.77 (4H, m, 2Ar(CO)-

CCHCHCP, JC,P = 10 Hz), 128.3 (4C, d, 4P(Ar)CCHCHCH, JC,P

=

2

OCH CH O), 3.70−3.61 (16H, m, 2Ar(CO)O(CH ) OCH CH ,

10 Hz), 111.57, 111.61 (1C, CH (Ar)CCHCHC), 96.5 (1C, CH (Ar)

3

2

(

Ar(CO)O(CH ) OCH CH , 2Ar(CO)O(CH ) O-

CCHCHC), 89.06, 89.03 (2C, 2CH (Ar)CCHCHC), 87.51, 87.46

2

3

CH ) OCH ), 2Ar(CO)O(CH ) O(CH ) OCH CH ), 2.85

(2C, 2CH (Ar)CCHCHC), 30.4 (1C, (Ar)CHCHCCH(CH ) ), 22.0

2

3

3 2

3

2H, sept, 2(Ar)CCHCHCCH(CH ) , J = 6.9 Hz), 1.85 (6H, s,

(2C, (Ar)CHCHCCH(CH ) ), 17.9 (1C, CH (Ar)CCHCH). ESI-

3

2

H,H

3 2 3

+

2

CH (Ar)CCHCHC), 1.10 (12H, d, 2(Ar)CCHCHCCH(CH ) ,

MS(+). Calcd for C H O PRu : m/z 542.0949 ([M − 2Cl] ).

+

3

2

29 29

2

3

31

13

J_H_,_H= 6.9 Hz). P NMR (CDCl ): δ 24.94 (2P). C NMR

Found: m/z 542.0914. Calcd for C H ClO PRu : m/z 577.0637 ([M

3

P

29 29 2

+

(

2

CDCl ): δ 166.1 (2C, 2O(CO)(Ar)CCHCHCP), 139.4 (2C, d,

− Cl] ). Found: m/z 577.0648. Calcd for C29H29Cl NaO PRu : m/z

2 2

+

3

C

1

O(CO)(Ar)CCHCHCP, J = 44 Hz), 134.5 (4C, d, 4O(C

635.0223 ([M + Na] . Found: m/z 635.0228).

C,P

2

O)(Ar)CCHCHCP, J = 7 Hz), 134.4 (8C, d, 8P(Ar)CCHCHCH,

General Procedure for the Synthesis of the Digold Intermediates

1c−7c. The appropriate ligand,1a−7a (1 equiv), dissolved in dry

CH Cl (15 mL), was added to a solution of AuCl(tht) (2 equiv) in

C,P

2

1

J_C_,_P= 9 Hz), 133.4 (4C, d, 4P(Ar)CCHCHCH, J = 45 Hz), 131.4

C,P

4

(

4

2C, d, 2O(CO)(Ar)CCHCHCP, J = 2 Hz), 130.7 (4C, d,

2

C,P

4

dry CH Cl (10 mL) at 0 °C under N . The reaction mixture was

2 2 2

1

P(Ar)CCHCHCH, J = 2 Hz), 128.8 (4C, d, 4O(CO)(Ar)-

C,P

3

stirred at RT for 6 h, and the reaction evolution was monitored by H

CCHCHCP, J = 10 Hz), 128.3 (8C, d, 8P(Ar)CCHCHCH, J

=

C,P

and ³¹P NMR (CDCl ). The reaction mixture was concentrated under

1

2

8

2

0 Hz), 111.59, 111.56 (2C, 2CH (Ar)CCHCHC), 96.4 (2C,

3

reduced pressure, and the product was washed with hexane (5 × 25

CH (Ar)CCHCHC), 89.12, 89.09 (4C, 4CH (Ar)CCHCHC),

3

mL) and resolubilized in CH Cl (50 mL), before being concentrated

7.48, 87.42 (4C, 4CH (Ar)CCHCHC), 70.81, 70.73, 70.67 (8C,

2

3

and further dried under high vacuum. The product was isolated as a

white solid and stored at −20 °C in the dark.

(Ar)(CO)O(CH ) OCH , 2(Ar)(CO)O(CH ) OCH CH , 2-

2

(

Ar)(CO)O(CH ) O(CH ) OCH , 2(Ar)(CO)O(CH ) O-

2

2 2

Compound 1c. According to the general procedure, AuCl(tht)

0.188 g, 0.588 mmol, 2 equiv), 1a (0.188 g, 0.294 mmol, 1 equiv),

CH ) OCH CH ), 69.3 (2C, 2(Ar)(CO)OCH CH O), 64.5

2 2 2 2 2 2

(

2C, 2(Ar)(CO)OCH CH O), 30.4 (2C, 2(Ar)CHCHCCH-

2

and CH Cl (35 mL) were stirred for 6 h at RT. The product was

CH ) ), 22.0 (4C, 2(Ar)CHCHCCH(CH ) ), 17.9 (2C, 2CH (Ar)-

2

3

2

3

2

3

+

isolated as a white solid. Yield: 0.319 g, 0.289 mmol, 98%. Elem anal.

Calcd for C H Au Cl O P : C, 43.54; H, 2.92. Found: C, 43.55; H,

CCHCH). ESI-MS(+). Calcd for C H Cl O P Ru : m/z

1

C H Cl NaO P Ru : m/z 1581.2535 ([M + Na] ). Found: m/z

7

4

88

3

11

2

+

523.2949 ([M − Cl] ). Found: m/z 1523.2914. Calcd for

40 32

2

4 2

1

+

3.02. H NMR (CDCl ): δ 8.07−8.12 (4H, m, 4O(CO)(Ar)-

CCHCHCP, J = 8.4 Hz, J

H,H H,H

3

H

7

4

88

4

11

2

3

4

= 2.1 Hz), 7.45−7.60 (24H, m,

1

581.2789. UV−vis: λ_m_a_x= 250 and 370 nm.

Compound 8b. According to the general procedure, [Ru(η -p-

cymene)Cl] Cl (0.30 g, 0.490 mmol, 1 equiv), PPh (0.26 g, 0.979

6

4O(CO)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)-

CCHCHCH, 4P(Ar)CCHCHCH), 4.68 (4H, s, Ar(CO)O-

2

3

31

13

(

CH ) O). P NMR (CDCl ): δ 33.14 (2P). C NMR (CDCl ):

mmol, 2 equiv), and CH Cl (12 mL) were stirred for 42 h at RT. The

2 2 3 P 3

2

^δC 165.3 (2C, 2O(CO)(Ar)CCHCHCP), 134.9 (2C, d, 2O(C

product was isolated as a dark-red solid. Yield: 0.54 g, 0.950 mmol, 9.

Elem anal. Calcd for C H Cl PRu: C, 59.16; H, 5.14. Found: C,

1

O)(Ar)CCHCHCP, J = 59 Hz), 134.3 (8C, d, 8P(Ar)CCHCHCH,

C,P

2

8

29

2

1

^JC,P = 14 Hz), 134.1 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 14

5

6

(

4

(

9.26; H, 4.90. H NMR (CDCl ): δ 7.77−7.85 (6H, m,

C,P

3

H

4

P(Ar)CCHCHCH), 7.32−7.46 (9H, m, 6P(Ar)CCHCHCH, 3P-

Hz), 132.9 (2C, d, 2O(CO)(Ar)CCHCHCP, JC,P = 3 Hz), 132.5

3

4

Ar)CCHCHCH), 5.19 (2H, d, 2CH (Ar)CCHCHC, J = 6.2 Hz),

(4C, d, 4P(Ar)CCHCHCH, JC,P = 3 Hz), 130.2 (4C, d, 4O(C

3

H,H

3

.98 (2H, d, 2CH (Ar)CCHCHC, J

Ar)CCHCHCCH(CH ) , J

CCHCHC), 1.09 (6H, d, (Ar)CCHCHCCH(CH ) , J = 7.1 Hz).

P NMR (CDCl ): δ 24.18 (1P). C NMR (CDCl ): δ 134.5 (6C,

= 6.2 Hz), 2.84 (1H, sept,

O)(Ar)CCHCHCP, JC,P = 12 Hz), 129.6 (8C, d, 8P(Ar)CCHCHCH,

3

H,H

3

1

= 7.1 Hz), 1.86 (3H, s, CH (Ar)-

J

C,P = 12 Hz), 127.9 (4C, d, 4P(Ar)CCHCHCH, JC,P = 63 Hz), 63.3

3

2

H,H

3

(2C, 2(Ar)(CO)O(CH ) O). ESI-MS(+). Calcd for

3

2

H,H

2 2

3

1

13

+

C H Au ClO P : m/z 1067.0795 ([M − Cl] ). Found: m/z

3

P

3

C

40 32

2

4 2

J

DOI: 10.1021/acs.inorgchem.7b01082

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

+

1

067.0825. Calcd for C H Au Cl NaO P : m/z 1125.0382 ([M +

Calcd for C H Au ClO P : m/z 1199.1582 ([M − Cl] ). Found:

40

32

2

4

2

46 44

2

7 2

+

Na] ). Found: m/z 1125.0388.

m/z 1199.1633. Calcd for C H Au Cl NaO P : m/z 1257.1168 ([M

46 44 2 2 7 2

+

Compound 2c. According to the general procedure, AuCl(tht)

+ Na] ). Found: m/z 1257.1218.

(

0.235 g, 0.735 mmol, 2 equiv), 2a (0.250 g, 0.366 mmol,1 equiv), and

Compound 5c. According to the general procedure, AuCl(tht)

CH Cl (35 mL) were stirred for 6 h at RT. The product was isolated

(0.162 g,0.507 mmol, 2 equiv), 5a (0.206 g, 0.253 mmol, 1 equiv), and

2

as a white solid. Yield: 0.403 g, 0.351 mmol, 96. Elem anal. Calcd for

CH

Cl (35 mL), were stirred for 6 h at RT. The product was isolated

2 2

1

C H Au Cl O P : C, 43.96; H, 3.16. Found: C, 43.83; H, 3.23. H

as a white solid. Yield: 0.308 g, 0.241 mmol, 95%. Elem anal. Calcd for

4

2

36

2

5 2

1

NMR (CDCl ): δ 8.06−8.10 (4H, m, 4O(CO)(Ar)CCHCHCP,

C

48

H

48Au

2

Cl

O P : C, 45.05; H, 3.78. Found: C, 45.05; H, 3.79. H

2 8 2

3

H

3

J_H_,_H= 8.2 Hz, ⁴J

= 2 Hz), 7.44−7.60 (24H, m, 4O(C

NMR (CDCl

3

): δ₄

H

J

8.09−8.12 (4H, m, 4O(CO)(Ar)CCHCHCP,

H,H

3

^JH,H = 8.6 Hz,

= 2.4 Hz), 7.46−7.60 (24H, m, 4O(C

O)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)CCHCHCH, 4P-

H,H

(

3

δ

Ar)CCHCHCH), 4.48−4.50 (4H, m, 2Ar(CO)OCH CH O),

O)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)CCHCHCH, 4P-

2

31

.85−3.87 (4H, m, 2Ar(CO)OCH CH O). P NMR (CDCl ):

(Ar)CCHCHCH), 4.47−4.49 (4H, m, 2Ar(CO)OCH

3.80−3.82 (4H, m, 2Ar(CO)OCH CH O), 3.66−3.68 (4H, m,

2Ar(CO)O(CH OCH CH ), 3.62−3.64 (4H, m, 2Ar(CO)O-

CH ) OCH CH ), 3.63 (4H, s, 2Ar(CO)O(CH ) O-

CH O),

2 2

2

3

1

3

33.02 (2P). C NMR (CDCl ): δ 165.4 (2C, 2O(C

2

P

3

C

O)(Ar)CCHCHCP), 134.6 (2C, d, 2O(CO)(Ar)CCHCHCP,

2

)

2

1

2

(

J

= 62 Hz), 134.3 (8C, d, 8P(Ar)CCHCHCH, J = 14 Hz),

2

2 2

C,P

31

13

2

(CH ) OCH ). P NMR (CDCl ): δ 32.99 (2P). C NMR

1

34.0 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 14 Hz), 133.2 (2C,

2 2 2 3 P

C,P

4

(CDCl ): δ 165.4 (2C, 2O(CO)(Ar)CCHCHCP), 134.3 (2C, d,

d, 2O(CO)(Ar)CCHCHCP,

J

= 2 Hz), 132.5 (4C, d,

3

C

C,P

1

4

2O(CO)(Ar)CCHCHCP, J = 57 Hz), 134.3 (8C, d, 8P(Ar)-

4

P(Ar)CCHCHCH, J = 2 Hz), 130.1 (4C, d, 4O(CO)(Ar)-

C,P

2

3

CCHCHCH,

J

C,P

= 14 Hz), 134.0 (4C, d, 4O(CO)(Ar)-

CCHCHCP, J = 12 Hz), 129.6 (8C, d, 8P(Ar)CCHCHCH, J

1

2

ESI-MS(+). Calcd for C H Au ClO P : m/z 1111.1058 ([M −

Cl] ). Found: m/z 1111.1104. Calcd for C H Au Cl NaO P : m/z

=

C,P

CCHCHCP, ₄²J

= 14 Hz), 133.3 (2C, d, 2O(CO)(Ar)

1

2 Hz), 128.0 (4C, d, 4P(Ar)CCHCHCH, J_C_,_P= 63 Hz), 69.2 (2C,

(Ar)(CO)OCH CH O), 64.6 (2C, 2(Ar)(CO)OCH CH O).

4

CCHCHCP, J = 2 Hz), 132.4 (4C, d, 4P(Ar)CCHCHCH, J

C,P

2

3

+

= 3 Hz), 130.1 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 12 Hz),

C,P

42

36

2

5

2

3

+

129.5 (8C, d, 8P(Ar)CCHCHCH, J = 12 Hz), 127.9 (4C, d,

C,P

4

2

36

2

5

2

1

+

4P(Ar)CCHCHCH, J = 63 Hz), 70.71, 70.66 (6C, 2(Ar)(C

C,P

1

169.0644 ([M + Na] ).. Found: m/z 1169.0690

Compound 3c. According to the general procedure, AuCl(tht)

0.221 g, 0.692 mmol, 2 equiv), 3a (0.250 g, 0.344 mmol, 1 equiv),

and CH Cl (35 mL) were stirred 6 h at RT. The product was isolated

O)O(CH ) OCH , 2(Ar)(CO)O(CH ) OCH CH , 2(Ar)(C

2

O)O(CH ) O(CH ) OCH ), 69.1 (2C, 2(Ar)(CO)OCH CH O),

2

(

6

4.7 (2C, 2(Ar)(CO)OCH CH O). ESI-MS(+). Calcd for

2

+

C H Au ClO P : m/z 1243.1844 ([M − Cl] ). Found: m/z

1243.1903. Calcd for C48H48Au Cl NaO P : m/z 1301.1430 ([M +

48 48 2 8 2

as a white solid. Yield: 0.406 g, 0.341 mmol, 98%. Elem anal. Calcd for

+

1

2 2 8 2

C H Au Cl O P : C, 44.35; H, 3.38. Found: C, 44.30; H, 3.51. H

4

40

2

6

2

+

Na] ). Found: m/z 1301.1469.

NMR (CDCl ): δ 8.07−8.11 (4H, m, 4O(CO)(Ar)CCHCHCP,

3

H

3

J_H_,_H= 8.4 Hz, 4_J

Compound 6c. According to the general procedure, AuCl(tht)

0.192 g,0.601 mmol, 2 equiv), 6a (0.257 g, 0.299 mmol, 1 equiv), and

= 2.2 Hz), 7.45−7.60 (24H, m, 4O(C

H,H

(

O)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)CCHCHCH, 4P-

CH Cl (35 mL) were stirred 6 h at RT. The product was isolated as a

white solid. Yield: 0.376 g, 0.284 mmol, 95%. Elem anal. Calcd for

2

(

3

Ar)CCHCHCH), 4.44−4.48 (4H, m, 2Ar(CO)OCH CH O),

2

.79−3.83 (4H, m, 2Ar(CO)OCH CH O), 3.69 (4H, s, 2Ar(C

1

2

C H Au Cl O P : C, 45.37; H, 3.96. Found: C, 45.44; H, 3.84. H

31

13

50 52

2

9 2

O)O(CH ) OCH ). P NMR (CDCl ): δ 33.07 (2P). C NMR

2

3

P

NMR (CDCl ): δ 8.08−8.12 (4H, m, 4O(CO)(Ar)CCHCHCP,

3

H

(

2

CDCl ): δ 165.4 (2C, 2O(CO)(Ar)CCHCHCP), 134.5 (2C, d,

3

^JH,H = 8.4 Hz, 4_J

3

C

= 2 Hz), 7.45−7.59 (24H, m, 4O(C

1

H,H

O(CO)(Ar)CCHCHCP, J = 60 Hz), 134.3 (8C, d, 8P(Ar)-

C,P

2

O)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)CCHCHCH, 4P-

CH O),

.79−3.82 (4H, m, 2Ar(CO)OCH CH O), 3.65−3.68 (4H, m,

CCHCHCH,

J

= 14 Hz), 134.2 (4C, d, 4O(CO)(Ar)-

C,P

^C^C^H^C^H^C^P^,4 2_J

(Ar)CCHCHCH), 4.46−4.49 (4H, m, 2Ar(CO)OCH

2

= 14 Hz), 133.3 (2C, d, 2O(CO)(Ar)

C,P

3

2

4

2

CCHCHCP, J = 3 Hz), 132.5 (4C, d, 4P(Ar)CCHCHCH, J

C,P

Ar(CO)O(CH ) OCH CH ), 3.60−3.64 (4H, m, 2Ar(CO)O-

3

2

=

1

4

(

2

2 Hz), 130.2 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 12 Hz),

J = 12 Hz), 128.0 (4C, d,

C,P

(

2

CH ) OCH CH ), 3.59−3.62 (8H, m, 2Ar(CO)O(CH ) O-

3

2

2 2

29.5 (8C, d, 8P(Ar)CCHCHCH,

31

13

CH ) O(CH ) . P NMR (CDCl ): δ 33.03 (2P). C NMR

1

2

3

P

P(Ar)CCHCHCH, J_C_,_P= 63 Hz), 70.8 (2C, 2(Ar)(CO)O-

CDCl ): δ 165.4 (2C, 2O(CO)(Ar)CCHCHCP), 134.4 (2C, d,

3

C

CH ) OCH ), 69.3 (2C, 2(Ar)(CO)OCH CH O), 64.7 (2C,

1

2

O(CO)(Ar)CCHCHCP, J = 59 Hz), 134.3 (8C, d, 8P(Ar)-

C,P

( A r ) ( C  O ) O CH C H O ) . E S I - M S ( + ) . C a l c d f o r

2

CCHCHCH,

J

C,P

= 14 Hz), 134.1 (4C, d, 4O(CO)(Ar)-

+

C H Au ClO P : m/z 1155.1320 ([M − Cl] ). Found: m/z

1

Na] ). Found: m/z 1213.0951.

2

4

40

2

6 2

CCHCHCP, J = 14 Hz), 133.4 (2C, 2O(CO)(Ar)CCHCHCP),

+

C,P

155.1376. Calcd for C H Au Cl NaO P : m/z 1213.0906 ([M +

44 40 2 2 6 2

1

32.5 (4C, 4P(Ar)CCHCHCH), 130.2 (4C, d, 4O(CO)(Ar)-

=

C,P C,P

+

3

CCHCHCP, J = 12 Hz), 129.5 (8C, d, 8P(Ar)CCHCHCH, J

Compound 4c. According to the general procedure, AuCl(tht)

0.208 g, 0.651 mmol, 2 equiv), 4a (0.250 g, 0.324 mmol, 1 equiv),

1

2 Hz), 128.0 (4C, d, 4P(Ar)CCHCHCH, J = 62 Hz), 70.78,

0.74, 70.68 (8C, 2(Ar)(CO)O(CH ) OCH , 2(Ar)(CO)O-

C,P

(

7

2

and CH Cl (35 mL) were stirred 6 h at RT. The product was isolated

2

(

CH ) OCH CH , 2(Ar)(CO)O(CH ) O(CH ) OCH , 2(Ar)-

2

as a white solid. Yield: 0.389 g, 0.315 mmol, 97%. Elem anal. Calcd for

CO)O(CH ) O(CH ) OCH CH ), 69.2 (2C, 2(Ar)(CO)-

1

2 2 2 2 2 2

C H Au Cl O P : C, 44.71; H, 3.59. Found: C, 44.78; H, 3.57. H

4

6

44

2

7 2

OCH CH O), 64.8 (2C, 2(Ar)(CO)OCH CH O). ESI-MS(+).

2

NMR (CDCl ): δ 8.08−8.12 (4H, m, 4O(CO)(Ar)CCHCHCP,

+

3

H

Calcd for C H Au ClO P : m/z 1287.2106 ([M − Cl] ). Found:

3

^JH,H = 8.4 Hz, ⁴J

50 52

2

9 2

= 2 Hz), 7.46−7.60 (24H, m, 4O(C

+

H,H

m/z 1287.2147.Calcd for C H Au Cl NaO P : m/z 1345.1692 ([M

50 52 2 2 9 2

O)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)CCHCHCH, 4P-

+

Na] ). Found: m/z 1345.1719.

Compound 7c. According to the general procedure, AuCl(tht)

(

Ar)CCHCHCH), 4.46−4.49 (4H, m, 2Ar(CO)OCH CH O),

2

3

2

.79−3.82 (4H, m, 2Ar(CO)OCH CH O), 3.61−3.72 (8H, m,

2

(0.230 g, 0.720 mmol, 2 equiv), 7a (0.340 g, 0.359 mmol, 1 equiv),

and CH Cl (35 mL) were stirred for 6 h at RT. The product was

isolated as a white solid. Yield: 0.485 g, 0.344 mmol, 96%. Elem anal.

Calcd for C H Au Cl O P : C, 45.94; H, 4.28; Found: C, 45.82; H,

4.04. H NMR (CDCl ): δ 8.08−8.12 (4H, m, 4O(CO)(Ar)-

CCHCHCP, J = 8.2 Hz, J

H,H H,H

31

Ar(CO)O(CH ) O(CH ) ). P NMR (CDCl ): δ 33.01 (2P).

2 2 2 2 3 P

2

1

3

C NMR (CDCl ): δ 165.4 (2C, 2O(CO)(Ar)CCHCHCP),

3

C

1

34.5 (2C, d, 2O(CO)(Ar)CCHCHCP, J = 58 Hz), 134.3 (8C,

C,P

54 60

2

11 2

2

1

d, 8P(Ar)CCHCHCH,

J

= 14 Hz), 134.0 (4C, d, 4O(C

C,P

3

H

2

3

4

O)(Ar)CCHCHCP, J = 14 Hz), 133.3 (2C, d, 2O(CO)(Ar)

= 2 Hz), 7.45−7.59 (24H, m,

C,P

4

CCHCHCP, J = 2 Hz), 132.4 (4C, d, 4P(Ar)CCHCHCH, J = 2

4O(CO)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)-

CCHCHCH, 4P(Ar)CCHCHCH), 4.46−4.49 (4H, m, 2Ar(C

O)OCH CH O), 3.80−3.82 (4H, m, 2Ar(CO)OCH CH O),

C,P

3

Hz), 130.1 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 12 Hz), 129.5

C,P

3

(

8C, d, 8P(Ar)CCHCHCH, J = 12 Hz), 127.9 (4C, d, 4P(Ar)

C,P

2

1

CCHCHCH, J = 63 Hz), 70.7 (4C, 2(Ar)(CO)O(CH ) OCH ,

3.66−3.69 (4H, m, 2Ar(CO)O(CH ) OCH CH ), 3.61−3.64

C,P

2

(Ar)(CO)O(CH ) OCH CH ), 69.1 (2C, 2(Ar)(CO)-

(4H, m, 2Ar(CO)O(CH ) OCH CH ), 3.60−3.62 (8H, m,

2

2 2 2 2

OCH CH O), 64.7 (2C, 2(Ar)(CO)OCH CH O). ESI-MS(+).

2Ar(CO)O(CH ) O(CH ) O(CH ) , 3.61 (8H, s, 2Ar(CO)O-

2

2 2 2 2 2 2

K

DOI: 10.1021/acs.inorgchem.7b01082

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

3

1

Ar(CO)O(CH ) O), 4.20 (2H, dd, CH OAc, J = 12.2 Hz, ³J_H_,_H

= 4.7 Hz), 4.09 (2H, dd, CH OAc, J = 12.2 Hz, J = 2.3 Hz),

2 H,H H,H

2

(

CH ) O(CH ) O(CH ) O(CH ) . P NMR (CDCl ): δ 33.01

2 2 2 2 2 2 2 2 3 P

2

H,H

1

3

2

3

2P). C NMR (CDCl ): δ 165.4 (2C, 2O(CO)(Ar)-

3

C

1

3

CCHCHCP), 134.4 (2C, d, 2O(CO)(Ar)CCHCHCP, J = 58

3.75 (2H, ddd, CHCH OAc, J = 9.7 Hz, J = 4.7 Hz, J = 2.3

C,P

2 H,H H,H H,H

2

Hz), 134.3 (8C, d, 8P(Ar)CCHCHCH, J = 14 Hz), 134.0 (4C, d,

Hz), 2.04 (6H, s, 2CH O(CO)CH ), 2.00 (6H, s, 2(CO)CH ),

3 3

C,P

2

3

2

31

4

O(CO)(Ar)CCHCHCP, J_C_,_P= 14 Hz), 133.4 (2C, 2O(C

1.96 (6H, s, 2(CO)CH ), 1.89 (6H, s, 2(CO)CH ). P NMR

4

13

O)(Ar)CCHCHCP, J = 2 Hz), 132.4 (4C, 4P(Ar)CCHCHCH,

(CDCl ): δ 38.71 (2P). C NMR (CDCl ): δ 170.8 (2C, 2(C

C,P

3 P 3 C

4

3

J_C_,_P= 2 Hz), 130.2 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 12

O)CH ), 170.3 (2C, 2(CO)CH ), 169.7 (2C, 2(CO)CH ), 169.6

C,P

3

Hz), 129.5 (8C, d, 8P(Ar)CCHCHCH, J = 12 Hz), 128.0 (4C, d,

(2C, 2(CO)CH

3

), 165.4 (2C, 2O(CO)(Ar)CCHCHCP), 135.8

C,P

1

4

2

(

2

P(Ar)CCHCHCH, J_C_,_P= 63 Hz), 70.77, 70.72, 70.66 (12C,

(Ar)(CO)O(CH ) OCH , 2(Ar)(CO)O(CH ) OCH CH , 2-

(2C, d, 2O(CO)(Ar)CCHCHCP, JC,P = 53 Hz), 134.5 (4C, d,

2

4P(Ar)CCHCHCH, JC,P = 14 Hz), 134.4 (4C, d, 4P(Ar)CCHCHCH,

2

Ar)(CO)O(CH ) O(CH ) OCH , 2(Ar)(CO)O(CH ) O-

J

C,P = 14 Hz), 134.2 (4C, d, 4O(CO)(Ar)CCHCHCP, JC,P = 14

2

2 2

4

CH ) OCH CH , 2(Ar)(CO)O(CH ) O(CH ) O(CH ) OCH ,

Hz), 132.5 (2C, d, 2O(CO)(Ar)CCHCHCP, J = 2 Hz), 132.1

2

C,P

(Ar)(CO)O(CH ) O(CH ) O(CH ) OCH CH ), 69.2 (2C, 2-

(4C, m, 4P(Ar)CCHCHCH), 130.1 (4C, d, 4O(CO)(Ar)-

CCHCHCP, J = 12 Hz), 129.5 (8C, d, 8P(Ar)CCHCHCH, J

C,P C,P

2

3

(

Ar)(CO)OCH CH O), 64.8 (2C, 2(Ar)(CO)OCH CH O).

2

+

1

ESI-MS(+). Calcd for C H Au ClO P : m/z 1375.2630 ([M −

= 12 Hz), 128.8 (4C, d, 4P(Ar)CCHCHCH, J = 57 Hz), 83.2 (2C,

54

60

2

11

2

C,P

+

Cl] ). Found: m/z 1375.2667. Calcd for C H Au Cl NaO P : m/z

2CHCH OAc), 77.8 (2C, SCHCHCHOAc), 75.9 (2C, SCHCHOAc),

74.2 (2C, SCHCHOAc), 69.0 (2C, 2CHCHCH OAc), 63.2 (2C,

54

60

2

11

2

+

1

433.2217 ([M + Na] ). Found: m/z 1433.2239.

Compound 8c. According to the general procedure, AuCl(tht)

0.318 g, 0.995 mmol, 1 equiv), PPh (0.260 g, 0.991 mmol, 1 equiv),

and CH Cl (25 mL) were stirred for 4 h at RT. The product was

isolated as a white solid. Yield: 0.471 g, 0.952 mmol, 96%. Elem anal.

Calcd for C H AuClP: C, 43.70; H, 3.06. Found: C, 44.02; H, 2.74.

2

2(Ar)(CO)O(CH ) O), 62.9 (2C, 2CHCH (CO)CH ), 21.2

2

3

(

(2C, 2CH O(CO)CH ), 20.82 (2C, 2(CO)CH ), 20.77 (2C,

3

2

3

2(CO)CH ), 20.72 (2C, 2(CO)CH ). ESI-MS(+). Calcd for

2

3

+

C H Au NaO P S : m/z 1781.2499 ([M + Na] ). Found: m/z

68 70 2 22 2 2

+

1781.2609. Calcd for C H Au O P S : m/z 1395.1851 ([M −

18

15

54 51

2

13 2

1

− +

H NMR (CDCl ): δ 7.42−7.58 (15H, m, 6P(Ar)CCHCHCH,

RS ] ). Found: m/z 1395.2070. UV−vis: λ = 250 nm.

3

H

max

31

6

P(Ar)CCHCHCH, 3P(Ar)CCHCHCH). P NMR (CDCl ): δ

Compound 2d. According to the general procedure, β-D-

3

P

3

3.19 (1P). ¹³C NMR (CDCl ): δ 134.2 (6C, d, 6P(Ar)CCHCHCH,

thioglucosetetraacetate (0.107 g, 0.294 mmol, 2 equiv), K CO

2 3

3

C

2

4

J_C_,_P= 14 Hz), 132.1 (3C, d, 3P(Ar)CCHCHCH, J = 3 Hz), 129.3

6C, d, 6P(Ar)CCHCHCH, J = 12 Hz), 128.8 (3C, d, 3P(Ar)

CCHCHCH, J = 62 Hz). ESI-MS(+). Calcd for C H AuClNaP :

m/z 517.0163 ([M + Na] ). Found: m/z 517.0163.

Compound 9c. According to the general procedure, AuCl(tht)

0.590 g, 1.846 mmol, 1 equiv), 4-(diphenylphosphanyl)benzoic acid

0.564 g, 1.841 mmol, 1 equiv), and CH Cl (25 mL) were stirred for

h at RT. The product was isolated as a white solid. Yield: 0.962 g,

.786 mmol, 97%. Elem anal. Calcd for C H AuClO P: C, 42.36; H,

(0.082 g, 0.593 mmol, 4 equiv), and 2c (0.170 g, 0.148 mmol, 1

equiv) in acetone (25 mL) were stirred for 48 h at RT in the dark. The

product was isolated as a white solid. Yield: 0.223 g, 0.123 mmol, 84%.

C,P

3

(

C,P

1

+

C,P

18 15

+

Elem anal. Calcd for C70H74Au O P S : C, 46.62; H, 4.14. Found: C,

2 23 2 2

1

46.74; H, 4.10. H NMR (CDCl

): δ

8.08−8.12 (4H, m, 4O(C

3

H

3

4

(

6

1

2

O)(Ar)CCHCHCP, JH,H = 8.5 Hz, JH,H = 2 Hz), 7.47−7.65 (24H, m,

4O(CO)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)-

2

CCHCHCH, 4P(Ar)CCHCHCH), 5.13−5.17 (4H, m, SCHCHOAc,

3

SCHCHCHOAc), 5.08 (2H, t, CHCHCH

OAc, JH,H = 9.2 Hz), 5.04

19

15

2

1

3

.81. Found: C, 42.60; H, 2.59. H NMR (CDCl ): δ 8.05−8.19 (2H,

(2H, t, SCHCHOAc, JH,H = 9.2 Hz), 4.48−4.50 (4H, m, 2Ar(C

CH O), 4.21 (2H, dd, CH OAc, JH,H = 12.2 Hz, JH,H = 4.8

2 2 2

3

H

3

4

2

3

m, 2O(CO)(Ar)CCHCHCP, J = 8.4 Hz, J = 2.1 Hz), 7.47−

O)OCH

Hz), 4.09 (2H, dd, CH OAc, JH,H = 12.2 Hz, JH,H = 2.4 Hz), 3.84−

H,H

2

3

7

4

3

.64 (12H, m, 2O(CO)(Ar)CCHCHCP, 4P(Ar)CCHCHCH,

2

31

P(Ar)CCHCHCH, 2P(Ar)CCHCHCH). P NMR (CDCl ): δ

3.87 (4H, m, 2Ar(CO)OCH

2

CH

2

O), 3.75 (2H, ddd, CHCH

H,H = 2.4 Hz), 2.04 (6H, s,

2

OAc,

3

P

3.21 (1P). ¹³C NMR (CDCl ): δ 170.5 (1C, O(CO)(Ar)-

3

H,H = 9.7 Hz, ³

3

J

H,H = 4.8 Hz,

J

3

C

1

CCHCHCP), 135.8 (1C, d, O(CO)(Ar)CCHCHCP, J = 58

2CH

2

O(CO)CH

3

), 2.00 (6H, s, 2(CO)CH

3

), 1.96 (6H, s,

): δ

), 170.4

C,P

2

31

Hz), 134.4 (4C, d, 2P(Ar)CCHCHCH, J = 14 Hz), 134.1 (2C, d,

2(CO)CH

3

), 1.89 (6H, s, 2(CO)CH

3

). P NMR (CDCl

3

P

C,P

2

13

2

O(CO)(Ar)CCHCHCP, J = 14 Hz), 132.4 (2C, m, O(C

38.77 (2P). C NMR (CDCl

3

): δ

C

170.9 (2C, 2(CO)CH

3

C,P

O)(Ar)CCHCHCP, 2P(Ar)CCHCHCH), 130.6 (2C, d, 2O(C

(2C, 2(CO)CH

3

), 169.8 (2C, 2(CO)CH

3

), 169.7 (2C, 2(C

3

O)(Ar)CCHCHCP, J = 12 Hz), 129.6 (4C, d, 4P(Ar)CCHCHCH,

O)CH

3

), 165.6 (2C, 2O(CO)(Ar)CCHCHCP), 135.6 (2C, d,

C,P

3

1

J_C_,_P= 12 Hz), 128.1 (2C, d, 2P(Ar)CCHCHCH, J_C_,_P= 61 Hz).

2O(CO)(Ar)CCHCHCP, JC,P = 54 Hz), 134.6 (4C, d, 4P(Ar)-

2

Calcd for C H AuClO P: m/z 538.0164. ESI-MS(−). Found: m/z

CCHCHCH, JC,P = 14 Hz), 134.5 (4C, d, 4P(Ar)CCHCHCH, JC,P

=

19

15

2

−

2

5

37.0193 ([M − H] ). Found: m/z 1074.8335 ([2M − H] ).

14 Hz), 134.2 (4C, d, 4O(CO)(Ar)CCHCHCP, JC,P = 14 Hz),

4

General Procedure for the Synthesis of the Digold Complexes

132.9 (2C, d, 2O(CO)(Ar)CCHCHCP, JC,P = 2 Hz), 132.1 (4C, d,

4

1

d−7d. The appropriate digold intermediate 1c−7c (1 equiv) was

4P(Ar)CCHCHCH, J = 2 Hz), 130.1 (4C, d, 4O(CO)(Ar)-

C,P

3

added to a suspension of β-D-thioglucosetetraacetate (2 equiv) and

CCHCHCP, J = 12 Hz), 129.5 (8C, d, 8P(Ar)CCHCHCH, J

=

C,P

1

K CO (4 equiv) in degassed acetone under N . The reaction mixture

12 Hz), 129.0 (4C, d, 4P(Ar)CCHCHCH, J = 57 Hz), 83.3 (2C,

2

3

2

C,P

was stirred under N at RT for 48 h in the dark, and the reaction

2CHCH OAc), 77.8 (2C, SCHCHCHOAc), 75.9 (2C, SCHCHOAc),

2

1

31

evolution was veriﬁed by H and P NMR (CDCl ). The reaction

74.3 (2C, SCHCHOAc), 69.2 (2C, 2CHCHCH OAc), 69.1 (2C,

3

2

mixture was concentrated under reduced pressure, the crude was

2(Ar)(CO)OCH CH O), 64.6 (2C, 2(Ar)(CO)OCH CH O),

2

resuspended in CH Cl and ﬁltered under vacuum. The ﬁltrate was

63.0 (2C, 2CHCH (CO)CH ), 21.3 (2C, 2CH O(CO)CH ),

2

3

2

3

concentrated under reduced pressure and further dried under high

20.86 (2C, 2(CO)CH ), 20.82 (2C, 2(CO)CH ), 20.77 (2C,

3

+

vacuum. The product was isolated as a white solid and stored at −20

2(CO)CH ). ESI-MS(+). Calcd for C H Au NaO P S : m/z

3 70 74 2 23 2 2

+

°

C in the dark.

1825.2761 ([M + Na] ). Found: m/z 1825.2839. Calcd for

+

− +

Compound 1d. According to the general procedure, β-D-

C H Au O P S : m/z 1439.2113 ([M − RS ] ). Found: m/z

56

55

2

14 2

thioglucosetetraacetate (0.026 g, 0.071 mmol, 2 equiv), K CO₃

1439.2242. UV−vis: λ = 250 nm.

2

max

(

0.050 g, 0.362 mmol, 4 equiv), and 1c (0.100 g, 0.091 mmol, 1

Compound 3d. According to the general procedure, β-D-

equiv) in acetone (25 mL) were stirred for 48 h at RT in the dark. The

product was isolated as a white solid. Yield: 0.145 g, 0.0824 mmol,

thioglucosetetraacetate (0.107 g, 0.294 mmol, 2 equiv), K CO

2

3

(0.081 g, 0.586 mmol, 4 equiv), and 3c (0.175 g, 0.147 mmol, 1

equiv) in acetone (25 mL) were stirred for 48 h at RT in the dark. The

product was isolated as a white solid. Yield: 0.258 g, 0.140 mmol, 95%.

Elem anal. Calcd for C H Au O P S : C, 46.81; H, 4.26. Found: C,

9

0%. Elem anal. Calcd for C H Au O P S : C, 46.42; H, 4.01.

68 70 2 22 2 2

1

Found: C, 46.37; H, 3.92. H NMR (CDCl ): δ 8.09−8.12 (4H, m,

3

H

3

4

7

8

O(CO)(Ar)CCHCHCP, J

= 8.6 Hz, J

= 2.0 Hz), 7.46−

H,H

72 78

2

24 2 2

1

.63 (24H, m, 4O(CO)(Ar)CCHCHCP, 8P(Ar)CCHCHCH,

47.02; H, 3.98. H NMR (CDCl ): δ 8.09−8.12 (4H, m, 4O(C

3

H

3

4

P(Ar)CCHCHCH, 4P(Ar)CCHCHCH), 5.12−5.17 (4H, m,

O)(Ar)CCHCHCP, J = 8.5 Hz, J = 2.0 Hz), 7.47−7.67 (24H,

H,H H,H

3

SCHCHOAc, SCHCHCHOAc), 5.05 (2H, t, CHCHCH OAc, J

m, 4O(CO)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)-

2

H,H

3

=

9.7 Hz), 5.03 (2H, t, SCHCHOAc, J

= 9.2 Hz), 4.67 (4H, s,

H,H

CCHCHCH, 4P(Ar)CCHCHCH), 5.11−5.18 (4H, m, SCHCHOAc,

L

DOI: 10.1021/acs.inorgchem.7b01082

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

3

SCHCHCHOAc), 5.07 (2H, t, CHCHCH OAc, J = 9.1 Hz), 5.04

equiv) in acetone (25 mL) were stirred for 48 h at RT in the dark. The

product was isolated as a white solid. Yield: 0.253 g, 0.131 mmol, 96%.

Elem anal. Calcd for C H Au O P S : C, 47.16; H, 4.48. Found: C,

2

H,H

3

(

2H, t, SCHCHOAc, J

= 9.2 Hz), 4.46−4.48 (4H, m, 2Ar(C

H,H

2

3

O)OCH CH O), 4.22 (2H, dd, CH OAc, J = 12.2 Hz, J = 4.8

2

2 H,H H,H

76 86

2

26 2 2

2

3

1

Hz), 4.10 (2H, dd, CH OAc, J = 12.2 Hz, J = 2.4 Hz), 3.80−

47.30; H, 4.20. H NMR (CDCl ): δ 8.09−8.13 (4H, m, 4O(C

2

H,H

3

H

3

4

3

J

.83 (4H, m, 2Ar(CO)OCH CH O), 3.76 (2H, ddd, CHCH OAc,

O)(Ar)CCHCHCP, J = 8.5 Hz, J = 2.0 Hz), 7.46−7.64 (24H,

2

H,H H,H

3

= 9.8 Hz, J = 4.8 Hz, J = 2.4 Hz), 3.69 (4H, s, 2Ar(C

m, 4O(CO)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)-

H,H

O)O(CH ) OCH ), 2.05 (6H, s, 2CH O(CO)CH ), 2.01 (6H, s,

CCHCHCH, 4P(Ar)CCHCHCH), 5.11−5.17 (4H, m, SCHCHOAc,

2

3

2

(CO)CH ), 1.97 (6H, s, 2(CO)CH ), 1.90 (6H, s, 2(C

O)CH ). P NMR (CDCl ): δ 38.79 (2P). C NMR (CDCl ): δ

C

SCHCHCHOAc), 5.08 (2H, t, CHCHCH

2

OAc, JH,H = 9.6 Hz), 5.04

3

31

13

3

(2H, t, SCHCHOAc, JH,H = 9.2 Hz), 4.46−4.48 (4H, m, 2Ar(C

CH O), 4.21 (2H, dd, CH OAc, JH,H = 12.2 Hz, JH,H = 4.7

2 2 2

3

P

3

2

3

1

70.9 (2C, 2(CO)CH ), 170.4 (2C, 2(CO)CH ), 169.8 (2C,

O)OCH

Hz), 4.10 (2H, dd, CH

3.82 (4H, m, 2Ar(CO)OCH

3

2

3

2

(CO)CH ), 169.7 (2C, 2(CO)CH ), 165.6 (2C, 2O(C

2

OAc, JH,H = 12.2 Hz, JH,H = 2.3 Hz), 3.79−

CH O), 3.75 (2H, ddd, CHCH OAc,

H,H = 10.0 Hz, JH,H = 4.7 Hz, JH,H = 2.3 Hz), 3.66−3.68 (4H, m,

2Ar(CO)O(CH ) OCH CH ), 3.60−3.63 (4H, m, 2Ar(CO)O-

3

1

O)(Ar)CCHCHCP), 135.6 (2C, d, 2O(CO)(Ar)CCHCHCP, J

2

C,P

2

3

=

(

53 Hz), 134.6 (4C, d, 4P(Ar)CCHCHCH, J = 14 Hz), 134.5

J

C,P

2

4C, d, 4P(Ar)CCHCHCH, J = 14 Hz), 134.2 (4C, d, 4O(C

C,P

2

O)(Ar)CCHCHCP, J = 14 Hz), 133.0 (2C, d, 2O(CO)(Ar)

(CH ) OCH CH ), 3.62 (4H, s, 2Ar(CO)O(CH ) O-

C,P

2

2 2

4

CCHCHCP, J = 2 Hz), 132.1 (4C, m, 4P(Ar)CCHCHCH), 130.1

(CH ) OCH ), 2.04 (6H, s, 2CH O(CO)CH ), 2.00 (6H, s,

C,P

2 2 2 2 3

3

(

4C, d, 4O(CO)(Ar)CCHCHCP, J = 12 Hz), 129.5 (8C, d,

2(CO)CH ), 1.96 (6H, s, 2(CO)CH ), 1.89 (6H, s, 2(C

O)CH ). P NMR (CDCl ): δ 38.73 (2P). C NMR (CDCl ): δ

3 3 P 3 C

C,P

3

31

13

8

P(Ar)CCHCHCH, J = 12 Hz), 129.0 (4C, d, 4P(Ar)CCHCHCH,

C,P

1

J_C_,_P= 57 Hz), 83.3 (2C, 2CHCH OAc), 77.8 (2C, SCHCHCHOAc),

170.8 (2C, 2(CO)CH ), 170.4 (2C, 2(CO)CH ), 169.74 (2C,

2

3

7

5.9 (2C, SCHCHOAc), 74.3 (2C, SCHCHOAc), 70.8 (2C,

(Ar)(CO)O(CH ) OCH ), 69.3 (2C, 2(Ar)(CO)-

2(CO)CH

3

), 169.67 (2C, 2(CO)CH

3

), 165.6 (2C, 2O(C

1

2

O)(Ar)CCHCHCP), 135.4 (2C, d, 2O(CO)(Ar)CCHCHCP, JC,P

2

OCH CH O), 69.1 (2C, 2CHCHCH OAc), 64.6 (2C, 2(Ar)(C

= 54 Hz), 134.5 (4C, d, 4P(Ar)CCHCHCH, JC,P = 14 Hz), 134.4

2

O)OCH CH O), 63.0 (2C, 2CHCH (CO)CH ), 21.3 (2C,

(4C, d, 4P(Ar)CCHCHCH, JC,P = 14 Hz), 134.1 (4C, d, 4O(C

2

3

2

CH O(CO)CH ), 20.87 (2C, 2(CO)CH ), 20.84 (2C, 2(C

O)(Ar)CCHCHCP, JC,P = 14 Hz), 133.0 (2C, d, 2O(CO)(Ar)

2

3

4

O)CH ), 20.79 (2C, 2(CO)CH ). ESI-MS(+). Calcd for

CCHCHCP, JC,P = 3 Hz), 132.1 (4C, d, 4P(Ar)CCHCHCH, JC,P = 3

3

+

3

C H Au NaO P S : m/z 1869.3023 ([M + Na] ). Found: m/z

Hz), 130.1 (4C, d, 4O(CO)(Ar)CCHCHCP, JC,P = 12 Hz), 129.4

7

2

78

2

24 2 2

+

3

1

869.3127. Calcd for C H Au O P S : m/z 1483.2375 ([M −

(8C, d, 8P(Ar)CCHCHCH, JC,P = 12 Hz), 129.0 (4C, d, 4P(Ar)

58

59

2

15 2

−

+

1

RS ] ). Found: m/z 1483.2581. UV−vis: λ = 250 nm.

CCHCHCH, JC,P = 57 Hz), 83.2 (2C, 2CHCH

2

OAc), 77.8 (2C,

max

Compound 4d. According to the general procedure, β-D-

SCHCHCHOAc), 75.9 (2C, SCHCHOAc), 74.3 (2C, SCHCHOAc),

70.72, 70.74 (6C, 2(Ar)(CO)O(CH OCH , 2(Ar)(CO)O-

(CH OCH CH O(CH OCH ), 69.2

O), 69.1 (2C, 2CHCHCH OAc), 64.7

O), 63.0 (2C, 2CHCH ),

(CO)CH

), 20.84 (2C, 2(CO)CH ), 20.80

). ESI-MS(+). Calcd

thioglucosetetraacetate (0.103 g, 0.283 mmol, 2 equiv), K CO₃

0.079 g, 0.572 mmol, 4 equiv), and 4c (0.175 g, 1 equiv) in acetone

25 mL) were stirred for 48 h at RT in the dark. The product was

isolated as a white solid. Yield: 0.233 g, 0.123 mmol, 87%. Elem anal.

Calcd for C H Au O P S : C, 46.99; H, 4.37. Found: C, 47.02; H,

2

)

2

)

2

(

2

)

2

, 2(Ar)(CO)O(CH

2

)

2

(2C, 2(Ar)(CO)OCH

CH

2

(2C, 2(Ar)(CO)OCH

2

3

21.2 (2C, 2CH

O(CO)CH

7

4

82

2

25 2 2

2

3

1

4

.29. H NMR (CDCl ): δ 8.09−8.13 (4H, m, 4O(CO)(Ar)-

(2C, 2(CO)CH

for C76

1957.3685. Calcd for C62H67Au O P S : m/z 1571.2900 ([M −

2 17 2

3

), 20.75 (2C, 2(CO)CH

H86Au NaO26P S : m/z 1957.3547 ([M + Na] ). Found: m/z

2 2 2

3

H

3

4

+

CCHCHCP, J

= 8.5 Hz, J

= 2.0 Hz), 7.46−7.64 (24H, m,

H,H

+

4

O(CO)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)-

−

+

CCHCHCH, 4P(Ar)CCHCHCH), 5.13−5.18 (4H, m, SCHCHOAc,

RS ] ). Found: m/z 1571.3116. UV−vis: λmax = 250 nm.

3

SCHCHCHOAc), 5.09 (2H, t, CHCHCH OAc, J = 9.6 Hz), 5.04

Compound 6d. β-D-Thioglucosetetraacetate (0.128 g, 0.351 mmol,

2

H,H

3

(

2H, t, SCHCHOAc, J

= 9.2 Hz), 4.46−4.48 (4H, m, 2Ar(C

2 equiv), K

0.175 mmol, 1 equiv) in a mixture of H

2

CO

3

(0.053 g, 0.383 mmol, 2.2 equiv), and 6c (0.232 g,

O/EtOH/CH Cl [30 mL,

H,H

2

3

O)OCH CH O), 4.21 (2H, dd, CH OAc, J = 12.3 Hz, J = 4.8

2

H,H

2

3

Hz), 4.10 (2H, dd, CH OAc, J = 12.3 Hz, J = 2.3 Hz), 3.79−

1:1:1 (v/v/v)] were stirred for 72 h at RT in the dark. The reaction

mixture was concentrated to dryness, and the crude was suspended in

a mixture of acetone/CH Cl [30 mL, 1:1 (v/v)]. The inorganic salts

2 2

2

H,H

3

J

.81 (4H, m, 2Ar(CO)OCH CH O), 3.75 (2H, ddd, CHCH OAc,

2

3

= 9.8 Hz, J

= 4.8 Hz, J

= 2.3 Hz), 3.63−3.70 (8H, m,

H,H

were removed by ﬁltration, and the ﬁltrate was concentrated under

reduced pressure and further dried under vacuum to aﬀord the product

as a white solid. Yield: 0.323 g, 0.163 mmol, 94%. Elem anal. Calcd for

2

Ar(CO)O(CH ) O(CH ) ), 2.04 (6H, s, 2CH O(CO)CH ),

2

3

.01 (6H, s, 2(CO)CH ), 1.97 (6H, s, 2(CO)CH ), 1.90 (6H, s,

3

1

13

(CO)CH ). P NMR (CDCl ): δ 38.71 (2P). C NMR

3

P

1

C H Au O P S : C, 47.33; H, 4.58. Found: C, 47.43; H, 4.55. H

(

CDCl ): δ 170.9 (2C, 2(CO)CH ), 170.4 (2C, 2(CO)CH ),

78 90

2

27 2 2

3

C

3

NMR (CDCl ): δ 8.10−8.13 (4H, m, 4O(CO)(Ar)CCHCHCP,

1

69.8 (2C, 2(CO)CH ), 169.7 (2C, 2(CO)CH ), 165.6 (2C,

3

H

J

3

4

^JH,H = 8.4 Hz,

= 2.0 Hz), 7.45−7.63 (24H, m, 4O(C

2

O(CO)(Ar)CCHCHCP), 135.5 (2C, d, 2O(CO)(Ar)-

H,H

1

2

CCHCHCP, J = 54 Hz), 134.5 (4C, d, 4P(Ar)CCHCHCH, J

O)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)CCHCHCH, 4P-

(Ar)CCHCHCH), 5.11−5.17 (4H, m, SCHCHOAc,

C,P

2

=

(

2

14 Hz), 134.4 (4C, d, 4P(Ar)CCHCHCH, J = 14 Hz), 134.1

C,P

2

OAc, ³

4C, d, 4O(CO)(Ar)CCHCHCP, J = 14 Hz), 133.0 (2C, d,

SCHCHCHOAc), 5.08 (2H, t, CHCHCH

2

J

H,H = 9.6 Hz),

C,P

4

5.04 (2H, t, SCHCHOAc, ³

O(CO)(Ar)CCHCHCP, J = 2 Hz), 132.1 (4C, m, 4P(Ar)-

JH,H = 9.1 Hz), 4.46−4.49 (4H, m,

C,P

3

2

CCHCHCH), 130.1 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 12

2Ar(CO)OCH

CH O), 4.20 (2H, dd, CH OAc, JH,H = 12.2 Hz,

2 2 2

C,P

3

2

3

Hz), 129.5 (8C, d, 8P(Ar)CCHCHCH, J = 12 Hz), 129.0 (4C, d,

J

H,H = 4.8 Hz), 4.10 (2H, dd, CH

2

OAc, JH,H = 12.2 Hz, JH,H = 2.4

C,P

1

4

P(Ar)CCHCHCH, J_C_,_P= 57 Hz), 83.3 (2C, 2CHCH OAc), 77.8

2C, SCHCHCHOAc), 75.9 (2C, SCHCHOAc), 74.3 (2C,

Hz), 3.80−3.82 (4H, m, 2Ar(CO)OCH CH O), 3.76 (2H, ddd,

2

3

(

CHCH OAc, J = 9.8 Hz, J = 4.8 Hz, J = 2.8 Hz), 3.66−

2 H,H H,H H,H

SCHCHOAc), 70.80, 70.78 (4C, 2(Ar)(CO)O(CH ) OCH ,

3.68 (4H, m, 2Ar(CO)O(CH ) OCH CH ), 3.62−3.64 (4H, m,

2

(Ar)(CO)O(CH ) OCH CH ), 69.2 (2C, 2(Ar)(CO)-

2Ar(CO)O(CH ) OCH CH ), 3.60−3.63 (8H, m, 2Ar(CO)O-

2

OCH CH O), 69.1 (2C, 2CHCHCH OAc), 64.7 (2C, 2(Ar)(C

(CH ) O(CH ) O(CH ) ), 2.04 (6H, s, 2CH O(CO)CH ), 2.00

2

2 2 2 2 2 2 2 3

O)OCH CH O), 63.0 (2C, 2CHCH (CO)CH ), 21.3 (2C,

(6H, s, 2(CO)CH ), 1.96 (6H, s, 2(CO)CH ), 1.89 (6H, s,

3 3 P

2

3

1

13

2

CH O(CO)CH ), 20.86 (2C, 2(CO)CH ), 20.82 (2C, 2(C

2(CO)CH ). P NMR (CDCl ): δ 38.78 (2P). C NMR

2

3

O)CH ), 20.77 (2C, 2(CO)CH ). ESI-MS(+). Calcd for

(CDCl ): δ 170.8 (2C, 2(CO)CH ), 170.4 (2C, 2(CO)CH ),

3

3 C 3 3

+

C H Au NaO P S : m/z 1913.3285 ([M + Na] ). Found: m/z

169.7 (2C, 2(CO)CH ), 169.6 (2C, 2(CO)CH ), 165.6 (2C,

7

4

82

2

25

2

3

+

1

913.3390. Calcd for C H Au O P S : m/z 1527.2638 ([M −

2O(CO)(Ar)CCHCHCP), 135.5 (2C, d, 2O(CO)(Ar)-

CCHCHCP, J = 53 Hz), 134.5 (4C, d, 4P(Ar)CCHCHCH, J

C,P C,P

60

63

2

16 2

−

+

1

2

RS ] ). Found: m/z 1527.2816. UV−vis: λ = 250 nm.

max

2

Compound 5d. According to the general procedure, β-D-

= 14 Hz), 134.4 (4C, d, 4P(Ar)CCHCHCH, J = 14 Hz), 134.2

C,P

2

thioglucosetetraacetate (0.100 g, 0.274 mmol, 2 equiv), K CO₃

0.076 g, 0.550 mmol, 4 equiv), and 5c (0.175 g, 0.137 mmol, 1

(4C, d, 4O(CO)(Ar)CCHCHCP, J = 14 Hz), 133.0 (2C, d,

2

C,P

4

(

2O(CO)(Ar)CCHCHCP, J = 2 Hz), 132.1 (4C, m, 4P(Ar)-

C,P

M

DOI: 10.1021/acs.inorgchem.7b01082

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

3

2

3

CCHCHCH), 130.1 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 11

Hz), 4.19 (1H, dd, CH OAc, J = 12.2 Hz, J = 4.8 Hz), 4.09

2 H,H H,H

C,P

3

2

3

Hz), 129.4 (8C, d, 8P(Ar)CCHCHCH, J = 12 Hz), 129.0 (4C, d,

P(Ar)CCHCHCH, J_C_,_P= 56 Hz), 83.2 (2C, 2CHCH OAc), 77.8

(1H, dd, CH OAc, J = 12.2 Hz, J = 2.4 Hz), 3.74 (1H, ddd,

C,P

2 H,H H,H

1

3

4

CHCH OAc, J = 9.7 Hz, J = 4.8 Hz, J = 2.4 Hz), 2.02 (3H,

2 H,H H,H H,H

2

(

2C, SCHCHCHOAc), 75.9 (2C, SCHCHOAc), 74.3 (2C,

s, CH O(CO)CH ), 1.99 (3H, s, (CO)CH ), 1.95 (3H, s, (C

2

3

31

SCHCHOAc), 70.72, 70.70, 70.63 (8C, 2(Ar)(CO)O(CH ) OCH ,

O)CH ), 1.87 (3H, s, (CO)CH ). P NMR (CDCl ): δ 38.83

2

3 3 3 P

(1P). ¹C NMR (CDCl ): δ 170.9 (1C, (CO)CH ), 170.4 (1C,

3

2

(Ar)(CO)O(CH ) OCH CH , 2(Ar)(CO)O(CH ) O-

2

3

C

3

(

2

CH ) OCH , 2(Ar)(CO)O(CH ) O(CH ) OCH CH ), 69.2

(CO)CH ), 169.7 (1C, (CO)CH ), 169.7 (1C, (CO)CH ),

2 2 2 2 2 2 2 2 2

3

2

2C, 2(Ar)(CO)OCH CH O), 69.1 (2C, 2CHCHCH OAc), 64.6

134.4 (6C, d, 6P(Ar)CCHCHCH, J = 14 Hz), 131.7 (3C, d,

3P(Ar)CCHCHCH, J = 2 Hz), 129.8 (3C, d, 3P(Ar)CCHCHCH,

J_C_,_P= 57 Hz), 129.3 (6C, d, 6P(Ar)CCHCHCH, J = 11 Hz), 83.2

2

C,P

4

2C, 2(Ar)(CO)OCH CH O), 62.9 (2C, 2CHCH (CO)CH ),

2

3

C,P

1

3

1.2 (2C, 2CH O(CO)CH ), 20.80 (2C, 2(CO)CH ), 20.77

2

3

C,P

(

2C, 2(CO)CH ), 20.72 (2C, 2(CO)CH ). ESI-MS(+). Calcd

(1C, CHCH OAc), 77.8 (1C, SCHCHCHOAc), 75.8 (1C,

3

2

+

for C H Au NaO P S : m/z 2001.3809 ([M + Na] ). Found: m/z

SCHCHOAc), 74.3 (1C, SCHCHOAc), 69.1 (1C, CHCHCH OAc),

7

8

90

2

27

2

+

2

001.3790. Calcd for C H Au O P S : m/z 1615.3162 ([M −

63.0 (1C, CHCH (CO)CH ), 21.2 (1C, CH O(CO)CH ), 20.80

6

4

71

2

18

2

3

2

3

−

+

RS ] ). Found: m/z 1615.3180. UV−vis: λ = 250 nm.

(2C, 2(CO)CH ), 20.75 (1C, (CO)CH ). ESI-MS(+). Calcd for

max

3

+

Compound 7d. β-D-Thioglucosetetraacetate (0.130 g, 0.357 mmol,

C H AuO PS: m/z 822.1327 ([M + H] ). Found: m/z 823.1407.

32 34 9

+

2

0

1

equiv), K CO (0.054 g, 0.391 mmol, 2.2 equiv), and 7c (0.252 g,

Calcd for C H AuNaO PS : m/z 845.1224 ([M + Na] ). Found: m/

2

3

32 34 9

.178 mmol, 1 equiv) in a mixture of H O/EtOH/CH Cl [30 mL,

z 845.1239.

2

:1:1 (v/v/v)] were stirred for 72 h at RT in the dark. The reaction

Compound 9d. According to the general procedure, β-D-

mixture was concentrated to dryness, and the crude was suspended in

thioglucosetetraacetate (0.304 g, 0.834 mmol, 1 equiv), K CO

2

3

a mixture of acetone/CH Cl [30 mL, 1:1 (v/v)]. The inorganic salts

(0.231 g, 1.671 mmol, 2 equiv), and 9c (0.450 g, 0.835 mmol, 1

equiv) in acetone (35 mL) were stirred for 48 h at RT in the dark. The

product was isolated as a white solid. Yield: 0.687 g, 0.793 mmol, 95%.

Elem anal. Calcd for C H AuO PS·CDCl : C, 40.56; H, 3.70.

2

were removed by ﬁltration, and the ﬁltrate was concentrated under

reduced pressure and further dried under vacuum to aﬀord the product

as a white solid. Yield: 0.317 g, 0.153 mmol, 86%. Elem anal. Calcd for

3

34

11

3

1

C H Au O P S : C, 47.63; H, 4.78. Found: C, 47.85; H, 4.60. H

Found: C, 39.96; H, 3.57. CDCl originates from the NMR solvent. H

8

2

98

2

29

2

3

NMR (CDCl ): δ 8.10−8.13 (4H, m, 4O(CO)(Ar)CCHCHCP,

NMR (CDCl ): δ 7.81−7.90 (2H, m, 2O(CO)(Ar)CCHCHCP),

3

H

J

3

H

3

4

J_H_,_H= 8.4 Hz,

= 2.0 Hz), 7.47−7.64 (24H, m, 4O(C

7.30−7.48 (12H, m, 2O(CO)(Ar)CCHCHCP, 4P(Ar)-

CCHCHCH, 4P(Ar)CCHCHCH, 2P(Ar)CCHCHCH), 5.06−5.13

(2H, m, SCHCHOAc, SCHCHCHOAc), 4.99 (1H, t,

H,H

O)(Ar)CCHCHCP, 8P(Ar)CCHCHCH, 8P(Ar)CCHCHCH, 4P-

Ar)CCHCHCH), 5.11−5.18 (4H, m, ₃SCHCHOAc,

SCHCHCHOAc), 5.09 (2H, t, CHCHCH OAc, J = 9.6 Hz),

(

3

2

H,H

CHCHCH OAc, J = 9.2 Hz), 4.97 (1H, t, SCHCHOAc, J =

2

H,H

.04 (2H, t, SCHCHOAc, ³J_H_,_H= 9.1 Hz), 4.47−4.49 (4H, m,

2

3

5

9.3 Hz), 4.07 (1H, dd, CH OAc, J = 12.1 Hz, J = 5.1 Hz), 4.02

2 H,H H,H

2

Ar(CO)OCH CH O), 4.21 (2H, dd, CH OAc, J

= 12.2 Hz,

(1H, d, CH OAc, J = 12.1 Hz), 3.68 (1H, m, CHCH OAc), 2.16

2 H,H 2

2

H,H

3

2

3

J

= 4.8 Hz), 4.10 (2H, dd, CH OAc, J = 12.2 Hz, J = 2.4

(6H, s, 2CH O(CO)CH ), 2.00 (3H, s, (CO)CH ), 1.91 (3H, s,

): δ

3 3 3 P

H,H

2

H,H

2

3

31

Hz), 3.80−3.83 (4H, m, 2Ar(CO)OCH CH O), 3.76 (2H, ddd,

(CO)CH

), 1.90 (3H, s, (CO)CH

). P NMR (CDCl

2

3

13

CHCH OAc, J = 9.8 Hz, J = 4.8 Hz, J = 2.4 Hz), 3.66−

38.82 (1P). C NMR (CDCl

3

): δ

C

171.8 (1C, (CO)CH ), 171.4

3

2

H,H

3

2

.69 (4H, m, 2Ar(CO)O(CH ) OCH CH ), 3.62−3.65 (4H, m,

(1C, (CO)CH

3

), 170.2 (1C, (CO)CH

3

), 170.1 (1C, (C

2

Ar(CO)O(CH ) OCH CH ), 3.59−3.62 (8H, m, 2Ar(CO)O-

O)CH

3

), 169.8 (1C, O(CO)(Ar)CCHCHCP), 141.7 (1C, m,

2

(

2

CH ) O(CH ) O(CH ) ), 2.04 (6H, s, 2CH O(CO)CH ), 2.00

O(CO)(Ar)CCHCHCP), 134.3 (2C, d, 2P(Ar)CCHCHCH, JC,P

=

2

3

2

6H, s, 2(CO)CH ), 1.97 (6H, s, 2(CO)CH ), 1.90 (6H, s,

15 Hz), 134.2 (2C, d, 2P(Ar)CCHCHCH, JC,P = 15 Hz), 133.7 (2C,

3

31

13

2

(CO)CH ). P NMR (CDCl ): δ 38.71 (2P). C NMR

d, 2O(CO)(Ar)CCHCHCP, JC,P = 14 Hz), 131.9 (3C, m, O(C

3

P

(

CDCl ): δ 170.8 (2C, 2(CO)CH ), 170.4 (2C, 2(CO)CH ),

O)(Ar)CCHCHCP, 2P(Ar)CCHCHCH), 129.9 (2C, m, 2P(Ar)

3

C

3

1

69.71 (2C, 2(CO)−CH ), 169.65 (2C, 2(CO)CH ), 165.6 (2C,

CCHCHCH), 129.7 (2C, d, 2O(CO)(Ar)CCHCHCP, JC,P = 11

3

2

O(CO)(Ar)CCHCHCP), 135.4 (2C, d, 2O(CO)(Ar)-

Hz), 129.4 (2C, d, 2P(Ar)CCHCHCH, JC,P = 11 Hz), 129.3 (2C, d,

1

2

3

CCHCHCP, J = 53 Hz), 134.5 (4C, d, 4P(Ar)CCHCHCH, J

2P(Ar)CCHCHCH, JC,P = 12 Hz), 83.2 (1C, CHCH

2

OAc), 77.5

C,P

2

=

14 Hz), 134.4 (4C, d, 4P(Ar)CCHCHCH, J = 14 Hz), 134.1

(1C, SCHCHCHOAc), 75.6 (1C, SCHCHOAc), 74.1 (1C,

SCHCHOAc), 69.3 (1C, CHCHCH OAc), 63.3 (1C, CHCH

(C

O)CH ), 21.2 (1C, CH ), 20.8 (2C, 2(CO)CH ),

O(CO)CH

20.7 (1C, (CO)CH ). ESI-MS(+). Calcd for C H AuO PS: m/z

C,P

2

(

4C, d, 4O(CO)(Ar)CCHCHCP, J = 14 Hz), 133.0 (2C, d,

2

C,P

4

2

O(CO)(Ar)CCHCHCP, J = 2 Hz), 132.1 (4C, m, 4P(Ar)-

3

2

3

C,P

3

CCHCHCH), 130.1 (4C, d, 4O(CO)(Ar)CCHCHCP, J = 12

C,P

3

33 34

11

3

+

Hz), 129.4 (8C, d, 8P(Ar)CCHCHCH, J = 12 Hz), 128.9 (4C, d,

866.1225 ([M + H] ). Found: m/z 867.1310. Calcd for

C H AuNaO PS : m/z 889.1123 ([M + Na] ). Found: m/z

889.1143. Calcd for C H AuKO PS : m/z 905.0862 ([M + K] ).

33 34 11

C,P

1

+

4

(

P(Ar)CCHCHCH, J_C_,_P= 57 Hz), 83.2 (2C, 2CHCH OAc), 77.9

2

33 34 11

+

2C, SCHCHCHOAc), 75.8 (2C, SCHCHOAc), 74.2 (2C,

SCHCHOAc), 70.70, 70.68, 70.61 (8C, 2(Ar)(CO)O(CH ) OCH ,

Found: m/z 905.0881.

Stability Studies. The stability of complexes 1b−7b and 1d−7d in

2

(Ar)(CO)O(CH ) OCH CH , 2(Ar)(CO)O(CH ) O-

2

2 2

6

1

31

(

2

CH ) OCH , 2(Ar)(CO)O(CH ) O(CH ) OCH CH ), 69.2

DMSO-d was assessed via H (400 MHz) and P (162 MHz) NMR

at 298 K for 20 min. The stability of complexes 2d, 4d, and 6d in

pseudocell culture conditions was assessed in aqueous 100 mM NaCl

and 5% DMSO for 72 h at 298 K and monitored via ESI-MS(+).

Cell Culture and in Vitro Antiproliferative Activity. The

human ovarian carcinoma (A2780 and A2780cisR) cell lines were

obtained from the European Collection of Cell Cultures. The human

embryonic kidney (HEK-293) cell line was obtained from ATCC

(Sigma, Buchs, Switzerland). Penicillin streptomycin, RPMI 1640

GlutaMAX (where RPMI = Roswell Park Memorial Institute), and

DMEM GlutaMAX media (where DMEM = Dulbecco’s modiﬁed

Eagle medium) were obtained from Life Technologies, and fetal

bovine serum (FBS) was obtained from Sigma. The cells were cultured

in RPMI 1640 GlutaMAX (A2780 and A2780cisR) and DMEM

GlutaMAX (HEK-293) media containing 10% heat-inactivated FBS

and 1% penicillin streptomycin at 37 °C and CO₂(5%).The

A2780cisR cell line was routinely treated with cisplatin (2 μM) in

the media. The cytotoxicity was determined using the 3-(4,5-dimethyl-

2 2 2 2 2 2 2 2 2

2C, 2(Ar)(CO)OCH CH O), 69.0 (2C, 2CHCHCH OAc), 64.6

2

2C, 2(Ar)(CO)OCH CH O), 62.9 (2C, 2CHCH (CO)CH ),

2

3

1.2 (2C, 2CH O(CO)CH ), 20.82 (2C, 2(CO)CH ), 20.78

2

3

(

2C, 2(CO)CH ), 20.73 (2C, 2(CO)CH ). ESI-MS(+). Calcd

3

+

for C H Au NaO P S : m/z 2089.4334 ([M + Na] ). Found: m/z

82 98 2 29 2 2

089.4307. Calcd for C H Au O P S : m/z 1703.3686 ([M −

+

2

6

8

79

2

20 2

− +

RS ] ). Found: m/z 1703.3684. UV−vis: λ = 250 nm.

max

Compound 8d. According to the general procedure, β-D-

thioglucosetetraacetate (0.258 g, 0.708 mmol, 1 equiv), K CO₃

2

(

0.196 g, 1.418 mmol, 2 equiv), and 8c (0.350 g, 0.707 mmol, 1

equiv) in acetone (25 mL) were stirred for 24 h at RT in the dark. The

product was isolated as a white solid. Yield: 0.548 g, 0.666 mmol, 89%.

Elem anal. Calcd for C H AuO PS: C, 46.72; H, 4.17. Found: C,

3

2

34

9

1

4

6

5

6.97; H, 3.85. H NMR (CDCl ): δ 7.42−7.59 (15H, m,

P(Ar)CCHCHCH, 6P(Ar)CCHCHCH, 3P(Ar)CCHCHCH),

.12−5.17 (2H, m, SCHCHOAc, SCHCHCHOAc), 5.08 (1H, t,

3

H

3

CHCHCH OAc J = 9.5 Hz), 5.03 (1H, t, SCHCHOAc, J = 9.3

2

H,H

N

DOI: 10.1021/acs.inorgchem.7b01082

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

8

3

2

-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay.

(4) Hartinger, C. G.; Zorbas-Seifried, S.; Jakupec, M. A.; Kynast, B.;

Zorbas, H.; Keppler, B. K. From bench to bedside-preclinical and early

clinical development of the anticancer agent indazolium trans-

[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A). J.

Inorg. Biochem. 2006, 100, 891.

(5) Hartinger, C. G.; Jakupec, M. A.; Zorbas-Seifried, S.; Groessl, M.;

Egger, A.; Berger, W.; Zorbas, H.; Dyson, P. J.; Keppler, B. K. KP1019,

A New Redox-Active Anticancer Agent − Preclinical Development and

Results of a Clinical Phase I Study in Tumor Patients. Chem.

Biodiversity 2008, 5, 2140.

Cells were seeded in ﬂat-bottomed 96-well plates as a suspension in

a prepared medium (100 μL aliquots and approximately 4300 cells/

well) and preincubated for 24 h. Stock solutions of compounds were

prepared in DMSO and were rapidly diluted in a medium. The

solutions were sequentially diluted to give a ﬁnal DMSO concentration

of 0.5% and a ﬁnal compound concentration range (0−500 μM).

Cisplatin was tested as a positive control (0−100 μM). The

compounds were added to the preincubated 96-well plates in 100

μL aliquots, and the plates were incubated for 72 h. MTT (20 μL, 5

mg/mL in Dulbecco’s phosphate buﬀered saline) was added to the

cells, and the plates were incubated for a further 4 h. The culture

medium was aspirated, and the purple formazan crystals, formed by

the mitochondrial dehydrogenase activity of vital cells, were dissolved

in DMSO (100 μL/well). The absorbance of the resulting solutions,

directly proportional to the number of surviving cells, was quantiﬁed at

(6) Lentz, F.; Drescher, A.; Lindauer, A.; Henke, M.; Hilger, R. A.;

Hartinger, C. G.; Scheulen, M. E.; Dittrich, C.; Keppler, B. K.; Jaehde,

U. Pharmacokinetics of a novel anticancer ruthenium complex

(

KP1019, FFC14A) in a phase I dose-escalation study. Anti-Cancer

Drugs 2009, 20, 97.

7) Trondl, R.; Heffeter, P.; Kowol, C. R.; Jakupec, M. A.; Berger, W.;

(

5

90 nm using a microplate reader. The percentage of surviving cells

Keppler, B. K. NKP-1339, the first ruthenium-based anticancer drug

on the edge to clinical application. Chem. Sci. 2014, 5, 2925.

was calculated from the absorbance of wells corresponding to the

untreated control cells. The reported IC₅₀values (Table 3) are based

on the means from three independent experiments, each comprising

four tests per concentration level.

(

8) Singh, A. K.; Pandey, D. S.; Xu, Q.; Braunstein, P. Recent

advances in supramolecular and biological aspects of arene ruthenium

II) complexes. Coord. Chem. Rev. 2014, 270-271, 31.

9) Ang, W. H.; Casini, A.; Sava, G.; Dyson, P. J. Organometallic

(

ASSOCIATED CONTENT

■

ruthenium-based antitumor compounds with novel modes of action. J.

Organomet. Chem. 2011, 696, 989.

*

S

Supporting Information

(10) Nazarov, A. A.; Hartinger, C. G.; Dyson, P. J. Opening the lid on

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.inorg-

chem.7b01082.

piano-stool complexes: An account of ruthenium(II)−arene complexes

with medicinal applications. J. Organomet. Chem. 2014, 751, 251.

(11) Murray, B. S.; Babak, M. V.; Hartinger, C. G.; Dyson, P. J. The

Crystal data and reﬁnement for 9b and 9c, partition

coeﬃcient data, NMR spectroscopy stability data for

development of RAPTA compounds for the treatment of tumors.

Coord. Chem. Rev. 2016, 306, 86.

1

b−7b and 1d−7d, ESI-MS(+) stability data of 2d, 4d,

́

(12) Habtemariam, A.; Melchart, M.; Fernandez, R.; Parsons, S.;

and 6d, and NMR spectra of all compounds (PDF)

Oswald, I. D. H.; Parkin, A.; Fabbiani, F. P. A.; Davidson, J. E.;

Dawson, A.; Aird, R. E.; Jodrell, D. I.; Sadler, P. J. Structure−Activity

Relationships for Cytotoxic Ruthenium(II) Arene Complexes

Containing N,N-, N,O-, and O,O-Chelating Ligands. J. Med. Chem.

2006, 49, 6858.

Accession Codes

CCDC 1542726 and 1542742 contain the supplementary

crystallographic data for this paper. These data can be obtained

free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by

emailing data_request@ccdc.cam.ac.uk, or by contacting The

Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

(13) Allardyce, C. S.; Dyson, P. J.; Ellis, D. J.; Salter, P. A.; Scopelliti,

R. Synthesis and characterisation of some water soluble ruthenium-

(

II)−arene complexes and an investigation of their antibiotic and

antiviral properties. J. Organomet. Chem. 2003, 668, 35.

14) Morris, R. E.; Aird, R. E.; del Socorro Murdoch, P.; Chen, H.;

(

Cummings, J.; Hughes, N. D.; Parsons, S.; Parkin, A.; Boyd, G.;

Jodrell, D. I.; Sadler, P. J. Inhibition of cancer cell growth by

ruthenium(II) arene complexes. J. Med. Chem. 2001, 44, 3616.

(15) Scolaro, C.; Bergamo, A.; Brescacin, L.; Delfino, R.; Cocchietto,

M.; Laurenczy, G.; Geldbach, T. J.; Sava, G.; Dyson, P. J. In vitro and

in vivo evaluation of ruthenium(II)-arene PTA complexes. J. Med.

Chem. 2005, 48, 4161.

AUTHOR INFORMATION

Corresponding Author

E-mail: paul.dyson@ep ﬂ .ch.

■

*

ORCID

Paul J. Dyson: 0000-0003-3117-3249

Notes

(16) Weiss, A.; Berndsen, R. H.; Dubois, M.; Muller, C.; Schibli, R.;

The authors declare no competing ﬁnancial interest.

Griffioen, A. W.; Dyson, P. J.; Nowak-Sliwinska, P. In vivo anti-tumor

activity of the organometallic ruthenium(II)-arene complex [Ru(η -p-

6

ACKNOWLEDGMENTS

cymene)Cl

carcinomas. Chem. Sci. 2014, 5, 4742.

17) Nowak-Sliwinska, P.; van Beijnum, J. R.; Casini, A.; Nazarov, A.

A.; Wagnieres, G.; van den Bergh, H.; Dyson, P. J.; Griffioen, A. W.

Organometallic ruthenium(II) arene compounds with antiangiogenic

activity. J. Med. Chem. 2011, 54, 3895.

2

(pta)] (RAPTA-C) in human ovarian and colorectal

■

We thank the Swiss National Science Foundation for ﬁnancial

support and Dr. Euro Solari (EPFL) for elemental analysis and

assistance with crystal structure reﬁnement.

(

REFERENCES

(18) Weiss, A.; Ding, X.; van Beijnum, J. R.; Wong, I.; Wong, T. J.;

■

(

1) Johnstone, T. C.; Suntharalingam, K.; Lippard, S. J. The Next

Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle

Delivery, and Pt(IV) Prodrugs. Chem. Rev. 2016, 116, 3436.

2) Jakupec, M. A.; Galanski, M.; Arion, V. B.; Hartinger, C. G.;

Keppler, B. K. Antitumour metal compounds: more than theme and

variations. Dalton Trans. 2008, 2, 183.

3) Leijen, S.; Burgers, S. A.; Baas, P.; Pluim, D.; Tibben, M.; van

Werkhoven, E.; Alessio, E.; Sava, G.; Beijnen, J. H.; Schellens, J. H. M.

Phase I/II study with ruthenium compound NAMI-A and gemcitabine

in patients with non-small cell lung cancer after first line therapy.

Invest. New Drugs 2015, 33, 201.

Berndsen, R. H.; Dormond, O.; Dallinga, M.; Shen, L.; Schlingemann,

R. O.; Pili, R.; Ho, C. M.; Dyson, P. J.; van den Bergh, H.; Griffioen, A.

W.; Nowak-Sliwinska, P. Rapid optimization of drug combinations for

the optimal angiostatic treatment of cancer. Angiogenesis 2015, 18, 233.

(19) Bergamo, A.; Masi, A.; Peacock, A. F. A.; Habtemariam, A.;

Sadler, P. J.; Sava, G. In vivo tumour and metastasis reduction and in

vitro effects on invasion assays of the ruthenium RM175 and osmium

AFAP51 organometallics in the mammary cancer model. J. Inorg.

Biochem. 2010, 104, 79.

(

(20) Adhireksan, Z.; Davey, G. E.; Campomanes, P.; Groessl, M.;

Clavel, C. M.; Yu, H.; Nazarov, A. A.; Yeo, C. H. F.; Ang, W. H.;

O

DOI: 10.1021/acs.inorgchem.7b01082

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

Dro

̈

ge, P.; Rothlisberger, U.; Dyson, P. J.; Davey, C. A. Ligand

(40) Jodrell, D. I.; Evans, T. R. J.; Steward, W.; Cameron, D.;

Prendiville, J.; Aschele, C.; Noberasco, C.; Lind, M.; Carmichael, J.;

Dobbs, N.; Camboni, G.; Gatti, B.; De Braud, F. Phase II studies of

BBR3464, a novel tri-nuclear platinum complex, in patients with

gastric or gastro-oesophageal adenocarcinoma. Eur. J. Cancer 2004, 40,

1872.

(41) Hensing, T. A.; Hanna, N. H.; Gillenwater, H. H.; Camboni, M.

G.; Allievi, C.; Socinski, M. A. Phase II study of BBR 3464 as treatment

in patients with sensitive or refractory small cell lung cancer. Anti-

Cancer Drugs 2006, 17, 697.

substitutions between ruthenium-cymene compounds can control

protein versus DNA targeting and anticancer activity. Nat. Commun.

2

(

014, 5, 3462.

21) Palermo, G.; Magistrato, A.; Riedel, T.; von Erlach, T.; Davey,

C. A.; Dyson, P. J.; Rothlisberger, U. Fighting Cancer with Transition

Metal Complexes: From Naked DNA to Protein and Chromatin

Targeting Strategies. ChemMedChem 2016, 11, 1199.

(

22) Tiekink, E. R. T. Gold derivatives for the treatment of cancer.

Crit. Rev. Oncol. Hematol. 2002, 42, 225.

23) Tiekink, E. R.T. Anti-cancer potential of gold complexes.

Inflammopharmacology 2008, 16, 138.

24) Mirabelli, C. K.; Johnson, R. K.; Hill, D. T.; Faucette, L. F.;

(

(42) Stringer, T.; Therrien, B.; Hendricks, D. T.; Guzgay, H.; Smith,

G. S. Mono- and dinuclear (η6-arene) ruthenium(II) benzaldehyde

thiosemicarbazone complexes: Synthesis, characterization and cytotox-

icity. Inorg. Chem. Commun. 2011, 14, 956.

(

Girard, G. R.; Kuo, G. Y.; Sung, C. M.; Crooke, S. T. Correlation of

the in vitro cytotoxic and in vivo antitumor activities of gold (I)

coordination complexes. J. Med. Chem. 1986, 29, 218.

(43) Su, W.; Tang, Z.; Li, P.; Wang, G.; Xiao, Q.; Li, Y.; Huang, S.;

Gu, Y.; Lai, Z.; Zhang, Y. New dinuclear ruthenium arene complexes

containing thiosemicarbazone ligands: synthesis, structure and

cytotoxic studies. Dalton Trans. 2016, 45, 19329.

(

25) Messori, L.; Marcon, G. Gold Complexes for the Treatment of

Rheumatoid Arthritus. Met. Ions Biol. Syst. 2004, 41, 279.

26) Kean, W. F.; Hart, L.; Buchanan, W. W. Auranofin.

Rheumatology 1997, 36, 560.

27) Mirabelli, C. K.; Johnson, R. K.; Sung, C. M.; Faucette, L.;

(44) Mendoza-Ferri, M. G.; Hartinger, C. G.; Eichinger, R. E.;

(

Stolyarova, N.; Severin, K.; Jakupec, M. A.; Nazarov, A. A.; Keppler, B.

K. Influence of the Spacer Length on the in Vitro Anticancer Activity

of Dinuclear Ruthenium−Arene Compounds. Organometallics 2008,

(

Muirhead, K.; Crooke, S. T. Evaluation of the In Vivo Antitumor

Activity and In Vitro Cytotoxic Properties of Auranofin, a Coordinated

Gold Compound, in Murine Tumor Models. Cancer Res. 1985, 45, 32.

2

(

7, 2405.

45) Mendoza-Ferri, M. G.; Hartinger, C. G.; Mendoza, M. A.;

Groessl, M.; Egger, A. E.; Eichinger, R. E.; Mangrum, J. B.; Farrell, N.

P.; Maruszak, M.; Bednarski, P. J.; Klein, F.; Jakupec, M. A.; Nazarov,

A. A.; Severin, K.; Keppler, B. K. Transferring the Concept of

Multinuclearity to Ruthenium Complexes for Improvement of

Anticancer Activity. J. Med. Chem. 2009, 52, 916.

(

28) Madeira, J. M.; Gibson, D. L.; Kean, W. F.; Klegeris, A. The

biological activity of auranofin: implications for novel treatment of

diseases. Inflammopharmacology 2012, 20, 297.

(

29) Liu, C.; Liu, Z.; Li, M.; Li, X.; Wong, Y. S.; Ngai, S. M.; Zheng,

W.; Zhang, Y.; Chen, T. Enhancement of auranofin-induced apoptosis

in MCF-7 human breast cells by selenocystine, a synergistic inhibitor

of thioredoxin reductase. PLoS One 2013, 8, e53945.

(

́ ́

46) Novakova, O.; Nazarov, A. A.; Hartinger, C. G.; Keppler, B. K.;

Brabec, V. DNA interactions of dinuclear Ru II arene antitumor

complexes in cell-free media. Biochem. Pharmacol. 2009, 77, 364.

(

30) Park, S. H.; Lee, J. H.; Berek, J. S.; Hu, M. C. T Auranofin

(

́ ́

47) Chen, H.; Parkinson, J. A.; Novakova, O.; Bella, J.; Wang, F.;

displays anticancer activity against ovarian cancer cells through

FOXO3 activation independent of p53. Int. J. Oncol. 2014, 45, 1691.

Dawson, A.; Gould, R.; Parsons, S.; Brabec, V.; Sadler, P. J. Induced-fit

recognition of DNA by organometallic complexes with dynamic

stereogenic centers. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 14623.

(

31) Fan, C.; Zheng, W.; Fu, X.; Li, X.; Wong, Y. S.; Chen, T.

Enhancement of auranofin-induced lung cancer cell apoptosis by

selenocystine, a natural inhibitor of TrxR1 in vitro and in vivo. Cell

Death Dis. 2014, 5, e1191.

(

48) Pettinari, R.; Marchetti, F.; Pettinari, C.; Petrini, A.; Skelton, B.

W.; White, A. H.; Bonfili, L.; Cuccioloni, M.; Eleuteri, A. M. Dinuclear

η6-arene) ruthenium(II) acylpyrazolone complexes: Synthesis,

characterization and cytotoxicity. J. Organomet. Chem. 2015, 791, 1.

49) Eichhorn, T.; Hey-Hawkins, E.; Maksimovic-Ivanic, D.; Mojic,

M.; Schmidt, J.; Mijatovic, S.; Schmidt, H.; Kaluđerovic, G. N.

(

32) Li, H.; Hu, J.; Wu, S.; Wang, L.; Cao, X.; Zhang, X.; Dai, B.;

Cao, M.; Shao, R.; Zhang, R.; et al. Auranofin-mediated inhibition of

PI3K/AKT/mTOR axis and anticancer activity in non-small cell lung

cancer cells. Oncotarget 2016, 7, 3548.

(

́

Binuclear dichlorido(η6-p-cymene)ruthenium(II) complexes with

bis(nicotinate)- and bis(isonicotinate)-polyethylene glycol ester

ligands. Appl. Organomet. Chem. 2015, 29, 20.

(

33) Casini, A.; Gabbiani, C.; Sorrentino, F.; Rigobello, M. P.;

Bindoli, A.; Geldbach, T. J.; Marrone, A.; Re, N.; Hartinger, C. G.;

Dyson, P. J.; Messori, L. Emerging Protein Targets for Anticancer

Metallodrugs: Inhibition of Thioredoxin Reductase and Cathepsin B

by Antitumor Ruthenium(II)−Arene Compounds. J. Med. Chem.

(

50) Murray, B. S.; Menin, L.; Scopelliti, R.; Dyson, P. J.

Conformational control of anticancer activity: the application of

arene-linked dinuclear ruthenium(ii) organometallics. Chem. Sci. 2014,

2

(

008, 51, 6773.

34) Ang, W. H.; Parker, L. J.; De Luca, A.; Juillerat-Jeanneret, L.;

5

(

, 2536.

51) Murray, B. S.; Crot, S.; Siankevich, S.; Dyson, P. J. Potential of

Morton, C. J.; Lo Bello, M.; Parker, M. W.; Dyson, P. J. Rational

Design of an Organometallic Glutathione Transferase Inhibitor.

Angew. Chem., Int. Ed. 2009, 48, 3854.

Cycloaddition Reactions To Generate Cytotoxic Metal Drugs In Vitro.

Inorg. Chem. 2014, 53, 9315.

(52) Berners-Price, S. J.; Mirabelli, C. K.; Johnson, R. K.; Mattern, M.

(

35) Barnard, P. J.; Berners-Price, S. J. Targeting the mitochondrial

cell death pathway with gold compounds. Coord. Chem. Rev. 2007,

51, 1889.

36) Zou, T.; Lum, C. T.; Lok, C. N.; Zhang, J. J.; Che, C. M.

R.; McCabe, F. L.; Faucette, L. F.; Sung, C. M.; Mong, S. M.; Sadler, P.

J.; Crooke, S. T. In vivo antitumor activity and in vitro cytotoxic

properties of bis [1, 2-bis (diphenylphosphino) ethane] gold (I)

chloride. Cancer Res. 1986, 46, 5486.

2

(

Chemical biology of anticancer gold(iii) and gold(i) complexes. Chem.

Soc. Rev. 2015, 44, 8786.

(53) Mirabelli, C. K.; Jensen, B. D.; Mattern, M. R.; Sung, C. M.;

Mong, S. M.; Hill, D. T.; Dean, S. W.; Schein, P. S.; Johnson, R. K.;

Crooke, S. T. Cellular pharmacology of μ-[1,2-bis-

(diphenylphosphino)ethane] bis[(1-thio-beta-D-gluco pyranosato-S)

gold(I)]: a novel antitumor agent. Anticancer Drug Des. 1986, 1, 223.

(54) Humphreys, A. S.; Filipovska, A.; Berners-Price, S. J.;

Koutsantonis, G. A.; Skelton, B. W.; White, A. H. Gold(i) chloride

adducts of 1,3-bis(di-2-pyridylphosphino)propane: synthesis, struc-

tural studies and antitumour activity. Dalton Trans. 2007, 43, 4943.

(55) Liu, J. J.; Galettis, P.; Farr, A.; Maharaj, L.; Samarasinha, H.;

McGechan, A. C.; Baguley, B. C.; Bowen, R. J.; Berners-Price, S. J.;

McKeage, M. J. In vitro antitumour and hepatotoxicity profiles of

(

37) Roder, C.; Thomson, M. J. Auranofin: Repurposing an Old

Drug for a Golden New Age. Drugs R&D 2015, 15, 13.

38) Hartinger, C. G.; Phillips, A. D.; Nazarov, A. A. Polynuclear

(

ruthenium, osmium and gold complexes. The quest for innovative

anticancer chemotherapeutics. Curr. Top. Med. Chem. 2011, 11, 2688.

(

39) Manzotti, C.; Pratesi, G.; Menta, E.; Di Domenico, R.;

Cavalletti, E.; Fiebig, H. H.; Kelland, L. R.; Farrell, N.; Polizzi, D.;

Supino, R.; Pezzoni, G.; Zunino, F. BBR 3464: A Novel Triplatinum

Complex, Exhibiting a Preclinical Profile of Antitumor Efficacy

Different from Cisplatin. Clin. Cancer Res. 2000, 6, 2626.

P

DOI: 10.1021/acs.inorgchem.7b01082

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

Au(I) and Ag(I) bidentate pyridyl phosphine complexes and

relationships to cellular uptake. J. Inorg. Biochem. 2008, 102, 303.

(72) Gutier

́

rez, A.; Gracia-Fleta, L.; Marzo, I.; Cativiela, C.; Laguna,

A.; Gimeno, M. C. Gold (I) thiolates containing amino acid moieties.

Cytotoxicity and structure−activity relationship studies. Dalton Trans.

2014, 43, 17054.

(73) Allardyce, C. S.; Dyson, P. J.; Ellis, D. J.; Heath, S. L. [Ru (η6-p-

cymene) Cl2 (pta)](pta= 1, 3, 5-triaza-7-phosphatricyclo-[3.3. 1.1]

decane): a water soluble compound that exhibits pH dependent DNA

binding providing selectivity for diseased cells. Chem. Commun. 2001,

15, 1396.

(

56) Tian, S.; Siu, F. M.; Kui, S. C. F.; Lok, C. N.; Che, C. M.

Anticancer gold (i)−phosphine complexes as potent autophagy-

inducing agents. Chem. Commun. 2011, 47, 9318.

(

57) Li, B. B.; Jia, Y. X.; Zhu, P. C.; Chew, R. J.; Li, Y.; Tan, N. S.;

Leung, P. H. Highly selective anti-cancer properties of ester

functionalized enantiopure dinuclear gold(I)-diphosphine. Eur. J.

Med. Chem. 2015, 98, 250.

(

58) Atrian

M.; Cerrada, E. Synthesis of Gold(I) Derivatives Bearing Alkylated

,3,5-Triaza-7-phosphaadamantane as Selective Anticancer Metal-

lodrugs. Eur. J. Inorg. Chem. 2016, 17, 2791.

59) Mirabelli, C. K.; Hill, D. T.; Faucette, L. F.; McCabe, F. L.;

́

-Blasco, E.; Gascon

́

, S.; Rodríguez-Yoldi, M. J.; Laguna,

(74) Hill, D. T.; Sutton, B. M. (2, 3, 4, 6-TETRA-O-ACETYL-1-

T H I O - B E T A - D - G L U C O P Y R A N O S A T O - S ) -

(TRIETHYLPHOSPHINE) GOLD, C20H34AUO9PS. Cryst. Struct.

Commun. 1980, 9, 679.

(75) Tetko, I. V.; Gasteiger, J.; Todeschini, R.; Mauri, A.;

Livingstone, D.; Ertl, P.; Palyulin, V. A.; Radchenko, E. V.; Zefirov,

N. S.; Makarenko, A. S.; Tanchuk, V. Y.; Prokopenko, V. V. Virtual

Computational Chemistry Laboratory − Design and Description. J.

Comput.-Aided Mol. Des. 2005, 19, 453.

1

(

Girard, G. R.; Bryan, D. B.; Sutton, B. M.; Barus, J. O. L.; Crooke, S.

T.; Johnson, R. K. Antitumor activity of bis (diphenylphosphino)

alkanes, their gold (I) coordination complexes, and related

compounds. J. Med. Chem. 1987, 30, 2181.

(76) Tetko, I. V.; Bruneau, P. Application of ALOGPS to predict 1-

(

́

60) Meyer, A.; Gutierrez, A.; Ott, I.; Rodríguez, L. Phosphine-

octanol/water distribution coefficients, logP, and logD, of AstraZeneca

in-house database. J. Pharm. Sci. 2004, 93, 3103.

bridged dinuclear gold (I) alkynyl complexes: Thioredoxin reductase

inhibition and cytotoxicity. Inorg. Chim. Acta 2013, 398, 72.

(

Gonzalez, A.; Sordo, J.; Vazquez-Lopez, E. M. Mono and dinuclear

phosphinegold(I) sulfanylcarboxylates: Influence of nuclearity and

substitution of PPh3 for PEt3 on cytotoxicity. J. Inorg. Biochem. 2014,

(

77) Sangster, J. Octanol-water partition coeficients of simple organic

compounds. J. Phys. Chem. Ref. Data 1989, 18, 1111.

78) Tonnemann, J.; Risse, J.; Grote, Z.; Scopelliti, R.; Severin, K.

61) Barreiro, E.; Casas, J. S.; Couce, M. D.; San

́ ́

chez, A.; Sanchez-

́

(

̈

Efficient and Rapid Synthesis of Chlorido-Bridged Half-Sandwich

Complexes of Ruthenium, Rhodium, and Iridium by Microwave

Heating. Eur. J. Inorg. Chem. 2013, 26, 4558.

1

(

38, 89.

62) Zou, T.; Lum, C. T.; Lok, C.; To, W.; Low, K.; Che, C. A

(

79) Duisenberg, A. J. M.; Kroon-Batenburg, L. M. J.; Schreurs, A. M.

M. An intensity evaluation method: EVAL-14. J. Appl. Crystallogr.

003, 36, 220.

80) Blessing, R. H. An empirical correction for absorption

anisotropy. Acta Crystallogr., Sect. A: Found. Crystallogr. 1995, 51, 33.

81) Sheldrick, G. M. A short history of SHELX. Acta Crystallogr.,

Sect. A: Found. Crystallogr. 2008, 64, 112.

82) Sheldrick, G. M. Crystal structure refinement with SHELXL.

Acta Crystallogr., Sect. C: Struct. Chem. 2015, 71, 3.

83) Mosmann, T. Rapid colormetric assay for cellular growth and

Binuclear Gold(I) Complex with Mixed Bridging Diphosphine and

Bis(N-Heterocyclic Carbene) Ligands Shows Favorable Thiol

Reactivity and Inhibits Tumor Growth and Angiogenesis In Vivo.

Angew. Chem., Int. Ed. 2014, 53, 5810.

2

(

63) Barnard, P. J.; Wedlock, L. E.; Baker, M. V.; Berners-Price, S. J.;

(

Joyce, D. A.; Skelton, B. W.; Steer, J. H. Luminescence Studies of the

Intracellular Distribution of a Dinuclear Gold(I) N-Heterocyclic

Carbene Complex. Angew. Chem., Int. Ed. 2006, 45, 5966.

(

64) Rieb, J.; Dominelli, B.; Mayer, D.; Jandl, C.; Drechsel, J.;

(

Heydenreuter, W.; Sieber, S. A.; Kuhn, F. E. Influence of Wing-tip

Substituents and Reaction Conditions on Structure, Properties and

Cytotoxicity of Ag(I)- and Au(I)-bis(NHC) Complexes. Dalton Trans.

survival: Application to proliferation and cytotoxicity assays. J.

Immunol. Methods 1983, 65, 55.

2

(

017, 46, 2722.

65) De Nisi, A.; Bergamini, C.; Leonzio, M.; Sartor, G.; Fato, R.;

Naldi, M.; Monari, M.; Calonghi, N.; Bandini, M. Synthesis,

cytotoxicity and anti-cancer activity of new alkynyl-gold (I) complexes.

Dalton Trans. 2016, 45, 1546.

(

66) Vergara, E.; Cerrada, E.; Casini, A.; Zava, O.; Laguna, M.;

Dyson, P. J. Antiproliferative activity of gold (i) alkyne complexes

containing water-soluble phosphane ligands. Organometallics 2010, 29,

2

(

596.

67) Chui, C. H.; Wong, R. S. M.; Gambari, R.; Cheng, G. Y. M.;

Yuen, M. C. W.; Chan, K. W.; Tong, S. W.; Lau, F. Y.; Lai, P. B. S.;

Lam, K. H.; Ho, C. L.; Kan, C. W.; Leung, K. S. Y.; Wong, W. Y.

Antitumor activity of diethynylfluorene derivatives of gold (I). Bioorg.

Med. Chem. 2009, 17, 7872.

(

68) Altaf, M.; Monim-ul-Mehboob, M.; Isab, A. A.; Dhuna, V.;

Bhatia, G.; Dhuna, K.; Altuwaijri, S. The synthesis, spectroscopic

characterization and anticancer activity of new mono and binuclear

phosphanegold(i) dithiocarbamate complexes. New J. Chem. 2015, 39,

3

(

77.

69) Sun, R. W. Y.; Zhang, M.; Li, D.; Zhang, Z. F.; Cai, H.; Li, M.;

Xian, Y. J.; Ng, S. W.; Wong, A. S. T. Dinuclear Gold(I)

Pyrrolidinedithiocarbamato Complex: Cytotoxic and Antimigratory

Activities on Cancer Cells and the Use of Metal−Organic Framework.

Chem. - Eur. J. 2015, 21, 18534.

(

70) Uson, R.; Laguna, A. Polyaryl Derivatives of gold(I), silver(I) and

gold(III); Elsevier: Amsterdam, The Netherlands, 1986; Vol. 3, p 322.

71) Vergara, E.; Miranda, S.; Mohr, F.; Cerrada, E.; Tiekink, E. R.

(

T.; Romero, P.; Mendía, A.; Laguna, M. Gold (I) and Palladium (II)

Thiolato Complexes Containing Water-Soluble Phosphane Ligands.

Eur. J. Inorg. Chem. 2007, 18, 2926.

Q

DOI: 10.1021/acs.inorgchem.7b01082

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Influence of the Linker Length on the Cytotoxicity of Homobinuclear Ruthenium(II) and Gold(I) Complexes

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