Highly Cytotoxic Palladium(II) Pincer Complexes Based on Picolinylamides Functionalized with Amino Acids Bearing Ancillary S-Donor Groups

Article

pubs.acs.org/IC

Highly Cytotoxic Palladium(II) Pincer Complexes Based on

Picolinylamides Functionalized with Amino Acids Bearing Ancillary

S‑Donor Groups

Svetlana G. Churusova,^†Diana V. Aleksanyan,*^,†Ekaterina Yu. Rybalkina,^‡Olga Yu. Susova,^‡

Valentina V. Brunova,^†Rinat R. Aysin,^†Yulia V. Nelyubina,^†Alexander S. Peregudov,^†Evgenii I. Gutsul,^†

Zinaida S. Klemenkova,^†and Vladimir A. Kozlov^†

^†A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Ulitsa Vavilova 28, Moscow 119991,

Russia

^‡Institute of Carcinogenesis, N. N. Blokhin Russian Cancer Research Center, Kashirskoe Shosse 24, Moscow 115478, Russia

S

* Supporting Information

ABSTRACT: The reactions of picolinyl and 4-chloropicolinyl

chlorides with methyl esters of S-methyl-^L-cysteine, L- and D-

methionine, and ^L-histidine aﬀorded a series of functionalized

carboxamides, which readily formed pincer-type complexes upon

interaction with PdCl₂(NCPh)₂in solution under mild conditions.

The direct cyclopalladation of the ligands derived was also

accomplished in the solid phase, in particular, mechanochemically,

although it was complicated by the partial deactivation of the

starting amides. The resulting complexes with 5,5- and 5,6-

membered fused metallocycles were fully characterized by IR and

NMR spectroscopy, including variable-temperature and 2D-NMR studies. In the case of some cysteine- and methionine-based

derivatives, the realization of κ³-N,N,S-coordination was supported by X-ray diﬀraction. The cytotoxic eﬀects of these complexes

were examined on HCT116, MCF7, and PC3 human cancer cell lines as well as HEK293 as a representative of normal cells. The

comparative studies allowed us to determine that the presence of the sulﬁde ancillary donor group is crucial for cytotoxic activity

of this type of Pd(II) complexes. The main structure−activity relationships and the most promising palladocycles were outlined.

The additional studies by gel electrophoresis revealed that 4-chloropicolinyl derivatives, despite the nature of an amino acid, can

bind with DNA and inhibit topoisomerase I activity.

palladium(II) complexes with sterically hindered N-donor

ligands were found to possess pronounced cytotoxic proper-

ties.⁷Even more promising results were demonstrated by

application of chelating bidentate ligands, especially those of

hemilabile nature.⁸The introduction of an additional ancillary

donor group into the ligand framework, i.e., transition from bi-

to multidentate ligand systems, oﬀering ample opportunities for

directed structural modiﬁcations, can provide the resulting

palladium complexes with even higher thermodynamic and

controlled kinetic stability. Although these advantages of

palladocycles based on multidentate ligands has been

successfully used in catalysis and organic synthesis for several

decades,⁹in the ﬁeld of palladium(II)-based anticancer drug

design this is a relatively new and unexplored strategy.

However, already known cyclopalladated complexes featuring

functionalized thiosemicarbazone,¹⁰diimine,¹¹terpyridine,¹²

and bis(2-pyridylmethyl)amine^12b,13ligands and single exam-

ples of related derivatives with other skeletons,¹⁴⁻¹⁷including

6-phenyl-2,2′-bipyridine complexes with auxiliary NHC ligands

INTRODUCTION

■

The discovery of anticancer activity of cis-[PtCl₂(NH₃)₂]

provoked an enormous interest of researchers in development

of platinum(II)-based chemotherapeutic agents.¹Nowadays, a

range of Pt(II) complexes are successfully used in clinical

practice for treatment of various cancers (above-mentioned

cisplatin and its analogs−carboplatin, oxaliplatin, nedaplatin,

lobaplatin, and heptaplatin).²However, because of the intrinsic

and acquired resistance as well as high toxicity of platinum-

based drugs, leading to severe side eﬀects,^2cthere is a constant

need for creation of more eﬀective and selective anticancer

agents. Many investigations have been focused on nonplatinum

transition metal complexes, including gold, ruthenium, and

titanium derivatives.³⁻⁵At the same time, despite obvious

similarities in structure and coordination behavior between

Pt(II) and Pd(II) complexes, the potential of palladium(II)-

based compounds as anticancer agents seems to be under-

appreciated.^2c,5c,6The main obstacle consists in the essentially

higher reactivity of Pd(II) complexes compared to their Pt(II)

analogs, which often leads to deactivation of palladium(II) drug

candidates in biological environment (due to hydrolysis and

ligand-exchange processes). Nevertheless, a series of

Received: May 26, 2017

A

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

Figure 1. Cytotoxic palladium(II) complexes based on multidentate ligands (sac−saccharinate).

Scheme 1. Synthesis of Multidentate Ligands Based on Picolinylamides Functionalized with Amino Acid Esters

possessing high in vivo anticancer activity,¹⁸show a lot of

promise (Figure 1).

researchers, because they have been shown to play an

important role in biological activity of these complexes.²²

Furthermore, the combination of transition metals with

naturally occurring compounds is often exploited in medicinal

chemistry, for example, to achieve the desired binding modes

with diﬀerent biological targets.²³Note that the strong binding

of potential anticancer Pd(II) complexes with sulfur-containing

biomolecules, e.g., glutathione can reduce their bioavailability.¹⁸

In this respect, the introduction of a sulfur ancillary donor

group into the ligand framework can have positive eﬀect on the

cytotoxic activity of the resulting complexes. For comparison, ^L-

histidine featuring N-donor imidazole moiety was also used as

an amino component. In turn, pyridine-2-carboxylic (picolinic)

acids were preferred as acid components in order to acquire

hemilabile ligation of the metal ions in cysteine- and

methionine-based derivatives, especially in view of the strong

trans-labilizing eﬀect of sulfur donors.

Within the project devoted to pincer complexes having a

speciﬁc tridentate monoanionic framework, the importance of

which expands from catalytic applications to materials

science,^9,19,20recently we have shown that functionalized

carboxamides with ancillary donor groups both in the amine

and acid parts can act as pincer-type ligands upon coordination

with the Pd(II) ions.²¹The resulting N-metalated palladocycles

proved to be eﬃcient and readily tunable catalysts for the

Suzuki cross-coupling. Following our interest in such non-

classical pincer complexes based on readily available and

metalated ligands with a secondary amide central unit, it

seemed interesting to develop related systems potentially

attractive from the viewpoint of biological activity of their

palladium(II) complexes. Taking into account the high aﬃnity

of the soft Pd(II) ions to sulfur and biological relevance of S-

donor amino acids, enantiomerically pure ^S-methyl-L-cysteine

and ^L-methionine were chosen as the main amino components.

Interactions of Pt(II) anticancer agents and their Pd(II) analogs

with sulfur-containing amino acids have been the focus of many

Herein, we report on the synthesis and characterization of

novel pincer-type palladium(II) complexes derived from N-

picolinylamides functionalized with S-methyl-cysteine, methio-

nine and histidine in enantiomerically pure forms. The results

B

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

on cytotoxicity studies against several human cancer cell lines

and the main structure−activity relationships are discussed.

All the sulﬁde ligands obtained readily underwent direct

cyclometalation upon interaction with PdCl₂(NCPh)₂in

dichloromethane solution at room temperature in the presence

of triethylamine, leading to 5,5- and 5,6-membered pincer

complexes 7−12 in high yields (Scheme 3). Note that the same

palladocycles were formed in the absence of Et₃N, but the

yields of the isolated products in these cases were somewhat

lower, which was associated with an adverse eﬀect of HCl

liberated upon metalation. Therefore, triethylamine was used to

trap HCl.

Unfortunately, we failed to isolate palladium(II) complex

(R)-8o based on ^L-cysteine bearing the sulfoxide ancillary

donor group. This compound appeared to be unstable and

gradually decomposed upon storage and isolation. Presumably,

this is caused by the highly constrained character of the

complex structure, arising from the presence of two fused

metallocycles leading to severe distortion of the square-planar

geometry around the metal ion. However, its counterpart (S)-

10o with the elongated S-coordination arm was readily isolated

and characterized.

RESULTS AND DISCUSSION

■

Synthesis in Solution and Spectroscopic Character-

ization of Cyclopalladated Complexes. The target

functionalized carboxamides were obtained by reactions of

methyl esters of ^S-methyl-L-cysteine, L-methionine and L-

histidine, in situ generated from the corresponding hydro-

chlorides, with picolinyl chloride in dichloromethane at −5 °C

in the presence of Et₃N (Scheme 1). Note that the latter

actually represented a mixture of picolinyl chloride and 4-

chloropicolinyl chloride, since, unlike the literature data,^21c,24in

our hands the reaction of picolinic acid with an excess of SOCl₂

under reﬂux was accompanied by the chlorination of the

pyridine ring. The ratio of 4-chloropicolinyl and picolinyl

amides in crude products was ∼2:1. Nevertheless, in each case,

the resulting pair of amides of picolinic and 4-chloropicolinic

acids were readily separated by column chromatography on

silica gel, so that all the ligands were isolated in the individual

forms as crystalline solids. In general 4-chloropicolinylamides

((R)-2, (S)-4, (S)-6) featured lower adsorption capacity than

the unsubstituted analogs ((R)-1, (S)-3, (S)-5).

To compare the cytotoxic properties of palladocycles derived

from diﬀerent enantiomers of amino acids, we synthesized the

ligands analogous to (S)-3 and (S)-4 starting from ^D-

methionine methyl ester hydrochloride (compounds (R)-3

and (R)-4, respectively, Scheme 1).

Taking into account an important role of such weak donor

ligands as sulfoxides in transition metal chemistry and diﬀerent

biochemical processes,²⁵it seemed interesting to obtain the

corresponding sulfoxide analogs of the above-mentioned

ligands. Thus, oxidation of (R)-2 and (S)-4 with H₂O₂in

^tBuOH smoothly aﬀorded the desired sulfoxide derivatives in

high yields (Scheme 2). It should be emphasized that the

Complexes 7−12, 10o are moisture- and air-resistant brightly

colored crystalline solids. Their structures were unambiguously

conﬁrmed based on the IR and NMR spectroscopic data. The

IR spectra of all the palladocycles obtained lack the absorption

bands corresponding to the stretching and bending vibrations

associated with the NH moiety of the amide group. Similarly,

1

their H NMR spectra did not reveal the downﬁeld signals of

the amide NH protons, indicating the occurrence of metalation.

A strong low-frequency displacement of the amide CO

stretching vibrations compared to the IR spectra of the free

ligands (Δν = 24−53 cm⁻¹) is also characteristic of N-

metalated pincer complexes derived from functionalized

carboxamides.²¹The realization of S-coordination by the

palladium(II) ion in palladocycles 7−10 and (S)-10o is

supported by the downﬁeld shifts of the carbon and proton

signals corresponding to SMe or S(O)Me groups both in the

¹H (Δδ_H= 0.43−0.92 ppm) and ¹³C (Δδ_C= 4.79−8.70 ppm)

NMR spectra. The coordination of the imidazole moiety in

complexes (S)-11 and (S)-12 is reﬂected in strong downﬁeld

shifts of the NH proton signal and the signal of H(C8) proton

between two nitrogen atoms (Δδ_H∼ 4.0 and 0.7 ppm,

respectively). An upﬁeld shift of the resonance of tertiary

carbon nuclei adjacent to the nitrogen atom of the pyridine

moiety (Δδ_C5= 0.31−1.10 ppm), observed in the ¹³C NMR

spectra of most of the complexes obtained, serves as indirect

evidence for the heterocycle complexation.

Scheme 2. Synthesis of Sulfoxide Ligands

products of further oxidation, namely, sulfones were not

detected in the reaction mixtures. Note that ligands (R)-2o and

(S)-4o actually represent mixtures of two diastereomers, which

diﬀer in the conﬁguration of the sulfur atom relative to the

chiral carbon center. The diastereomeric ratio for ligand (R)-2o

composes 68:32. In the case of its methionine-based counter-

part, the diastereomeric ratio cannot be accurately deﬁned due

to considerable overlapping of the signals in the NMR spectra.

The structures and compositions of the resulting functionalized

picolinylamides were supported by the IR and NMR

spectroscopic data as well as elemental analyses (see

Experimental Section).

Interestingly, the ¹H and ¹³C NMR spectra of N,N,S-

complexes 7−10 in CDCl₃at room temperature show a double

set of signals, which correspond to two diﬀerent isomeric forms.

The ratio of the isomers composes approximately 3:2. For 5,5-

membered palladocycles (R)-7 and (R)-8 based on ^L-cysteine

derivatives, the signals of the major and minor isomers can be

readily assigned, while their analogs with the elongated S-

coordination arm−complexes (S)-9, (S)-10 and (R)-9, (R)-10,

C

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

Scheme 3. Cyclopalladation of Picolinylamide Ligands

featuring more conformationally ﬂexible structures, undergo

dynamic transformations at room temperature, which result in

the broadened and unresolved signals of the aliphatic carbon

and hydrogen nuclei. The variable-temperature NMR spectral

studies in CDCl₃showed that the resonances of two isomers

collapse at 28−30 °C (see, for example, Figure S1). In contrast,

cooling to −30 °C resulted in the resolution of all the signals,

including those of both methylene (CH₂and CH₂S) units. 2D-

NMR spectral studies in CDCl₃at −30 °C (COSY, HSQC, and

HMBC experiments) allowed us to make the unequivocal

assignment of the resonances of two isomeric forms in each

case of methionine-based derivatives (complexes 9 and 10, see

Figures S2 −S11). As for the nature of these isomeric forms,

one should note that the coordination of the sulﬁde group by

the Pd(II) ion can lead to conﬁgurational stability of the sulfur

center. The complicated inversion between the coordinated and

noncoordinated electron pairs of the sulfur atom along with the

presence of the chiral carbon center in one deﬁnite absolute

conﬁguration can result in the existence of two diastereomers.

Investigation of complex (R)-8 by the ROESY technique

conﬁrmed that the major and minor isomers diﬀer in the

disposition of the methyl substituent at the sulfur atom and the

substituents at the chiral carbon center relative to the main

molecular plane (Figure S12). In complex (S)-10o, such an

inversion of the sulfur atom conﬁguration is impossible due to

the presence of the S−O bond, and its diastereomers are

signiﬁcantly more stable. Thus, the ratio of the isomers of (S)-

10o almost does not depend on the solvent nature (∼3:2 in

CDCl₃and CD₃CN and 4:3 in C₆D₆) and remains unchanged

upon heating to 60 °C in C₆D₆. Therefore, they were readily

separated by thin-layer chromatography and fully characterized

individually.

X-ray Structural Description. The structures of complexes

(R)-7, (S)-9, (R)-9, (S)-10, (R)-10 and (S)-10o were

additionally conﬁrmed by X-ray diﬀraction (Figures 2a−f).

According to the results obtained, all the palladocycles with the

sulﬁde ancillary donor group crystallize in a noncentrosym-

metric space group P2₁and have two symmetry-independent

molecules with opposite location of the methyl group at the

sulfur atom relative to Pd(1)N(1)N(2)Cl(1)S(1) mean plane,

which answer to two diﬀerent diastereomeric forms; the

relevant torsion angles (C_MeS(1)Pd(1)N(1)) range from −

104.2 to −90.6° and from 105.8 to 120.4°, respectively. In the

crystal of the major isomer of (S)-10o, four independent

complex molecules, as was expected for a single diastereomer,

have one and the same arrangement of the substituents at the

sulfur donor atom relative to Pd(1)N(1)N(2)Cl(1)S(1) mean

plane. The corresponding torsion angle (C_MeS(1)Pd(1)N(1))

composes 123.3−126.5°. Unfortunately we failed to grow single

crystals of the minor isomer of this palladocycle.

The conformation of a ﬁve-membered metal-containing ring

formed by the pyridine moiety in all the complexes explored

represents a ﬂattened envelope with the N(1) atom deviating

by 0.08−0.26 Å. The second ﬁve-membered ring in (R)-7 also

adopts an envelope conformation with the C(10) atom

deviating by 0.62 Å (or 0.53 Å in the second independent

molecule of this complex). A six-membered metallocycle in (S)-

9, (R)-9, (R)-10, (S)-10, and (S)-10o is either in a half-chair

conformation (all independent molecules in (S)-10o and one

in complexes 9 and 10) with the deviation of the C(10) and

C(11) atoms by 0.40−0.64 Å and from −0.55 to −0.18 Å,

respectively, or in an envelope conformation (the second

independent molecule in 9 and 10) with the deviation of the

C(10) atom by 0.72−0.81 Å. The environment of the

palladium atom varies from square-planar (all independent

molecules in (R)-7 and (S)-10o and one in (S)-10 and (R)-10)

to ﬂattened tetrahedral with a folding along S(1)···N(2) line

(all independent molecules in (S)-9 and (R)-9 and the second

one in (S)-10 and (R)-10); the corresponding angles

(N(1)Pd(1)Cl(1)), dihedral angles between Pd(1)N(1)S(1)-

N(2) and Pd(1)Cl(1)S(1)N(2) planes, and deviations of the

chlorine atoms are as follows: 169.9(2)−174.73(18)°, 3.4−

12.9°, and 0.14−0.52 Å, respectively. The main bond lengths

and angles of the complexes explored are given in Table S1.

Solid-Phase Cyclopalladation. Recently, we have shown

that solid-phase cyclopalladation can serve as an eﬃcient and

green alternative to the conventional synthesis of organo-

metallic pincer complexes in solution.²⁶Simple heating of

homogenized mixtures of a ligand and appropriate Pd(II)

precursor, obtained by manual grinding of the reactants in a

mortar, in the absence of a solvent readily aﬀorded several

series of C-metalated pincer complexes having ancillary S- and

N-donor groups. In the case of the most active ligands, the

formation of pincer complexes can be accomplished even at

room temperature.^26bMore importantly, the synthesis of an

organometallic palladium(II) pincer complex was realized for

the ﬁrst time via C−H bond activation of the bis-

(thiocarbamate) ligand with PdCl₂(NCPh)₂under mechano-

chemical conditions both by grinding of the reactants in a

mortar and in a vibration ball mill at gram scale.^26aIn

continuation of these studies, it seemed interesting to estimate

whether the solid-phase approach can be applied to the systems

requiring the activation of the N−H bond. Indeed, heating of a

homogenized mixture of ^L-histidine-based ligand (S)-6 and

PdCl₂(NCPh)₂at 85−90 °C for 10 min gave rise to

palladocycle (S)-12. The cyclopalladation of more reactive

D

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

Figure 2. General views of complexes (a) (R)-7, (b) (S)-9, (c) (R)-9, (d) (S)-10, (e) (R)-10, and (f) (S)-10o in representation of non-hydrogen

atoms via thermal ellipsoids at 50% probability level. Only one symmetry-independent molecule of the complex is shown in each case.

Figure 3. Monitoring of a reaction of ligand (R)-2 with PdCl₂(NCPh)₂in a mortar: a mixture of (R)-2 and Pd(II) precursor (a) before grinding, and

after grinding for (b) 0.5, (c) 1, and (d) 2 min.

E

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

Scheme 4. Solid-Phase Cyclopalladation of Picolinylamide Ligands (LH, ligand)

Table 1. Cytotoxicity of the Pd(II) Complexes Obtained against Human Cell Lines HCT116, MCF7, PC3, and HEK293 (IC₅₀/

μM)

cancer cell lines

MCF7

normal cell line

HEK293

entry

compound

HCT116

PC3

>30

1

2

3

4

5

6

7

(R)-7

1.8 0.2

1.2 0.4

6.2 0.5

0.45 0.05

7.0 0.2

4.4 0.8

400.0

22.0 1.4

10.0 1.5

15.5 2.5

5.5 0.4

15.0 0.5

11.7 0.3

25.0

18.0 3.2

8.0 2.0

16.5 3.5

4.0 2.0

16.2 1.6

11.0 0.5

28.0

(R)-8

16.5 2.0

13.5 0.5

4.2 0.6

8.5 2.5

4.5 0.5

120.0

(S)-9

(S)-10

(R)-9

(R)-10

Cisplatin

ligands (R)-2, (S)-4, and (R)-4 based on sulfur-containing

amino acids was accomplished already upon grinding of the

reactants in a mortar (Figure 3).

(in this case, both pyridine and histidine moieties of the free

ligand can bind with HCl). The latter slowly converts to

complex (S)-12 in solution (Figures S26 and S27). Scheme 4

outlines the results of the solid-phase experiments.

In all cases, the IR and Raman spectra of the solid residues

did not reveal the absorption bands and lines of free ligands

and, at the same time, clearly demonstrated the signals

characteristic for the target pincer complexes (see representa-

tive IR and Raman spectra in Supporting Information for one

series of methionine derivatives (Figures S13 −S19) and

histidine derivatives (Figures S20 −S22)). However, careful

inspection of the shape and position of some of the bands and

lines along with the additional signals (not typical for the

complexes) allowed us to suppose the presence of at least one

byproduct. Note that unlike other pincer systems,²⁶for the

ligands under consideration, the liberation of hydrogen chloride

(as a result of cyclometalation) was not detected with a paper

indicator. This allowed us to assume that liberated HCl could

be trapped by the unreacted ligand to form hydrochloride salts.

Furthermore, the IR and Raman spectra of the samples rinsed

with hexane and Et₂O still revealed CN stretching vibrations

(Figure S16), which may arise from partially unreacted

PdCl₂(NCPh)₂, because residual benzonitrile should be

Taking into account the ease of formation of the complexes

under consideration in solution even in the absence of a base,

we tried to enhance the eﬃciency of mechanochemical

synthesis via performing the reaction of (S)-4 with

PdCl₂(NCPh)₂in a vibration ball mill of simple construction

(Narva DDR GM 9458 vibration ball mill, stainless jar, two

grinding balls, 30 W, 50 Hz) (Figure S28). Unfortunately, in

this case, the formation of palladocycle (S)-10 was again

accompanied by the generation of (S)-4·HCl (Figure S29).

Nevertheless, the results obtained show a principal possibility of

synthesis of N-metalated Pd(II) pincer complexes by the solid-

phase methodology. Presumably, limitations connected with

the partial deactivation of the ligands explored can be overcome

by high-energy ball milling.

Cytotoxicity Studies. To estimate the potential of

palladocycles 7−12 and (S)-10o as anticancer agents, their

cytotoxicity against three human cancer cell lines (human colon

cancer HCT116, human breast cancer MCF7, and human

prostate cancer PC3) was measured by the colorimetric MTT

assay. For comparison, cisplatin from a commercial source was

tested under the same experimental conditions. The results are

summarized in Table 1. The activity is presented as the

concentration required for reduction of cell survival by 50%

after 48 h of exposure to the compounds under investigation

(IC₅₀).

1

removed after such a puriﬁcation procedure. The H NMR

spectra of the solutions of solid residues obtained after

reactions with the ligands bearing sulfur-donor ancillary

group, registered directly after dissolution, contained mainly

the signals of the pincer complexes and PhCN (see, for

example, Figure S23). However, for less reactive histidine-

1

derivative (S)-6, the analogous H NMR spectrum registered

immediately after dissolution (Figures S24 and S25), conﬁrmed

the presence of a hydrochloride salt of (S)-6·2HCl formulation

As can be seen from Table 1, almost all the κ³-N,N,S-

palladocycles with the sulﬁde ancillary donor group demon-

F

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

strated high cytotoxic activity against the explored cancer cell

lines, with IC₅₀values falling in the low micromolar range.

Notably, all these complexes were found to be much more

active than the reference−cisplatin. Unlike its unoxidized

analog, sulfoxide-based complex (S)-10o (both isomers were

tested individually) did not aﬀord 50% growth inhibition even

at the concentration of 30 μM. Furthermore, in the case of κ³-

N,N,N-palladocycle (S)-11 with the histidine-derived ligand,

only 20−30% growth inhibition was achieved at the

concentration of 200 μM. Its counterpart with the chlorine

substituent in the pyridine ring (complex (S)-12) even

facilitated the growth of cancer cells at the concentration of

80 μM. Therefore, the presence of the sulﬁde ancillary donor

group appears to be crucial for the cytotoxic activity of this type

of palladium(II) complexes.

Using complex (S)-10 as a representative example, it was

shown that this type of cyclopalladated derivatives is stable not

only in neat DMSO, but also in DMSO−water or DMSO−PBS

solutions (see UV−vis spectra in Figures S30 and S31). Thus,

the UV−vis spectrum of (S)-10 in DMSO at room temperature

shows broad overlapping bands, which refer mainly to MLCT

transitions involving metal-based orbitals. In DMSO−water and

DMSO−PBS solutions, these bands display hypsochromic shift

with increasing medium polarity. This implies the retention of a

pincer structure in solution. The only possible change is the

displacement of the auxiliary chloride ligand by DMSO in the

inner coordination sphere of the metal ion, which is likely to be

responsible for the observed increase in the intensity in

DMSO−water and DMSO−PBS solutions. However, there is

no evidence for the decomposition of a pincer structure over a

period of 120 h.

A wide range of current chemotherapeutic agents, including

cisplatin and its analogs, target DNA either through direct

interaction or prevention of DNA relaxation by inhibition of

topoisomerase activity. To estimate the possibility of

interaction of the pincer palladium(II) complexes under

investigation with DNA, we have studied their eﬀect on

electrophoretic mobility of supercoiled plasmid DNA. The

electrophoretic mobility patterns of the supercoiled form of

pHOT1 DNA (TopoGEN), incubated with diﬀerent amounts

of complexes (R)-8, (S)-9, (S)-10, and (S)-12, are shown in

Figure 4. A decrease in the DNA mobility with increasing

In general, complexes 7−10 exhibited better cytotoxicity

against HCT116 cancer cell line than the others, which clearly

indicates that they are more speciﬁc on this particular cancer

lineage. An extraordinary high cytotoxic eﬀect on HCT116

cancer cells was observed for palladocycle (S)-10 based on ^L-

methionine-derived carboxamide ligand (with IC₅₀value as low

as 0.45

0.05 μM). Furthermore, this complex essentially

outperformed its analog based on ^D-methionine, although in

the other cases there were no signiﬁcant diﬀerences in the

activities between ^L- and D-methionine derivatives (complexes

(S)-9 and (S)-10 (entries 3, 4) vs complexes (R)-9 and (R)-10

(entries, 5, 6)).

The comparison of cytotoxic properties of 5,5- and 5,6-

membered sulﬁde-based palladium complexes shows that a

reduction in the size of one of the fused metallocycles (i.e.,

transition from methionine to cysteine-based derivatives) leads

to a drop in the activity against MCF7 and PC3 cancer cell

lines. However, toward HCT116 cancer cells, cysteine-based

complexes (R)-7 and (R)-8 still demonstrate the high level of

activity (entries 1, 2). Interestingly, unlike histidine derivatives,

the introduction of the chlorine substituent into the pyridine

ring facilitates the improvement of cytotoxic activity of N,N,S-

complexes (entries 2 vs 1, 4 vs 3, and 6 vs 5). Note that the

positive eﬀect of nonreactive chlorine substituents in aromatic

or heteroaromatic moieties of some molecules on their intrinsic

biological activity has been already reported in the literature

and is often connected with an increase in the molecule

lipophilicity and possibility of nonbonding interaction of the

chlorine atom in the binding site.²⁷

Figure 4. Gel electrophoresis diagrams showing the eﬀect of

complexes (R)-8, (S)-9, (S)-10, and (S)-12 on supercoiled pHOT1

DNA.

Taking into account that most of the drugs used for cancer

treatment are not cancer cell speciﬁc and are potentially toxic

also against normal cells, the cytotoxicity of palladocycles 7−10

was also evaluated against human embryonic kidney cells

(HEK293) as a representative of normal cell lines. The results

obtained suggest that in some cases the complexes under study

are less toxic to normal cell line than to the assayed cancer cell

lineages (for example, the selectivity indices toward HCT116

cancer cells reach up to 10.00), although in most cases similar

levels of sensitivity were observed (see Table S2). Finally, it

seemed reasonable to estimate the cytotoxic activity of the free

ligands against the same cell lines. The experiments showed

that the starting functionalized carboxamides exhibited static

rather than toxic eﬀect, because at the concentration of 30 μM,

they resulted in a reduction of cell growth no more than by

20%. Therefore, the observed cytotoxic properties of the

palladocycles under investigation are mainly determined by

coordination with the palladium ions.

concentration of the complexes is observed for all the

compounds explored, which clearly indicates their binding

with DNA. At the same time, methionine-based derivative (S)-

9 is likely to form stronger complexes, because it uncoils

plasmid DNA already at the concentration of 10 μM, whereas

the other complexes cause its retardation only at the

concentration of 20 μM.

An essential role in the processes of DNA replication,

transcription, recombination, and repair is played by nuclear

enzymes−topoisomerases. They form potentially toxic single-

or double-strand DNA breaks (depending on a particular type

of topoisomerases) and, therefore, can also serve as targets for

anticancer agents and antibiotics. Owing to the capability of

changing the topological state of DNA, they readily transform

supercoiled plasmid DNA into a population of relaxed products

(topoisomers), which can be distinguished by agarose gel

electrophoresis. Figure 5 demonstrates the eﬀect of complexes

G

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

Figure 5. Gel electrophoresis diagrams showing the eﬀect of complexes (R)-8, (S)-9, (S)-10, and (S)-12 on human DNA topoisomerase I.

NMR spectra of complexes (S)-9, (S)-10, (R)-9, and (R)-10 was

carried out based on ¹H, ¹³C{¹H}, ¹H−¹H−COSY, HMQC, and

HMBC experiments. The results obtained were used for interpretation

of the NMR spectra of the other compounds. Palladocycle (R)-8 was

additionally studied by the ROESY technique. UV−vis spectra were

registered on a Cary50 spectrometer in CaF₂cells with 0.4 mm path

length.

IR spectra were recorded on a Nicolet Magna-IR750 FT-

spectrometer, resolution 2 cm⁻¹, 128 scans. The assignment of

absorption bands in the IR spectra was made according to ref.³²

Column chromatography was carried out using Macherey-Nagel silica

gel 60 (MN Kieselgel 60, 70−230 mesh). Melting points were

determined with an MPA 120 EZ-Melt automated melting point

apparatus (Stanford Research Systems).

Syntheses. General Procedure for the Synthesis of Ligands 1−6.

A mixture of pyridine-2-carboxylic acid (0.46 g, 3.74 mmol) and SOCl₂

(16 mL) was reﬂuxed for 2 h. After cooling to room temperature, all

the volatiles were removed under reduced pressure. The resulting

residue, representing a mixture of pyridine- and 4-chloropyridine-2-

carbonyl chlorides in ∼2:1 ratio,²⁴was suspended in 15 mL of CH₂Cl₂

and added dropwise to a suspension of the amino acid methyl ester in

situ generated from the corresponding hydrochloride (3.74 mmol) and

Et₃N (9.32 mmol in the case of the cysteine and methionine

derivatives or 13.50 mmol in the case of the histidine derivative) in 10

mL of CH₂Cl₂at −5 °C. The reaction mixture was stirred overnight

and poured into 50 mL of distilled water. The organic layer was

separated, washed with saturated aqueous solution of NaHCO₃, dried

over anhydrous Na₂SO₄, and evaporated to dryness. The residue

obtained was puriﬁed by column chromatography on silica gel

(gradient elution using neat CH₂Cl₂and CH₂Cl₂/MeOH mixtures

(from 100:1 to 75:1)) to give the desired ligands as white (1−5) or

light-beige (6) crystalline solids.

(R)-8, (S)-9, (S)-10, and (S)-12 on inhibition of activity of

human DNA topoisomerase I. All the tested palladocycles

inhibited signiﬁcantly DNA relaxation in a concentration-

dependent manner, with complex (S)-10 being slightly less

eﬀective than the others.

However, it should be taken into account that the DNA

relaxation experiment is very sensitive to DNA intercalators,

which can counteract the activity of topoisomerase I by

unwinding DNA. Furthermore, there are no substantial

diﬀerences in the DNA binding and topoisomerase I inhibition

abilities between N,N,S- and N,N,N-complexes, although their

cytotoxic properties strongly diﬀer. In addition, according to

the results of preliminary staining assays using ﬂuorescence

microscopic analysis, the cytotoxic complexes under consid-

eration (compound (S)-10 as a representative example) do not

induce signiﬁcant levels of apoptosis in HCT116 cancer cells.

Therefore, further detailed investigations are required to

elucidate the mechanism of cytotoxic action of palladium(II)

pincer complexes based on picolinylamides functionalized with

amino acids.

EXPERIMENTAL SECTION

■

General Remarks. Unless otherwise noted, all manipulations were

carried out without taking precautions to exclude air and moisture.

Dichloromethane was distilled from P₂O₅. Methionine methyl ester

hydrochlorides (^L- and D-isomers) were synthesized by the

esteriﬁcation of the corresponding amino acids under action of

dimethylsulﬁte, in situ generated by the reaction of SOCl₂with an

excess of methanol at low temperature.²⁸L-S-Methylcysteine methyl

ester hydrochloride was obtained from ^L-cysteine methyl ester

hydrochloride via sequential treatment with di-tert-butyl dicarbonate,²⁹

methyl iodide,³⁰and acetyl chloride.³¹A solution of hydrogen

Methyl (2R)-3-(methylsulfanyl)-2-[(pyridin-2-ylcarbonyl)amino]-

propanoate, (R)-1. Yield: 0.16 g (17%). Mp: 50−52 °C (hexane).

t

peroxide in BuOH was obtained from 30% aq. H₂O₂and BuOH.

The concentration of H₂O₂was determined by iodine/thiosulfate

titration. All other chemicals, including ^L-histidine methyl ester

dihydrochloride, and solvents were used as purchased.

NMR spectra were recorded on Bruker AV-300, AV-400 and AV-

600 spectrometers, and the chemical shifts (δ) were referenced

internally by the residual solvent signals relative to tetramethylsilane.

In most cases, ¹³C{¹H} NMR spectra were registered using the

JMODECHO mode; the signals for the C nuclei bearing odd and even

numbers of protons have opposite polarities. The assignment of the

[α]_D²⁵+2.4 (c = 0.7, CHCl₃). ¹H NMR (400.13 MHz, CDCl₃): δ 2.18

(s, 3H, SMe), 3.06−3.16 (m, 2H, CH₂), 3.83 (s, 3H, OMe), 5.03−5.08

3

(m, 1H, CH), 7.48 (ddd, 1H, H(C4), J_HH= 7.7 Hz, J_HH= 4.8 Hz,

3

4

⁴J_HH= 1.2 Hz), 7.88 (dt, 1H, H(C3), J_HH= 7.7 Hz, J_HH= 1.6 Hz),

H

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

3

8.20 (d, 1H, H(C2), J_HH= 7.7 Hz), 8.63 (d, 1H, H(C5), J_HH= 4.8

Hz), 8.77 (br. d, 1H, NH, ³J_HH= 7.6 Hz) ppm. ¹³C{¹H} NMR (75.47

MHz, CDCl₃): δ 16.07 (s, SMe), 36.33 (s, CH₂S), 51.69 (s, OMe),

52.49 (s, CH), 122.13 and 126.31 (both s, C2 and C4), 137.13 (s, C3),

148.20 (s, C5), 148.95 (s, C1), 163.97 (s, C(O)NH), 170.99 (s,

C(O)OMe) ppm. IR (KBr, ν/cm⁻¹): 504(w), 558(w), 619(m),

700(w), 759(m), 824(w), 844(w), 859(w), 942(w), 997(m), 1023(w),

1086(w), 1106(w), 1213(m), 1236(w), 1271(w), 1291(w), 1307(w),

1326(w), 1355(m), 1410(w), 1438(m), 1463(m), 1514(s) (C(O)-

NH), 1570(w), 1589(w), 1682(s) (νCO in C(O)NH), 1743(s)

(νCO in C(O)OMe), 2852(vw), 2901(vw), 2933(w), 2955(w),

3033(vw), 3059(vw), 3383(m) (νNH). Anal. Calcd for C₁₁H₁₄N₂O₃S:

C, 51.95; H, 5.55; N, 11.02. Found: C, 52.23; H, 5.68; N, 10.95%.

Methyl (2R)-2-{[(4-chloropyridin-2-yl)carbonyl]amino}-3-

(methylsulfanyl)propanoate, (R)-2. Yield: 0.34 g (31%). Mp: 51−

NH) ppm. ¹³C{¹H} NMR (100.61 MHz, CDCl₃): δ 15.38 (s, SMe),

29.93 and 31.83 (both s, CH₂S and CH₂), 51.50 (s, OMe), 52.53 (s,

CH), 122.90 and 126.51 (both s, C2 and C4), 145.78 (s, C3), 149.10

(s, C5), 150.61 (s, C1), 162.95 (s, C(O)NH), 171.89 (s, C(O)OMe)

ppm. IR (KBr, ν/cm⁻¹): 519(w), 563(vw), 681(w), 748(w), 787(vw),

847(w), 905(w), 931(vw), 985(w), 1056(vw), 1110(w), 1158(w),

1177(w), 1220(m), 1284(w), 1355(w), 1431(w), 1449(w), 1536(s)

(C(O)NH), 1556(m), 1579(w), 1663(s) and 1674(m) (both νCO

in C(O)NH), 1748(s) (νCO in C(O)OMe), 2921(w), 2953(w),

3062(vw), 3330(m) (νNH). Anal. Calcd for C₁₂H₁₅ClN₂O₃S: C,

47.60; H, 4.99; N, 9.25. Found: C, 47.55; H, 5.06; N, 9.21%.

Methyl (2R)-4-(methylsulfanyl)-2-[(pyridin-2-ylcarbonyl)amino]-

butanoate, (R)-3. Yield: 0.24 g (24%). Mp: 49−51 °C (hexane).

25

1

53 °C (hexane). [α]_D+1.3 (c = 1.9, CHCl₃). H NMR (300.13

MHz, CDCl₃): δ 2.18 (s, 3H, SMe), 3.05−3.18 (m, 2H, CH₂), 3.84 (s,

3H, OMe), 5.02−5.08 (m, 1H, CH), 7.48−7.50 (m, 1H, H(C4)), 8.21

4

3

(d, 1H, H(C2), J_HH= 1.6 Hz), 8.54 (d, 1H, H(C5), J_HH= 5.1 Hz),

8.71 (br. d, 1H, NH, ³J_HH= 7.5 Hz) ppm. ¹³C{¹H} NMR (75.47 MHz,

CDCl₃): δ 16.05 (s, SMe), 36.27 (s, CH₂S), 51.72 (s, OMe), 52.55 (s,

CH), 122.78 and 126.44 (both s, C2 and C4), 145.63 (s, C3), 149.12

(s, C5), 150.42 (s, C1), 162.80 (s, C(O)NH), 170.79 (s, C(O)OMe)

ppm. IR (KBr, ν/cm⁻¹): 528(w), 637(w), 690(m), 697(m), 743(m),

780(vw), 803(vw), 833(w), 854(w), 884(w), 909(vw), 962(vw),

991(w), 1014(w), 1044(w), 1097(w), 1112(w), 1172(m), 1190(w),

1228(m), 1242(m), 1269(m), 1312(w), 1330(w), 1398(w), 1432(m),

1465(m), 1526(s) (C(O)NH), 1557(m), 1580(m), 1666(s) (νCO

in C(O)NH), 1718(s) and 1730(s) (both νCO in C(O)OMe),

2836(vw), 2919(w), 2950(w), 3058(w), 3102(vw), 3312(m) and

3350(m) (both νNH). Anal. Calcd for C₁₁H₁₃ClN₂O₃S: C, 45.75; H,

4.54; N, 9.70. Found: C, 45.72; H, 4.73; N, 9.51%.

25

1

[α]_D−10.3 (c = 0.6, CHCl₃). H NMR (400.13 MHz, CDCl₃): δ

2.10−2.19 (m, 1H, CH₂), 2.12 (s, 3H, SMe), 2.27−2.36 (m, 1H,

CH₂), 2.55−2.66 (m, 2H, CH₂S), 3.80 (s, 3H, OMe), 4.92−4.97 (m,

1H, CH), 7.45−7.48 (m, 1H, H(C4)), 7.87 (dt, 1H, H(C3), J_HH

3

=

7.7 Hz, ⁴J_HH= 1.3 Hz), 8.19 (d, 1H, H(C2), ³J_HH= 7.7 Hz), 8.57−8.61

(m, 2H, H(C5) + NH) ppm. ¹³C{¹H} NMR (100.61 MHz, CDCl₃): δ

15.34 (s, SMe), 29.95 and 31.92 (both s, CH₂and CH₂S), 51.38 (s,

OMe), 52.42 (s, CH), 122.22 and 126.33 (both s, C2 and C4), 137.24

(s, C3), 148.12 (s, C5), 149.10 (s, C1), 164.05 (s, C(O)NH), 172.03

(s, C(O)OMe) ppm. IR (KBr, ν/cm⁻¹): 547(vw), 621(w), 675(w),

755(w), 822(w), 842(w), 925(w), 998(w), 1041(w), 1058(w),

1085(w), 1104(w), 1173(m), 1217(m), 1270(w), 1296(w),

1360(w), 1433(m), 1451(w), 1467(w), 1532(s) (C(O)NH),

1570(w), 1590(w), 1661(s) and 1671(s) (both νCO in C(O)NH),

1728(w) and 1746(s) (both νCO in C(O)OMe), 2922(w),

2953(w), 3053(vw), 3065(vw), 3344(m) (νNH). Anal. Calcd for

C₁₂H₁₆N₂O₃S: C, 53.71; H, 6.01; N, 10.44. Found: C, 53.89; H, 6.02;

N, 10.19%.

Methyl (2S)-4-(methylsulfanyl)-2[(pyridin-2-ylcarbonyl)amino]-

butanoate, (S)-3. Yield: 0.10 g (10%). Mp: 46−48 °C (hexane).

Methyl (2R)-2-{[(4-chloropyridin-2-yl)carbonyl]amino}-4-

(methylsulfanyl)butanoate, (R)-4. Yield: 0.30 g (26%). Mp: 46−48

25

1

[α]_D+11.0 (c = 0.2, CHCl₃). H NMR (400.13 MHz, CDCl₃): δ

2.11−2.20 (m, 1H, CH₂), 2.13 (s, 3H, SMe), 2.28−2.37 (m, 1H,

CH₂), 2.56−2.67 (m, 2H, CH₂S), 3.81 (s, 3H, OMe), 4.93−4.98 (m,

3

1H, CH), 7.46−7.49 (m, 1H, H(C4)), 7.88 (dt, 1H, H(C3), J_HH

=

7.7 Hz, ⁴J_HH= 1.7 Hz), 8.20 (d, 1H, H(C2), ³J_HH= 7.7 Hz), 8.58 (br.

d, 1H, NH, ³J_HH= 8.3 Hz), 8.62 (d, 1H, H(C5), ³J_HH= 4.8 Hz) ppm.

¹³C{¹H} NMR (100.61 MHz, CDCl₃): δ 15.36 (s, SMe), 29.96 and

°C (hexane). [α]_D²⁵−58.0 (c = 0.25, CHCl₃). ¹H NMR (400.13 MHz,

CDCl₃): δ 2.09−2.18 (m, 1H, CH₂), 2.11 (s, 3H, SMe), 2.27−2.35

(m, 1H, CH₂), 2.55−2.64 (m, 2H, CH₂S), 3.80 (s, 3H, OMe), 4.90−

3

4

31.94 (both s, CH₂and CH₂S), 51.39 (s, OMe), 52.45 (s, CH), 122.22

and 126.34 (both s, C2 and C4), 137.23 (s, C3), 148.16 (s, C5),

149.13 (s, C1), 164.09 (s, C(O)NH), 172.06 (s, C(O)OMe) ppm. IR

(KBr, ν/cm⁻¹): 548(vw), 620(w), 685(m), 753(w), 786(vw), 823(w),

859(w), 925(w), 997(w), 1042(w), 1058(w), 1085(w), 1101(w),

1170(m), 1216(m), 1294(w), 1363(m), 1430(m), 1451(w), 1466(m),

1531(s) (C(O)NH), 1570(w), 1590(w), 1658(s) and 1671(s) (both

νCO in C(O)NH), 1747(s) (νCO in C(O)OMe), 2853(w),

2919(m), 2952(w), 3331(m) (νNH). Anal. Calcd for C₁₂H₁₆N₂O₃S:

C, 53.71; H, 6.01; N, 10.44. Found: C, 53.85; H, 5.85; N, 10.22%.

Methyl (2S)-2-{[(4-chloropyridin-2-yl)carbonyl]amino}-4-

(methylsulfanyl)butanoate, (S)-4. Yield: 0.28 g (25%). Mp: 50−52

4.95 (m, 1H, CH), 7.47 (dd, 1H, H(C4), J_HH= 5.2 Hz, J_HH= 1.8

Hz), 8.19 (d, 1H, H(C2), ⁴J_HH= 1.8 Hz), 8.49−8.52 (m, 2H, H(C5) +

NH) ppm. ¹³C{¹H} NMR (100.61 MHz, CDCl₃): δ 15.35 (s, SMe),

29.90 and 31.79 (both s, CH₂S and CH₂), 51.47 (s, OMe), 52.49 (s,

CH), 122.87 and 126.47 (both s, C2 and C4), 145.75 (s, C3), 149.06

(s, C5), 150.57 (s, C1), 162.90 (s, C(O)NH), 171.85 (s, C(O)OMe)

ppm. IR (KBr, ν/cm⁻¹): 519(w), 563(vw), 681(w), 748(w), 787(vw),

847(w), 905(w), 931(vw), 985(w), 1056(vw), 1093(w), 1110(w),

1158(w), 1177(w), 1220(m), 1284(w), 1355(w), 1431(w), 1449(w),

1536(s) (C(O)NH), 1556(m), 1579(w), 1663(s) and 1674(m) (both

νCO in C(O)NH), 1748(s) (νCO in C(O)OMe), 2921(w),

2953(w), 3063(vw), 3330(m) (νNH). Anal. Calcd for

C₁₂H₁₅ClN₂O₃S: C, 47.60; H, 4.99; N, 9.25. Found: C, 47.69; H,

5.06; N, 9.26%.

1

°C (hexane). [α]_D²⁵+23.0 (c = 0.5, CHCl₃). H NMR (400.13 MHz,

CDCl₃): δ 2.10−2.19 (m, 1H, CH₂), 2.12 (s, 3H, SMe), 2.27−2.36

(m, 1H, CH₂), 2.54−2.65 (m, 2H, CH₂S), 3.81 (s, 3H, OMe), 4.91−

Methyl (2S)-3-(1H-imidazol-4-yl)-2-[(pyridin-2-ylcarbonyl)-

3

4

4.96 (m, 1H, CH), 7.47 (dd, 1H, H(C4), J_HH= 5.2 Hz, J_HH= 1.8

Hz), 8.19 (d, 1H, H(C2), ⁴J_HH= 1.8 Hz), 8.50−8.52 (m, 2H, H(C5) +

amino]propanoate, (S)-5. Yield: 0.21 g (20%). Mp: 174−176 °C

1

(compare with 174−175 °C in ref 33). H NMR spectroscopy was

I

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

m) (νCO in C(O)OMe), 2920(vw), 2953(w), 3003(vw), 3060(w),

3263(br, w) (NH). Anal. Calcd for C₁₁H₁₃ClN₂O₄S: C, 43.35; H, 4.30;

N, 9.19. Found: C, 43.15; H, 4.49; N, 8.91%.

Methyl (2S)-2-{[(4-chloropyridin-2-yl)carbonyl]amino}-4-

1

(methylsulﬁnyl)butanoate, (S)-4o. H NMR spectrum is described

used to control the individuality of compounds (S)-5 and (S)-6 upon

separation by column chromatography.

Methyl (2S)-2-{[(4-chloropyridin-2-yl)carbonyl]amino}-(1H-imi-

dazol-4-yl)propanoate, (S)-6. Yield: 0.55 g (48%). Mp: 134−136

as for a single compound, because most of the signals of the isomers

(except for the NH proton signals) coincide, resulting in slightly

1

broadened patterns. Yield: 0.121 g (76%). H NMR (400.13 MHz,

CDCl₃): δ 2.26−2.36 (m, 1H, CH₂), 2.51−2.60 (m, 1H, CH₂), 2.60

(br. s, 3H, S(O)Me), 2.73−2.90 (m, 2H, CH₂S(O)), 3.83 (br. s, 3H,

OMe), 4.90−4.98 (m, 1H, CH), 7.48−7.50 (m, 1H, H(C4)), 8.18 (br.

25

°C (EtOAc/Et₂O). [α]_D+41.25 (c = 0.24, CHCl₃). ¹H NMR

(400.13 MHz, CDCl₃): δ 3.23−3.32 (m, 2H, CH₂), 3.75 (s, 3H,

OMe), 5.02−5.07 (m, 1H, CH), 6.10 (br. s, 1H, NH), 6.86 (s, 1H,

H(C7)), 7.44 (dd, 1H, H(C4), ³J_HH= 5.2 Hz, ⁴J_HH= 1.8 Hz), 7.63 (s,

1H, H(C8)), 8.15 (d, 1H, H(C2), ⁴J_HH= 1.8 Hz), 8.50 (d, 1H, H(C5),

3

s, 1H, H(C2)), 8.52 (d, 1H, H(C5), J_HH= 5.2 Hz), 8.62 and 8.64

3

(both br. d, 0.5H + 0.5H, NH, J_HH= 8.8 Hz) ppm. ¹³C{¹H} NMR

(100.61 MHz, CDCl₃): δ 25.80 and 26.26 (both s, CH₂), 38.58 and

38.66 (both s, S(O)Me), 50.24 and 50.50 (both s, CH₂S(O)), 51.22

and 51.51 (both s, OMe), 52.76 and 52.80 (both s, CH), 122.97 (br. s,

C2 or C4), 126.67 and 126.69 (both s, C4 or C2), 145.93 and 145.95

(both s, C3), 149.11 (br. s, C5), 150.25 and 150.29 (both s, C1),

163.19 (br. s, C(O)NH), 171.15 and 171.18 (both s, C(O)OMe)

ppm. IR (thin layer, ν/cm⁻¹): 526(m), 692(w), 743(w), 784(w),

846(vw), 996(w), 1024(m) and 1043(m) (both νSO), 1098(w),

1175(w), 1222(m), 1261(w), 1308(w), 1350(w), 1446(w), 1462(w),

1520(s) (C(O)NH), 1556(m), 1579(w), 1674(s) (νCO in

C(O)NH), 1742(s) (νCO in C(O)OMe), 2852(vw), 2923(w),

2954(w), 3001(vw), 3058(vw), 3371(br, w) (NH). Anal. Calcd for

C₁₂H₁₅ClN₂O₄S: C, 45.21; H, 4.74; N, 8.79. Found: C, 45.06; H, 4.41;

N, 8.43%.

³J_HH= 5.2 Hz), 8.95 (br. d, 1H, NHC(O), J_HH= 7.8 Hz) ppm.

3

¹³C{¹H} NMR (100.61 MHz, CDCl₃): δ 29.49 (s, CH₂), 52.40 and

52.46 (both s, OMe and CH), 116.19 (s, C7), 122.83 and 126.40

(both s, C2 and C4), 133.47 (s, C6), 135.05 (s, C8), 145.64 (s, C3),

149.24 (s, C5), 150.72 (s, C1), 163.15 (s, C(O)NH), 171.57 (s,

C(O)OMe) ppm. IR (KBr, ν/cm⁻¹): 534(vw), 664(w), 692(w),

747(w), 782(vw), 816(w), 848(w), 877(vw), 908(vw), 948(w),

1002(w), 1063(w), 1109(w), 1233(w), 1250(w), 1276(m), 1322(w),

1343(w), 1447(w), 1465(w), 1532(s) (C(O)NH), 1555(m),

1579(w), 1665(s) (νCO in C(O)NH), 1736(s) (νCO in

C(O)OMe), 2849(w), 2959(w), 3063(w), 3351(m) (νNH). Anal.

Calcd for C₁₃H₁₃ClN₄O₃: C, 50.58; H, 4.24; N, 18.15. Found: C,

50.51; H, 4.29; N, 18.35%.

General Procedure for the Synthesis of [κ³-N,N,X-(L)Pd(II)Cl] (X =

S, N) Complexes 7−12, 10o. A solution of PdCl₂(NCPh)₂(76 mg,

0.198 mmol) in 4 mL of dichloromethane was added dropwise to a

solution of the corresponding ligand (0.198 mmol) and Et₃N (28 μL,

0.198 mmol) in 4 mL of CH₂Cl₂. The resulting mixture was stirred at

room temperature for 1 day and then puriﬁed by column

chromatography (eluent CH₂Cl₂/MeOH (100:1 (7−10, 10o) or

50:1 (11, 12)) to give the desired palladocycles as light-yellow ((S)-

11, (S)-12), yellow ((R)-7, (R)-8, (S)-9, (R)-9, (R)-10, and (S)-10o)

or red ((S)-10) crystalline solids.

General Procedure for the Synthesis of Ligands 2o, 4o. A mixture

of the corresponding sulﬁde ((R)-2 or (S)-4) (0.50 mmol) and 7%

t

solution of H₂O₂in BuOH (1.34 g, ∼5.5-fold excess) in 10 mL of

CHCl₃was stirred at room temperature for 1 day and then poured

into 30 mL of distilled water. The organic layer was separated, dried

over anhydrous Na₂SO₄, and evaporated to dryness. The resulting

residue was puriﬁed by column chromatography on silica gel (eluent

CH₂Cl₂/MeOH (75:1)) to give the desired sulfoxide ligands as a white

crystalline solid ((R)-2o) or a pale-yellow oil ((S)-4o).

Methyl (2R)-2{[(4-chloropyridin-2-yl)carbonyl]amino}-3-

(methylsulﬁnyl)propanoate, (R)-2o. Yield: 0.137 g (90%). Mp: 92−

Complex (R)-7 [κ³-N,N,S-(L)Pd(II)Cl]. Yield: 56 mg (72%). Mp:

197−199 °C. ¹H NMR (400.13 MHz, CDCl₃, major isomer (M) 62%,

1

94 °C (hexane/Et₂O). H NMR (400.13 MHz, CDCl₃, major isomer

(M) 68%, minor isomer (m) 32%): δ 2.70 (br. s, 3H, S(O)Me (M) +

3H, S(O)Me (m)), 3.29−3.53 (m, 2H, CH₂(M) + 2H, CH₂(m)),

3.83 (s, 3H, OMe (M)), 3.86 (s, 3H, OMe (m)), 5.07−5.11 (m, 1H,

CH (m)), 5.17−5.22 (m, 1H, CH (M)), 7.47−7.50 (m, 1H, H(C4)

(M) + 1H, H(C4) (m)), 8.17 (br. s, 1H, H(C2) (m)), 8.19 (br. s, 1H,

H(C2) (M)), 8.51−8.53 (m, 1H, H(C5) (M) + 1H, H(C5) (m)),

minor isomer (m) 38%): δ 2.61 (s, 3H, SMe (m)), 2.72 (s, 3H, SMe

2

3

(M)), 3.18 (dd, 1H, CH₂(M), J_HH= 11.2 Hz, J_HH= 6.2 Hz), 3.34

(dd, 1H, CH₂(m), ²J_HH= 13.8 Hz, ³J_HH= 2.6 Hz), 3.47 (dd, 1H, CH₂

2

3

2

(m), J_HH= 13.8 Hz, J_HH= 7.0 Hz), 3.61 (dd, 1H, CH₂(M), J_HH

=

3

11.2 Hz, J_HH= 1.9 Hz), 3.79 (s, 3H, OMe (M)), 3.81 (s, 3H, OMe

(m)), 4.79 (dd, 1H, CH (m), ³J_HH= 7.0 Hz, ³J_HH= 2.6 Hz), 4.84 (dd,

3

8.96 (br. d, 1H, NH (m), J_HH= 6.2 Hz), 9.10 (br. d, 1H, NH (M),

1H, CH (M), J_HH= 6.2 Hz, J_HH= 1.9 Hz), 7.52−7.58 (m, 1H,

H(C4) (M) + 1H, H(C4) (m)), 7.91 (d, 1H, H(C2) (m), J_HH= 8.0

³J_HH= 7.5 Hz) ppm. ¹³C{¹H} NMR (100.61 MHz, CDCl₃): δ 39.06

(s, S(O)Me (m)), 39.30 (s, S(O)Me (M)), 48.76 (s, OMe (m)), 49.04

(s, OMe (M)), 52.99 (s, CH (M)), 53.08 (s, CH (m)), 55.00 (s, CH₂

(M)), 55.91 (s, CH₂(m)), 122.85 (s, C2 or C4 (m)), 123.03 (s, C2 or

C4 (M)), 126.65 (s, C4 or C2 (M)), 126.72 (s, C4 or C2 (m)), 145.93

(s, C3 (M)), 145.97 (s, C3 (m)), 149.11 (s, C5 (M)), 149.23 (s, C5

(m)), 150.09 (br. s, C1 (M+m)), 163.24 (br. s, C(O)NH (M+m)),

169.66 (s, C(O)OMe (m)), 169.80 (s, C(O)OMe (M)) ppm. IR

(KBr, ν/cm⁻¹): 524(w), 693(w), 751(w), 783(vw), 856(w), 900(vw),

995(w), 1020(m) and 1048(sh, w) (both νSO), 1105(w), 1239(m),

1262(m), 1293(m), 1398(w), 1430(w), 1462(w), 1520(s) (C(O)-

NH), 1557(m), 1581(w), 1681(s) (νCO in C(O)NH), 1725(br,

3

Hz), 7.94 (d, 1H, H(C2) (M), J_HH= 7.3 Hz), 8.03−8.07 (m, 1H,

H(C3) (M) + 1H, H(C3) (m)), 8.82 (d, 1H, H(C5) (M), ³J_HH= 4.7

Hz), 8.86 (d, 1H, H(C5) (m), J_HH= 4.9 Hz) ppm. ¹³C{¹H} NMR

3

(100.61 MHz, CDCl₃): δ 20.86 (s, SMe (m)), 22.50 (s, SMe (M)),

45.18 (s, CH₂(m)), 47.71 (s, CH₂(M)), 53.03 (s, OMe (M)), 53.12

(s, OMe (m)), 59.57 (s, CH, M), 61.43 (s, CH (m)), 125.86 (s, C2

(m)), 125.94 (s, C2 (M)), 127.17 (s, C4 (M)), 127.30 (s, C4 (m)),

140.35 (s, C3 (M)), 140.41 (s, C3 (m)), 147.78 (s, C5 (m)), 147.89

(s, C5 (M)), 155.62 (s, C1 (M)), 155.72 (s, C1 (m)), 169.38 (s, C(O)

N (M)), 169.77 (s, C(O)N (m)), 170.15 (s, C(O)OMe (M)), 171.44

(s, C(O)OMe (m)) ppm. IR (KBr, ν/cm⁻¹): 508(w), 659(vw),

J

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

682(m), 757(m), 809(vw), 974(w), 1019(m), 1050(w), 1092(w),

1162(m), 1187(w), 1199(w), 1252(w), 1271(w), 1289(w), 1325(w),

1359(w), 1374(m), 1436(w), 1567(w), 1601(s), 1631(s) and 1637(sh,

s) (both νCO in C(O)N), 1741(s) (νCO in C(O)OMe),

2852(vw), 2922(w), 2952(w), 3002(w), 3068(vw), 3090(vw). Anal.

Calcd for C₁₁H₁₃ClN₂O₃PdS: C, 33.43; H, 3.32; N, 7.09. Found: C,

33.61; H, 3.39; N, 6.92%.

C(O)N), 1747(s) (νCO in C(O)OMe), 2920(w), 2952(w),

3078(vw). Anal. Calcd for C₁₂H₁₅ClN₂O₃PdS: C, 35.22; H, 3.69; N,

6.85. Found (%): C, 35.12; H, 3.90; N, 6.72%.

Complex (S)-10 [κ³-N,N,S-(L)Pd(II)Cl]. Yield: 75 mg (85%). Mp:

1

165−168 °C. H NMR (600.22 MHz, CDCl₃, 243 K, major isomer

Complex (R)-8 [κ³-N,N,S-(L)Pd(II)Cl]. Yield: 56 mg (66%). Mp:

203−205 °C. ¹H NMR (400.13 MHz, CDCl₃, major isomer (M) 64%,

(M) 62%, minor isomer (m) 38%): δ 1.89−1.94 (m, 1H, CH₂(m)),

2.12−2.17 (m, 1H, CH₂(M) + 1H, CH₂S (m)), 2.24−2.32 (m, 2H,

CH₂S (M)), 2.55−2.60 (m, 1H, CH₂(m)), 2.62 (br. s, 3H, SMe (M)

+ 3H, SMe (m)), 2.72−2.76 (m, 1H, CH₂(M) + 1H, CH₂S (m)),

3.73 (s, 3H, OMe (M)), 3.76 (s, 3H, OMe (m)), 4.48−4.50 (m, 1H,

CH (m)), 4.64−4.65 (m, 1H, CH (M)), 7.50−7.52 (m, 1H, H(C4)

minor isomer (m) 36%): δ 2.61 (s, 3H, SMe (m)), 2.71 (s, 3H, SMe

2

3

(M)), 3.14 (dd, 1H, CH₂(M), J_HH= 9.0 Hz, J_HH= 5.0 Hz), 3.36

(dd, 1H, CH₂(m), ²J_HH= 11.0 Hz, ³J_HH= 1.8 Hz), 3.45 (dd, 1H, CH₂

(m), ²J_HH= 11.0 Hz, ³J_HH= 5.6 Hz), 3.63 (d, 1H, CH₂(M), ²J_HH= 9.0

Hz), 3.80 (s, 3H, OMe (M)), 3.83 (s, 3H, OMe (m)), 4.81 (dd, 1H,

4

(M) + 1H, H(C4) (m)), 7.90 (d, 1H, H(C2) (m), J_HH= 2.2 Hz),

4

7.94 (d, 1H, H(C2) (M), J_HH= 2.2 Hz), 8.89 (d, 1H, H(C5) (M),

3

³J_HH= 6.0 Hz), 8.91 (d, 1H, H(C5) (m), J_HH= 6.0 Hz) ppm.

CH (m), ³J_HH= 5.6 Hz, ³J_HH= 1.8 Hz), 4.85 (d, 1H, CH (M), ³J_HH

=

¹³C{¹H} NMR (150.93 MHz, CDCl₃, 243 K): δ 22.60 (s, SMe (M)),

24.03 (s, SMe (m)), 26.46 (s, CH₂S (M)), 28.07 (s, CH₂S (m)), 30.54

(s, CH₂(M)), 30.88 (s, CH₂(m)), 52.72 (s, CH (M)), 52.84 (s, OMe

(m)), 52.90 (s, OMe (M)), 53.75 (s, CH (m)), 125.98 (s, C2 (m)),

126.04 (s, C2 (M)), 127.09 (s, C4 (M)), 127.12 (s, C4 (m)), 148.35

(s, C5 (m)), 148.39 (s, C5 (M)), 149.02 (s, C3 (m)), 149.12 (s, C3

(M)), 153.85 (s, C1 (m)), 154.03 (s, C1 (M)), 172.05 (s, C(O)N

(m)), 172.11 (s, C(O)N (M)), 172.19 (s, C(O)OMe (M)), 172.79 (s,

C(O)OMe (m)) ppm. IR (KBr, ν/cm⁻¹): 517(w), 531(w), 658(vw),

730(w), 758(m), 782(w), 843(w), 972(w), 1035(w), 1071(w),

1107(w), 1124(w), 1148(m), 1158(w), 1174(m), 1192(m),

1281(w), 1337(m), 1353(m), 1421(m), 1559(w), 1595(s), 1622(s)

(νCO in C(O)N), 1739(m) and 1754(m) (both νCO in

C(O)OMe), 2922(w), 3024(vw), 3076(w). Anal. Calcd for

C₁₂H₁₄Cl₂N₂O₃PdS: C, 32.49; H, 3.18; N, 6.31. Found: C, 32.25;

H, 3.35; N, 6.49%.

5.0 Hz), 7.54−7.57 (m, 1H, H(C4) (M) + 1H, H(C4) (m)), 7.92 (d,

1H, H(C2) (m), ⁴J_HH= 1.3 Hz), 7.94 (d, 1H, H(C2) (M), ⁴J_HH= 1.5

3

Hz), 8.78 (d, 1H, H(C5) (M), J_HH= 4.9 Hz), 8.79 (d, 1H, H(C5)

3

(m), J_HH= 5.2 Hz) ppm. ¹³C{¹H} NMR (100.61 MHz, CDCl₃): δ

20.84 (s, SMe (m)), 22.47 (s, SMe (M)), 45.11 (s, CH₂(m)), 47.69

(s, CH₂(M)), 52.97 (s, OMe (M)), 53.05 (s, OMe (m)), 59.58 (s,

CH (M)), 61.50 (s, CH (m)), 126.18 (s, C2 (m)), 126.26 (s, C2

(M)), 127.20 (s, C4 (M)), 127.34 (s, C4 (m)), 148.28 (s, C5 (m)),

148.37 (s, C5 (M)), 149.00 (s, C3 (M)), 149.08 (s, C3 (m)), 156.63

(s, C1 (M)), 156.66 (s, C1 (m)), 168.13 (s, C(O)N (M)), 168.50 (s,

C(O)N (m)), 169.79 (s, C(O)OMe (M)), 171.09 (s, C(O)OMe

(m)) ppm. IR (KBr, ν/cm⁻¹): 534(w), 701(vw), 767(m), 778(w),

836(w), 852(w), 912(w), 975(w), 1026(m), 1108(m), 1168(m),

1197(m), 1253(m), 1282(w), 1368(m), 1422(m), 1555(w), 1594(s),

1633(s) and 1642(s) (both νC = O in C(O)N), 1732(s) (νCO in

C(O)OMe), 2850(vw), 2929(w), 2947(w), 2999(w), 3061(vw),

3078(vw). Anal. Calcd for C₁₁H₁₂Cl₂N₂O₃PdS: C, 30.75; H, 2.82;

N, 6.52. Found: C, 31.09; H, 2.88; N, 6.54%.

Complex (R)-9 [κ³-N,N,S-(L)Pd(II)Cl]. Yield: 80 mg (99%). Mp:

1

157−159 °C. H NMR (600.22 MHz, CDCl₃, 243 K, major isomer

Complex (S)-9 [κ³-N,N,S-(L)Pd(II)Cl]. Yield: 72 mg (89%). Mp:

1

155−157 °C. H NMR (600.22 MHz, CDCl₃, 243 K, major isomer

(M) 61%, minor isomer (m) 39%): δ 1.87−1.92 (m, 1H, CH₂(m)),

2.14−2.18 (m, 1H, CH₂(M) + 1H, CH₂S (m)), 2.29−2.31 (m, 2H,

CH₂S (M)), 2.59−2.63 (m, 1H, CH₂(m)), 2.65 (s, 3H, SMe (M)),

2.66 (s, 3H, SMe (m)), 2.74−2.77 (m, 1H, CH₂(M) + 1H, CH₂S

(m)), 3.76 (s, 3H, OMe (M)), 3.79 (s, 3H, OMe (m)), 4.56−4.57 (m,

1H, CH (m)), 4.70−4.71 (m, 1H, CH (M)), 7.53−7.57 (m, 1H,

(M) 62%, minor isomer (m) 38%): δ 1.88−1.93 (m, 1H, CH₂(m)),

2.12−2.19 (m, 1H, CH₂(M) + 1H, CH₂S (m)), 2.24−2.32 (m, 2H,

CH₂S (M)), 2.56−2.61 (m, 1H, CH₂(m)), 2.63 (s, 3H, SMe (m)),

2.64 (s, 3H, SMe (M)), 2.72−2.76 (m, 1H, CH₂(M) + 1H, CH₂S

(m)), 3.74 (s, 3H, OMe (M)), 3.77 (s, 3H, OMe (m)), 4.51−4.53 (m,

1H, CH (m)), 4.66−4.68 (m, 1H, CH (M)), 7.52−7.56 (m, 1H,

3

H(C4) (M) + 1H, H(C4) (m)), 7.98 (d, 1H, H(C2) (m), J_HH= 7.9

3

H(C4) (M) + 1H, H(C4) (m)), 7.95 (d, 1H, H(C2) (m), J_HH= 7.3

Hz), 7.99 (d, 1H, H(C2) (M), J_HH= 7.9 Hz), 8.04−8.07 (m, 1H,

3

Hz), 7.98 (d, 1H, H(C2) (M), J_HH= 7.4 Hz), 8.03−8.06 (m, 1H,

H(C3) (M) + 1H, H(C3) (m)), 9.02 (d, 1H, H(C5) (M), ³J_HH= 5.4

3

H(C3) (M) + 1H, H(C3) (m)), 8.96 (d, 1H, H(C5) (M), ³J_HH= 5.1

Hz), 9.05 (d, 1H, H(C5) (m), J_HH= 5.3 Hz) ppm. ¹³C{¹H} NMR

3

Hz), 9.01 (d, 1H, H(C5) (m), J_HH= 5.2 Hz) ppm. ¹³C{¹H} NMR

(150.93 MHz, CDCl₃, 243 K): δ 22.57 (s, SMe (M)), 24.05 (s, SMe

(m)), 26.52 (s, CH₂S (M)), 28.05 (s, CH₂S (m)), 30.64 (s, CH₂

(M)), 31.00 (s, CH₂(m)), 52.70 (s, CH (M)), 52.80 (s, OMe (m)),

52.86 (s, OMe (M)), 53.67 (s, CH (m)), 125.61 (s, C2 (m)), 125.63

(s, C2 (M)), 127.01 (s, C4 (M)), 127.03 (s, C4 (m)), 140.55 (s, C3

(m)), 140.63 (s, C3 (M)), 147.75 (s, C5 (m)), 147.79 (s, C5 (M)),

152.83 (s, C1 (m)), 152.97 (s, C1 (M)), 172.45 (s, C(O)OMe (M)),

173.02 (s, C(O)OMe (m)), 173.27 (s, C(O)N (m)), 173.30 (s, C(O)

N (M)) ppm. IR (KBr, ν/cm⁻¹): 509(w), 660(w), 683(w), 762(w),

813(w), 983(w), 1028(w), 1056(w), 1070(w), 1112(w), 1163(m),

1193(m), 1242(w), 1281(w), 1294(w), 1342(w), 1370(sh, m),

1375(m), 1432(w), 1481(w), 1569(w), 1600(s), 1628(s) (νCO in

C(O)N), 1747(s) (νCO in C(O)OMe), 2852(vw), 2883(vw),

(150.93 MHz, CDCl₃, 243 K): δ 22.53 (s, SMe (M)), 24.03 (s, SMe

(m)), 26.42 (s, CH₂S (M)), 28.02 (s, CH₂S (m)), 30.54 (s, CH₂

(M)), 30.94 (s, CH₂(m)), 52.71 (s, CH (M)), 52.88 (s, OMe (m)),

52.95 (s, OMe (M)), 53.74 (s, CH (m)), 125.62 (s, C2 (m)), 125.68

(s, C2 (M)), 127.07 (s, C4 (M)), 127.12 (s, C4 (m)), 140.63 (s, C3

(m)), 140.73 (s, C3 (M)), 147.73 (br. s, C5 (M+m)), 152.69 (s, C1,

(m)), 152.82 (s, C1 (M)), 172.51 (s, C(O)OMe (M)), 173.08 (s,

C(O)OMe (m)), 173.28 (s, C(O)N (m)), 173.32 (s, C(O)N (M))

ppm. IR (KBr, ν/cm⁻¹): 509(w), 660(w), 682(w), 726(vw), 762(m),

812(w), 983(w), 1027(w), 1056(w), 1071(w), 1111(w), 1163(m),

1193(m), 1242(w), 1281(w), 1294(w), 1342(w), 1368 (sh, m),

1374(m), 1431(w), 1481(w), 1569(w), 1600(s), 1629(s) (νCO in

K

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

2920(w), 2952(w), 3078(w). Anal. Calcd for C₁₂H₁₅ClN₂O₃PdS: C,

35.22; H, 3.69; N, 6.85. Found: C, 34.93; H, 3.66; N, 6.62%.

Complex (R)-10 [κ³-N,N,S-(L)Pd(II)Cl]. Yield: 87 mg (99%). Mp:

²J_HH= 15.1 Hz, ³J_HH= 3.9 Hz, ⁴J_HH= 1.0 Hz), 3.45 (dd, 1H, CH₂, ²J_HH

= 15.1 Hz, ³J_HH= 3.9 Hz), 3.60 (s, 3H, OMe), 4.94 (vt, 1H, CH, ³J_HH

= 3.9 Hz), 6.93 (s, 1H, H(C7)), 7.47 (dd, 1H, H(C4), ³J_HH= 6.1 Hz,

1

4

⁴J_HH= 2.4 Hz), 7.99 (d, 1H, H(C2), J_HH= 2.4 Hz), 8.30 (s, 1H,

165−170 °C. H NMR (600.22 MHz, CDCl₃, 243 K, major isomer

3

H(C8)), 9.05 (d, 1H, H(C5), J_HH= 6.1 Hz), 10.04 (br. s, 1H, NH)

ppm. ¹³C{¹H} NMR (100.61 MHz, (CD₃)₂SO): δ 30.81 (s, CH₂),

52.14 and 52.26 (both s, OMe and CH), 115.11 (s, C7), 125.25 and

127.94 (both s, C2 and C4), 131.71 (s, C6), 141.37 (s, C8), 148.02 (s,

C3), 150.34 (s, C5), 155.51 (s, C1), 169.70 and 171.54 (both s, C(O)

N and C(O)OMe) ppm. IR (KBr, ν/cm⁻¹): 538(vw), 629(w),

700(vw), 767(m), 824(vw), 988(vw), 1020(vw), 1084(w), 1108(w),

1177(m), 1203(m), 1275(w), 1376(m), 1428(m), 1501(w), 1555(w),

1594(s), 1613(s) (νCO in C(O)N), 1740(m) (νCO in

C(O)OMe), 2907(w), 3037(w), 3101(w), 3147(w). Anal. Calcd for

C₁₃H₁₂Cl₂N₄O₃Pd: C, 34.73; H, 2.69; N, 12.46. Found: C, 34.79; H,

2.72; N, 12.29%.

(M) 61%, minor isomer (m) 39%): δ 1.89−1.93 (m, 1H, CH₂(m)),

2.13−2.17 (m, 1H, CH₂(M) + 1H, CH₂S (m)), 2.25−2.31 (m, 2H,

CH₂S (M)), 2.56−2.61 (m, 1H, CH₂(m)), 2.63 (br. s, 3H, SMe (M)

+ 3H, SMe (m)), 2.73−2.76 (m, 1H, CH₂(M) + 1H, CH₂S (m)),

3.74 (s, 3H, OMe (M)), 3.77 (s, 3H, OMe (m)), 4.50−4.52 (m, 1H,

CH (m)), 4.65−4.66 (m, 1H, CH (M)), 7.51−7.53 (m, 1H, H(C4)

(M) + 1H, H(C4) (m)), 7.92 (br. s, 1H, H(C2) (m)), 7.95 (br. s, 1H,

H(C2) (M)), 8.90−8.93 (m, 1H, H(C5) (M) + 1H, H(C5) (m))

ppm. ¹³C{¹H} NMR (150.93 MHz, CDCl₃, 243 K): δ 22.61 (s, SMe

(M)), 24.05 (s, SMe (m)), 26.49 (s, CH₂S (M)), 28.08 (s, CH₂S

(m)), 30.56 (s, CH₂(M)), 30.91 (s, CH₂(m)), 52.72 (s, CH (M)),

52.84 (s, OMe (m)), 52.90 (s, OMe (M)), 53.73 (s, CH (m)), 126.00

(s, C2 (m)), 126.04 (s, C2 (M)), 127.09 (s, C4 (M)), 127.11 (s, C4

(m)), 148.36 (s, C5 (m)), 148.41 (s, C5 (M)), 149.03 (s, C3 (m)),

149.13 (s, C3 (M)), 153.89 (s, C1 (m)), 154.06 (s, C1 (M)), 172.07

(s, C(O)N) (m)), 172.13 (s, C(O)N (M)), 172.19 (s, C(O)OMe

(M)), 172.78 (s, C(O)OMe (m)) ppm. IR (KBr, ν/cm⁻¹): 517(w),

531(w), 658(vw), 730(w), 758(m), 782(w), 842(w), 904(w), 972(w),

1035(w), 1108(w), 1124(w), 1148(m), 1158(w), 1174(m), 1192(m),

1281(w), 1337(m), 1353(m), 1422(m), 1558(w), 1595(s), 1622(s)

(νCO in C(O)N), 1739(m) and 1754(m) (both νCO in

C(O)OMe), 2922(w), 3024(vw), 3076(w). Anal. Calcd for

C₁₂H₁₄Cl₂N₂O₃PdS: C, 32.49; H, 3.18; N, 6.31. Found: C, 32.33;

H, 2.93; N, 6.23%.

Complex (S)-10o [κ³-N,N,S-(L)Pd(II)Cl]. A mixture of two isomers

(major isomer 62%, minor isomer 38%) was separated by thin layer

chromatography on silica gel plates (eluent CHCl₃/MeOH (15:1)).

Major Isomer (isomer with the lower adsorption capacity). Yield:

1

50 mg (55%). Mp: 223−225 °C. H NMR (400.13 MHz, CDCl₃): δ

2.63−2.67 (m, 2H, CH₂), 2.88−2.95 (m, 1H, CH₂S(O)), 3.05−3.10

(m, 1H, CH₂S(O)), 3.50 (s, 3H, S(O)Me), 3.79 (s, 3H, OMe), 4.79−

3

4

4.81 (m, 1H, CH), 7.55 (dd, 1H, H(C4), J_HH= 6.0 Hz, J_HH= 2.0

Hz), 8.00 (d, 1H, H(C2), ⁴J_HH= 2.0 Hz), 9.04 (d, 1H, H(C5), ³J_HH

=

6.0 Hz) ppm. ¹³C{¹H} NMR (100.61 MHz, CDCl₃): δ 24.99 (s,

CH₂), 43.73 (s, S(O)Me), 47.98 (s, CH₂S(O)), 52.37 and 53.96 (both

s, OMe and CH), 126.19 (s, C2), 127.00 (s, C4), 148.52 (s, C5),

149.86 (s, C3), 153.81 (s, C1), 171.82 and 172.37 (both s, C(O)N

and C(O)OMe) ppm. IR (KBr, ν/cm⁻¹): 536(w), 677(w), 698(w),

734(w), 757(w), 784(w), 843(w), 901(vw), 981(w), 1015(w),

1036(w), 1069(w), 1128(m) and 1158(m) (both νSO), 1173(m),

1199(m), 1260(w), 1281(w), 1297(w), 1351(m), 1401(w), 1426(m),

1557(w), 1595(s), 1624(s) (νCO in C(O)N), 1738(s) (νCO in

C(O)OMe), 2917(w), 2953(w), 3000(vw), 3077(vw). Anal. Calcd for

C₁₂H₁₄Cl₂N₂O₄PdS: C, 31.36; H, 3.07; N, 6.09. Found: C, 31.50; H,

2.85; N, 5.88%.

Complex (S)-11 [κ³-N,N,N-(L)Pd(II)Cl]. Yield: 64 mg (74%). Mp:

175−177 °C (dec.). ¹H NMR (400.13 MHz, CDCl₃): δ 2.97 (ddd, ¹H,

2

3

4

CH₂, J_HH= 15.1 Hz, J_HH= 3.9 Hz, J_HH= 1.1 Hz), 3.43 (dd, 1H,

CH₂, ²J_HH= 15.1 Hz, ³J_HH= 3.9 Hz), 3.59 (s, 3H, OMe), 4.93 (vt, 1H,

Minor Isomer (isomer with the higher adsorption capacity).

1

3

Yield: 30 mg (33%). Mp: > 245 °C (dec.). H NMR (400.13 MHz,

CH, J_HH= 3.9 Hz), 6.91 (br. s, 1H, H(C7)), 7.48−7.51 (m, 1H,

H(C4)), 7.97 (dd, 1H, H(C2), ³J_HH= 7.6 Hz, ⁴J_HH= 1.0 Hz), 8.03 (dt,

1H, H(C3), ³J_HH= 7.6 Hz, ⁴J_HH= 1.3 Hz), 8.25 (s, 1H, H(C8)), 9.15

CDCl₃): δ 2.02−2.10 (m, 1H, CH₂), 2.57−2.66 (m, 1H, CH₂), 3.11−

3.14 (m, 2H, CH₂S(O)), 3.52 (s, 3H, S(O)Me), 3.74 (s, 3H, OMe),

3

(d, 1H, H(C5), J_HH= 5.4 Hz), 10.65 (br. s, 1H, NH) ppm. ¹³C{¹H}

3

4.55 (dd, 1H, CH, J_HH= 7.8 Hz, J_HH= 3.5 Hz), 7.47 (dd, 1H,

H(C4), ³J_HH= 6.0 Hz, ⁴J_HH= 2.4 Hz), 7.97 (d, 1H, H(C2), ⁴J_HH= 2.4

Hz), 8.91 (d, 1H, H(C5), ³J_HH= 6.0 Hz) ppm. ¹³C{¹H} NMR (100.61

MHz, CDCl₃): δ 25.62 (s, CH₂), 43.87 (s, S(O)Me), 49.21 (s,

CH₂S(O)), 52.47 and 55.38 (both s, OMe and CH), 126.31 (s, C2),

126.93 (s, C4), 148.45 (s, C5), 149.86 (s, C3), 153.61 (s, C1), 171.49

and 171.57 (both s, C(O)N and C(O)OMe) ppm. IR (KBr, ν/cm⁻¹):

532(w), 679(w), 698(w), 731(w), 761(w), 784(w), 842(w), 899(w),

980(w), 1036(w), 1111(w), 1133(m) and 1161(m) (both νSO),

1177(m), 1200(m), 1258(w), 1278(w), 1299(vw), 1354(m),

1428(m), 1557(w), 1595(s), 1626(s) (νCO in C(O)N), 1747(m)

(νCO in C(O)OMe), 2918(w), 2952(w), 3009(vw), 3076(vw).

Anal. Calcd for C₁₂H₁₄Cl₂N₂O₄PdS: C, 31.36; H, 3.07; N, 6.09.

Found: C, 31.06; H, 2.80; N, 5.86%.

NMR (100.61 MHz, CDCl₃): δ 30.71 (s, CH₂), 52.03 and 52.11 (both

s, OMe and CH), 113.53 (s, C7), 125.17 and 126.38 (both s, C2 and

C4), 132.75 (s, C6), 139.66 (c, C3), 149.24(c, C5), 154.85 (c, C1),

171.34 and 171.62 (both s, C(O)N) and C(O)OMe) ppm (the signal

of C8 carbon nucleus was not observed). IR (KBr, ν/cm⁻¹): 502(vw),

628(w), 687(w), 760(w), 808(vw), 987(vw), 1019(vw), 1054(w),

1085(w), 1175(m), 1202(m), 1275(w), 1292(w), 1356(w), 1400(m),

1437(w), 1501(w), 1569(m), 1588(s), 1618(m) (νCO in C(O)N),

1740(m) (νCO in C(O)OMe), 2917(m), 3033(w), 3114(w). Anal.

Calcd for C₁₃H₁₃ClN₄O₃Pd·0.25CH₂Cl₂: C, 36.47; H, 3.12; N, 12.84.

Found: C, 36.34; H, 3.47; N, 12.72%.

Complex (S)-12 [κ³-N,N,N-(L)Pd(II)Cl]. Yield: 77 mg (87%). Mp:

215−218 °C. ¹H NMR (400.13 MHz, CDCl₃): δ 2.96 (ddd, ¹H, CH₂,

Solid-Phase Syntheses Using a Mortar. Ligand (R)-2, (S)-4, (R)-

4, or (S)-6 (0.120 mmol) and PdCl₂(NCPh)₂(46 mg, 0.120 mmol)

were manually ground in a mortar. In the case of compounds (R)-2,

(S)-4, and (R)-4 with ancillary S-donor group, grinding for ∼2 min

aﬀorded a dark-yellow or brown paste, which slowly solidiﬁed and

lightened (for 2 h) to give a yellow ((S)-4) or dark yellow ((R)-2, (R)-

4) free-ﬂowing powder. The resulting sample was additionally rinsed

with hexane and Et₂O to remove residual benzonitrile. In the case of L-

L

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

Table 2. Crystal Data and Structure Reﬁnement Parameters for (R)-7, (S)-9, (S)-10, (R)-9, (R)-10, and (S)-10o

(R)-7

(S)-9

(S)-10

(R)-9

(R)-10

(S)-10o

empirical formula

formwt

T (K)

C₂₂H₂₆Cl₂N₄O₆Pd₂S₂

790.29

C₁₂H₁₅ClN₂O₃PdS

409.17

C₁₂H₁₄Cl₂N₂O₃PdS

443.61

C₁₂H₁₅ClN₂O₃PdS

409.17

C₁₂H₁₄Cl₂N₂O₃PdS

443.61

C₁₂H₁₄Cl₂N₂O₄PdS

459.61

120

296

120

cryst syst

space group

Z

monoclinic

P2₁

monoclinic

P2₁

monoclinic

P2₁

monoclinic

P2₁

monoclinic

P2₁

monoclinic

P2₁

4

8

a (Å)

7.880(2)

12.236(3)

14.380(4)

103.094(5)

1350.5(6)

1.943

11.4307(8)

8.3369(6)

15.8538(11)

92.6810(10)

1509.16(18)

1.801

8.3614(8)

11.6434(11)

15.9392(15)

102.379(2)

1515.7(2)

1.944

11.303(8)

8.322(6)

16.007(12)

92.767(19)

1503.9(18)

1.807

8.3586(7)

11.6211(8)

15.9479(12)

102.353(2)

1513.3(2)

1.947

11.296(2)

15.476(3)

18.931(4)

91.362(4)

3308.5(11)

1.845

b (Å)

c (Å)

β (deg)

V (Å³)

D_calcd(g cm⁻¹

)

linear absorption, μ 17.3

15.52

17.24

15.57

17.26

15.87

(cm⁻¹

)

F(000)

784

816

880

816

54

880

1824

60

2θ_max(deg)

56

58

56

no. of reﬂns measd

14 506

6501

30 500

8032

12 246

7861

5240

5148

11 651

6716

9930

no. of independent

reﬂns

no. of obsd reﬂns [I 5666

> 2σ(I)]

7372

7631

4942

6427

7436

params

347

365

383

365

383

801

R1

0.0684

0.1710

1.060

0.0224

0.0514

1.001

0.0255

0.0478

0.999

0.0414

0.0996

1.042

0.0259

0.0584

1.009

0.0546

0.1299

1.027

wR2

GOF

Δρ_max/ Δρ_min(e

5.295/−0.780

0.350/−0.386

0.494/−0.565

0.753/−1.831

0.676/−0.950

1.280/−1.228

Å⁻³

)

histidine-based ligand (S)-6, grinding for 2 min resulted in a light-

beige free-ﬂowing powder, which was heated in an open test tube at

85−90 °C for 10 min to yield a reddish powder. Note that the reaction

temperature was optimized by preliminary heating of a sample of the

homogenized mixture on an MPA 120 EZ-Melt automated melting

point apparatus (Stanford Research Systems) and corresponded to the

expected changes in the phase state (melting followed by solidiﬁcation

at the higher temperature).

Mechanochemical Synthesis in a Vibration Ball Mill. Ligand (S)-4

(315 mg, 1.04 mmol) and PdCl₂(NCPh)₂(400 g, 1.04 mmol) were

shaken in a stainless steel jar with two grinding balls using a Narva

DDR GM 9458 electrically powdered vibration ball mill. Grinding was

stopped after several intervals of time to analyze the reaction mixture

(Figure S28). The ﬁrst 10 s of grinding resulted in an essentially

compressed nonuniform mixture comprising large areas of dark

semisolid and dry yellow powder. Additional grinding for 30 s aﬀorded

a brown amorphous mass. In a further 20 s, the mixture converted to a

brown paste because of a large amount of benzonitrile released in the

reaction course. The resulting residue was thoroughly rinsed with

hexane to give a dark-yellow free-ﬂowing powder.

Crystallographic data for (R)-7, (S)-9, (S)-10, (R)-9, (R)-10, and

(S)-10o have been depostied with the Cambridge Crystallographic

Data Centre as CCDC 1473760−1473765.

Cytotoxicity Assays. The cytotoxicities of the complexes obtained

were tested against human colon cancer cell line HCT116, human

breast cancer cell line MCF7, human prostate cancer cell line PC3, and

normal human embryonic kidney cells HEK293. RPMI-1640 and

DMEM media were obtained from Gibco. Fetal bovine serum (FBS)

was purchased from HyClone. Cells were cultured in RPMI-1640 (in

the case of PC3) or DMEM (in the other cases) media supplemented

with 10% FBS, 100 units/L penicillin, and 100 μg/mL streptomycin in

a humidiﬁed incubator with 5% CO₂atmosphere. The eﬀect of the

compounds on cell viability was evaluated by the standard MTT assay

(ICN Biomedicals, Germany). Cells were seeded in triplicate at a cell

density of 5 × 10³/well in 96-well plates in 100 μL complete medium

and preincubated for 24 h. The tested compounds were initially

dissolved in DMSO. The compounds at various concentrations were

added to the media. The well plates were incubated for 48 h followed

by addition of MTT solution (Sigma) (20 μL, 5 mg/mL). The cells

were incubated at 37 °C for further 3 h; then the culture medium was

removed, and formazan crystals were dissolved in DMSO (70 μL).

The absorbance of the resulting solutions was measured on a multiwell

plate reader (Uniplan, Picon, Russia) at 590 nm to determine the

percentage of surviving cells. The reported values of IC₅₀are the

averages of three independent experiments (Table 1). Cisplatin from a

commercial source was used as a reference.

X-ray Diﬀraction. Single crystals suitable for X-ray experiments

were obtained by recrystallization from CH₂Cl₂/CHCl₃/hexane ((R)-

7), CH₂Cl₂/CHCl₃/Et₂O ((S)-9, (R)-9, (S)-10o), CH₂Cl₂/hexane

((S)-10), and CH₂Cl₂/hexane/Et₂O ((R)-10).

X-ray diﬀraction experiments were carried out with a SMART

APEX2 DUO CCD diﬀractometer for compounds (R)-7 and (R)-10

and with a SMART APEX2 CCD diﬀractometer for the others, using

graphite monochromated Mo−Kα radiation (λ = 0.71073 Å, ω-scans)

at room temperature ((S)-9) or 120 K (in the other cases). The

structures were solved by direct method and reﬁned by the full-matrix

least-squares against F²in anisotropic approximation for non-hydrogen

atoms. Positions of the hydrogen atoms were calculated and reﬁned in

isotropic approximation in riding model. Crystal data and structure

reﬁnement parameters for complexes (R)-7, (S)-9, (S)-10, (R)-9, (R)-

10, and (S)-10o are given in Table 2. All calculations were performed

using the SHELXTL software.³⁴

DNA Binding Experiments. The DNA binding abilities of

complexes (R)-8, (S)-9, (S)-10, and (S)-12 were evaluated by agarose

gel electrophoresis. In each experiment, a solution of 0.15 μg of

supercoiled pHOT1 plasmid DNA (TopoGEN) in TE buﬀer (1 M

Tris-HCl, pH 8.0, 0.1 M EDTA) and the mentioned amount of the

palladocycle (used as a stock solution in DMSO; the ﬁnal

concentration of the complexes ranged from 5 to 40 μM) was

incubated in the dark at 37 °C for 30 min. The samples of free DNA

were used as controls. After incubation, 20 μL aliquots of the resulting

solutions were loaded onto a 0.8% agarose gel. The electrophoresis

was carried out at 1.5−2.0 V/cm for 8−10 h in TE buﬀer. The gels

M

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

Temperature dependence of ¹H NMR spectrum of

complex (S)-9; ¹H, ¹³C{¹H}, COSY, HMQC, and

HMBC NMR spectra of complex (S)-9; ROESY

spectrum of complex (R)-8; IR and Raman spectra of

were stained with ethidium bromide (0.5 μg/mL) and visualized under

UV light.

Topoisomerase I Activity Inhibition Assays. The modulation of

topoisomerase I activity by complexes (R)-8, (S)-9, (S)-10, and (S)-

12 was studied using a TopoGEN Topoisomerase I Drug Screening

Kit. In the experiments, each of the mentioned palladocycles and one

unit of the puriﬁed topoisomerase from calf thymus (Fermentas,

Lithuania) were incubated with 0.13 μg of supercoiled pHOT1

plasmid DNA (TopoGEN) in a reaction buﬀer (10 mM Tris-HCl, pH

7.9, 1 mM EDTA, 0.15 M NaCl, 0.1% BSA, 0.1 mM spermidine, 5%

glycerol) for 30 min at 37 °C. The reactions were stopped with SDS.

After digestion with proteinase K (50 μg/mL, 30−60 min at 37 °C),

the samples were mixed with a DNA loading buﬀer and loaded onto a

0.9% agarose gel. The electrophoresis was performed at the maximal

voltage of 2−3 V/cm in a TAE buﬀer (2 M Tris base, 0.05 M EDTA,

1.56 M acetic acid). The gels were stained with ethidium bromide (0.5

μg/mL) and visualized via UV ﬂuorescence at wavelengths in the

range of 240 to 360 nm using a GelDoc-It TS imaging system. In the

absence of inhibitors, topoisomerase I relaxed scDNA through the

formation of a series of topoisomers. Topoisomerase I inhibition was

revealed by the ability of the complexes under investigation to retard

scDNA relaxation, which was observed as a decrease in the amount of

topoisomers and a retention of scDNA.

1

ligand (S)-4 and complex (S)-10; IR, Raman, and H

NMR spectra of the solid residues obtained after solvent-

free reactions of ligands (S)-4 and (S)-6 with

PdCl₂(NCPh)₂; photographs of the reaction mixture

during grinding of ligand (S)-4 with PdCl₂(NCPh)₂in a

vibration ball mill; UV−vis spectra of complex (S)-10 in

diﬀerent media; selected bond lengths and angles for

complexes (R)-7, (S)-9, (R)-9, (S)-10, (R)-10, and (S)-

10o; selectivity indices of complexes 7−10 (PDF)

Accession Codes

CCDC 1473760−1473765 contain the supplementary crystal-

lographic data for this paper. These data can be obtained free of

charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-

ing 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.

Investigation of Morphological Changes by Staining Assays. The

possibility of involvement of apoptosis in the cytotoxic action of the

complexes under investigation was estimated by a conventional

staining assay. For this purpose, HCT116 cancer cells were treated

with complex (S)-10 for 24 and 48 h. The morphological changes in

the cells were observed using a ﬂuorescence microscope after staining

with Hoechst 33342 (Sigma, USA) at 37 °C for 5 min and rinsing with

cold PBS. The percentage of apoptotic cells was no more than 1.5%.

AUTHOR INFORMATION

Corresponding Author

*E-mail: aleksanyan.diana@ineos.ac.ru.

ORCID

Diana V. Aleksanyan: 0000-0002-7083-2537

Yulia V. Nelyubina: 0000-0002-9121-0040

■

Notes

CONCLUSIONS

The authors declare no competing ﬁnancial interest.

■

To summarize the results presented, we have prepared and fully

characterized the rare examples of N-metalated Pd(II) pincer

complexes based on carboxamide ligands functionalized with

amino acids. We have also shown the possibility of solid-phase

synthesis of this type of palladocycles. The comparative studies

on cytotoxic activity against several human cancer cell lines

allowed us to follow the eﬀect of slight changes to the ligand

backbone on the properties of the resulting complexes. Thus,

the presence of the sulﬁde ancillary donor group is crucial for

manifestation of cytotoxic activity. The methionine-based

derivatives with the elongated S-coordination arm in most

cases appeared to be more active than their cysteine analogs.

The introduction of the chlorine substituent into the pyridine

ring facilitated the improvement of cytotoxic properties of

N,N,S-derivatives. In general, the cytotoxic activities of the

sulﬁde-based complexes are essentially higher than that of the

clinically used drug, cisplatin, and are mainly determined by the

presence of the transition metal ions. Therefore, the pallado-

cycles with multidentate ligands based on functionalized

carboxamides can be considered as a new potent class of

anticancer agents. Taking into account the strong DNA binding

and topoisomerase I inhibition activities of all the complexes

explored, further detailed investigations are required to

elucidate the mechanism of cytotoxic action of this type of

Pd(II) complexes.

ACKNOWLEDGMENTS

■

This work was supported by the Russian Foundation for Basic

Research, Projects 16-03-00695-a and 16-03-00915-a (solid-

phase cyclopalladation). The X-ray diﬀraction and NMR

spectroscopic data were obtained using the equipment of

Center for Molecule Composition Studies of INEOS RAS.

REFERENCES

■

(1) Rosenberg, B.; VanCamp, L.; Trosko, J. E.; Mansour, V. H.

Platinum Compounds: a New Class of Potent Antitumour Agents.

Nature 1969, 222, 385−386.

(2) (a) 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, 3436−3486.

(b) Mezencev, R. Interactions of Cisplatin with non-DNA Targets and

Their Influence on Anticancer Activity and Drug Toxicity: the

Complex World of the Platinum Complex. Curr. Cancer Drug Targets

2015, 14, 794−816. (c) Pranczk, J.; Jacewicz, D.; Wyrzykowski, D.;

́

Chmurzynski, L. Platinum(II) and Palladium(II) Complex Com-

pounds as Anti-Cancer Drugs. Methods of Cytotoxicity Determi-

nation. Curr. Pharm. Anal. 2014, 10, 2−9. (d) Wilson, J. J.; Lippard, S.

J. Synthetic Methods for the Preparation of Platinum Anticancer

Complexes. Chem. Rev. 2014, 114, 4470−4495. (e) Wang, X.; Guo, Z.

Targeting and Delivery of Platinum-Based Anticancer Drugs. Chem.

Soc. Rev. 2013, 42, 202−224. (f) Benedetti, M.; Malina, J.; Kasparkova,

J.; Brabec, V.; Natile, G. Chiral Discrimination in Platinum Anticancer

Drugs. Environ. Health Perspect. 2002, 110, 779−782.

ASSOCIATED CONTENT

(3) Metal Compounds in Cancer Therapy; Fricker, S. P., Ed.; Chapman

& Hall: London, 1994, DOI: 10.1007/978-94-011-1252-9.

(4) Farrell, N. Metal Complexes as Drugs and Anticancer

Chemotherapeutic Agents. In Comprehensive Coordination Chemistry

II, McCleverty, J. A., Mayer, T. J., Eds.; Elsevier: Amsterdam, 2003;

Vol. 9, pp 809−840, DOI: 10.1016/B0-08-043748-6/09021-6.

■

S

* Supporting Information

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.inorg-

chem.7b01348.

N

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

(5) (a) Muhammad, N.; Guo, Z. Metal-Based Anticancer Chemo-

therapeutic Agents. Curr. Opin. Chem. Biol. 2014, 19, 144−153.

(b) Barry, N. P. E.; Sadler, P. J. Exploration of the Medical Periodic

Table: Towards New Targets. Chem. Commun. 2013, 49, 5106−5131.

(c) Cutillas, N.; Yellol, G. S.; de Haro, C.; Vicente, C.; Rodríguez, V.;

Ruiz, J. Anticancer Cyclometalated Complexes of Platinum Group

Metal and Gold. Coord. Chem. Rev. 2013, 257, 2784−2797. (d) Gasser,

G.; Ott, I.; Metzler-Nolte, N. Organometallic Anticancer Compounds.

J. Med. Chem. 2011, 54, 3−25. (e) Casini, A.; Hartinger, C. G.;

Nazarov, A. A.; Dyson, P. J. Organometallic Antitumour Agents with

Alternative Modes of Action. Top. Organomet. Chem. 2010, 32, 57−80.

(6) (a) Kapdi, A. R.; Fairlamb, I. J. S. Anti-Cancer Palladium

Complexes: a Focus on PdX₂Cl₂, Palladacycles and Related

Complexes. Chem. Soc. Rev. 2014, 43, 4751−4777. (b) Garoufis, A.;

Hadjikakou, S. K.; Hadjiliadis, N. Palladium Coordination Compounds

as Anti-Viral, Anti-Fungal, Anti-Microbial and Anti-Tumor Agents.

Coord. Chem. Rev. 2009, 253, 1384−1397. (c) Abu-Surrah, A. S.; Al-

Sa’doni, H. H.; Abdalla, M. Y. Palladium-Based Chemotherapeutic

Agents: Routes toward Complexes with Good Antitumor Activity.

Cancer Ther. 2008, 6, 1−10. (d) Caires, A. C. F. Recent Advances

Involving Palladium(II) Complexes for the Cancer Therapy. Anti-

Cancer Agents Med. Chem. 2007, 7, 484−491.

2011, 111, 2048−2076. (e) Moreno, I.; SanMartin, R.; Ines, B.;

́

Herrero, M. T.; Domínguez, E. Recent Advances in the Use of

Unsymmetrical Palladium Pincer Complexes. Curr. Org. Chem. 2009,

13, 878−895. (f) Morales-Morales, D. Pincer Complexes. Applications

́

in Catalysis. Rev. Soc. Quim. Mex. 2004, 48, 338−346. (g) Singleton, J.

T. The Uses of Pincer Complexes in Organic Synthesis. Tetrahedron

2003, 59, 1837−1857. (h) van der Boom, M. E.; Milstein, D.

Cyclometalated Phosphine-Based Pincer Complexes: Mechanistic

Insight in Catalysis, Coordination, and Bond Activation. Chem. Rev.

2003, 103, 1759−1792.

(10) (a) Parrilha, G. L.; Ferraz, K. S. O.; Lessa, J. A.; Navakoski de

Oliveira, K.; Rodrigues, B. L.; Ramos, J. P.; Souza-Fagundes, E. M.;

Ott, I.; Beraldo, H. Metal Complexes with 2-Acetylpyridine-N(4)-

orthochlorophenylthiosemicarbazone: Cytotoxicity and Effect on the

Enzymatic Activity of Thioredoxin Reductase and Glutathione

Reductase. Eur. J. Med. Chem. 2014, 84, 537−544. (b) Kovala-

Demertzi, D.; Galani, A.; Miller, J. R.; Frampton, C. S.; Demertzis, M.

A. Synthesis, Structure, Spectroscopic Studies and Cytotoxic Effect of

Novel Palladium(II) Complexes with 2-Formylpyridine-4-N-ethyl-

thiosemicarbazone: Potential Antitumour Agents. Polyhedron 2013, 52,

1096−1102. (c) Ramachandran, E.; Senthil Raja, D.; Rath, N. P.;

Natarajan, K. Role of Substitution at Terminal Nitrogen of 2-Oxo-1,2-

dihydroquinoline-3-carbaldehyde Thiosemicarbazones on the Coordi-

nation Behavior and Structure and Biological Properties of Their

Palladium(II) Complexes. Inorg. Chem. 2013, 52, 1504−1514.

(d) Prabhakaran, P.; Kalaivani, P.; Poornima, P.; Dallemer, F.;

Huang, R.; Vijaya Padma, V.; Natarajan, K. Synthesis, DNA/Protein

Binding and in Vitro Cytotoxic Studies of New Palladium Metal-

lothiosemicarbazones. Bioorg. Med. Chem. 2013, 21, 6742−6752.

(e) Kalaivani, P.; Prabhakaran, R.; Dallemer, F.; Poornima, P.;

Vaishnavi, E.; Ramachandran, E.; Padma, V. V.; Renganathan, R.;

Natarajan, K. DNA, Protein Binding, Cytotoxicity, Cellular Uptake and

Antibacterial Activities of New Palladium(II) Complexes of Thio-

semicarbazone Ligands: Effects of Substitution on Biological Activity.

Metallomics 2012, 4, 101−113. (f) Stringer, T.; Hendricks, D. T.;

Guzgay, H.; Smith, G. S. Synthesis and Characterization of Multimeric

Salicylaldimine Thiosemicarbazones and Their Pd(II) and Pt(II)

Complexes. Polyhedron 2012, 31, 486−493. (g) Kalaivani, P.;

Prabhakaran, R.; Ramachandran, E.; Dallemer, F.; Paramaguru, G.;

Renganathan, R.; Poornima, P.; Padma, V. V.; Natarajan, K. Influence

of Terminal Substitution on Structural, DNA, Protein Binding,

Anticancer and Antibacterial Activities of Palladium(II) Complexes

Containing 3-Methoxy Salicylaldehyde-4(N) Substituted Thiosemi-

carbazones. Dalton Trans. 2012, 41, 2486−2499. (h) Ramachandran,

E.; Senthil Raja, D.; Bhuvanesh, N. S. P.; Natarajan, K. Mixed Ligand

Palladium(II) Complexes of 6-Methoxy-2-oxo-1,2-dihydroquinoline-3-

carbaldehyde 4N-Substituted Thiosemicarbazones with Triphenyl-

phosphine Co-ligand: Synthesis, Crystal Structure and Biological

Properties. Dalton Trans. 2012, 41, 13308−13323.

(7) (a) Abu-Surrah, A. S.; Al-Allaf, T. A. K.; Rashan, L. J.; Klinga, M.;

Leskela, M. Synthesis, Crystal Structure and Initial Biological

̈

Evaluation of the New Enantiomerically Pure Chiral Palladium(II)

Complex trans-Bis{endo-(1R)-1,7,7-trimethylbicyclo[2.2.1]-heptan-2-

amino}palladium(II)dichloride. Eur. J. Med. Chem. 2002, 37, 919−922.

̌

̌ ́ ̌ ́

(b) Tusek-Bozic, L. J.; Matijasic, I.; Bocelli, G.; Calestani, G.; Furlani,

A.; Scarcia, V.; Papaioannou, A. Preparation, Characterization and

Activity of Palladium(II) Halide Complexes with Diethyl 2-

Quinolylmethylphosphonate (2-dqmp). X-Ray Crystal Structures of

trans-[Pd(2-dqmp)₂X₂] (X = Cl or Br). J. Chem. Soc., Dalton Trans.

1991, 195−201.

́

(8) (a) Carreira, M.; Calvo-Sanjuan, R.; Sanau, M.; Marzo, I.; Contel,

M. Organometallic Palladium Complexes with a Water-Soluble

Iminophosphorane Ligand as Potential Anticancer Agents. Organo-

metallics 2012, 31, 5772−5781. (b) Carreira, M.; Calvo-Sanjuan

́

, R.;

Sanau, M.; Zhao, X.; Magliozzo, R. S.; Marzo, I.; Contel, M. Cytotoxic

́

Hydrophilic Iminophosphorane Coordination Compounds of d⁸

Metals. Studies of Their Interactions with DNA and HSA. J. Inorg.

Biochem. 2012, 116, 204−214. (c) Zhao, G.; Lin, H.; Ping, Y.; Sun, H.;

Zhu, S.; Xuncheng, S.; Chen, Y. Ethylenediamine-Palladium(II)

Complexes with Pyridine and Its Derivatives: Synthesis, Molecular

Structure and Initial Antitumor Studies. J. Inorg. Biochem. 1999, 73,

145−149. (d) Paul, A. K.; Mansuri-Torshizi, H.; Srivastava, T. S.;

Chavan, S. J.; Chitnis, M. P. Some Potential Antitumor 2,2′-

Dipyridylamine Pt(II)/Pd(II) Complexes with Amino Acids: Their

Synthesis, Spectroscopy, DNA Binding, and Cytotoxic Studies. J. Inorg.

Biochem. 1993, 50, 9−20. (e) Navarro-Ranninger, C.; Lop

́

ez-Solera, I.;

Perez, J. M.; Masaguer, J. R.; Alonso, C. In Vitro Antitumour Activity

́

(11) Cruz, S.; Bernes, S.; Sharma, P.; Vazquez, R.; Hernandez, G.;

̀

́

of Two Isomeric Cyclopalladated Compounds Derived from

Benzoylbenzylidenimines. Appl. Organomet. Chem. 1993, 7, 57−61.

(f) Taqui Khan, B.; Bhatt, J.; Najmuddin, K.; Shamsuddin, S.;

Annapoorna, K. Synthesis, Antimicrobial, and Antitumor Activity of a

Series of Palladium(II) Mixed Ligand Complexes. J. Inorg. Biochem.

1991, 44, 55−63. (g) Mansuri-Torshizi, H.; Mital, R.; Srivastava, T. S.;

Parekh, H.; Chitnis, M. P. Synthesis, Characterization, and Cytotoxic

Studies of α-Diimine/1,2-Diamine Platinum(II) and Palladium(II)

Complexes of Selenite and Tellurite and Binding of Some of These

Complexes to DNA. J. Inorg. Biochem. 1991, 44, 239−247.

Portillo, R.; Gutierrez, R. Synthesis, Characterization and Anticancer

́

activity of New Palladacycles Derived from Chiral α-Diimines. Appl.

Organomet. Chem. 2010, 24, 8−11.

(12) (a) Karakas, D.; Cevatemre, B.; Aztopal, N.; Ari, F.; Yilmaz, V.

T.; Ulukaya, E. Addition of Niclosamide to Palladium(II) Saccharinate

Complex of Terpyridine Results in Enhanced Cytotoxic Activity

Inducing Apoptosis on Cancer Stem Cells of Breast Cancer. Bioorg.

Med. Chem. 2015, 23, 5580−5586. (b) Icsel, C.; Yilmaz, V. T.; Kaya,

Y.; Durmus, S.; Sarimahmut, M.; Buyukgungor, O.; Ulukaya, E.

Cationic Pd(II)/Pt(II) 5,5-Diethylbarbiturate Complexes with Bis(2-

pyridylmethyl)amine and Terpyridine: Synthesis, Structures, DNA/

BSA Interactions, Intracellular Distribution, Cytotoxic Activity and

Induction of Apoptosis. J. Inorg. Biochem. 2015, 152, 38−52. (c) Kacar,

O.; Adiguzel, Z.; Yilmaz, V. T.; Cetin, Y.; Cevatemre, B.; Arda, N.;

Baykal, A. T.; Ulukaya, E.; Acilan, C. Evaluation of the Molecular

Mechanisms of a Palladium(II) Saccharinate Complex with Terpyr-

idine as an Anticancer Agent. Anti-Cancer Drugs 2014, 25, 17−29.

(d) Coskun, M. D.; Ari, F.; Oral, A. Y.; Sarimahmut, M.; Kutlu, H. M.;

Yilmaz, V. T.; Ulukaya, E. Promising Anti-Growth Effects of

(9) (a) Asay, M.; Morales-Morales, D. Non-Symmetric Pincer

Ligands: Complexes and Applications in Catalysis. Dalton Trans. 2015,

44, 17432−17447. (b) van Koten, G. Pincer Ligands as Powerful

Tools for Catalysis in Organic Synthesis. J. Organomet. Chem. 2013,

730, 156−164. (c) Niu, J.-L.; Hao, X.-Q.; Gong, J.-F.; Song, M.-P.

Symmetrical and Unsymmetrical Pincer Complexes with Group 10

Metals: Synthesis via Aryl C−H activation and Some Catalytic

Applications. Dalton Trans. 2011, 40, 5135−5150. (d) Selander, N.;

́

Szabo, K. J. Catalysis by Palladium Pincer Complexes. Chem. Rev.

O

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

Palladium(II) Saccharinate Ccomplex of Terpyridine by Inducing

Apoptosis on Transformed Fibroblasts in Vitro. Bioorg. Med. Chem.

2013, 21, 4698−4705. (e) Ulukaya, E.; Frame, F. M.; Cevatemre, B.;

Pellacani, D.; Walker, H.; Mann, V. M.; Simms, M. S.; Stower, M. J.;

Yilmaz, V. T.; Maitland, N. J. Differential Cytotoxic Activity of a Novel

Palladium-Based Compound on Prostate Cell Lines, Primary Prostate

Epithelial Cells and Prostate Stem Cells. PLoS One 2013, 8 (5),

e64278. (f) Ulukaya, E.; Ari, F.; Dimas, K.; Ikitimur, E. I.; Guney, E.;

Yilmaz, V. T. Anti-Cancer Activity of a Novel Palladium(II) Complex

on Human Breast Cancer Cells in Vitro and in Vivo. Eur. J. Med. Chem.

2011, 46, 4957−4963.

S.; Kozlov, V. A. Synthesis and Complexing Properties of Phosphorus-

Substituted Pyridine-2-Carboxylic Acid Anilides. Phosphorus, Sulfur

Silicon Relat. Elem. 2014, 189, 1028−1042. (d) Vasil’ev, A. A.;

Aleksenko, V. Yu.; Aleksanyan, D. V.; Kozlov, V. A. Catalytic Activity

of κ³-X,N,Y-Palladium Pincer Complexes (X, Y = O, S) with

(Thio)phosphoryl-substituted Carbamoylmethylphosphine oxide and

Sulfide Ligands in the Suzuki Cross-coupling. Mendeleev Commun.

2013, 23, 344−346. (e) Aleksenko, V. Yu.; Sharova, E. V.; Artyushin,

O. I.; Aleksanyan, D. V.; Klemenkova, Z. S.; Nelyubina, Yu. V.;

Petrovskii, P. V.; Kozlov, V. A.; Odinets, I. L. Coordination of P(X)-

Modified (X = O, S) N-Aryl-carbamoylmethylphosphine Oxides and

Sulfides with Pd(II) and Re(I) Ions: Facile Formation of 6,6-

Membered Pincer Complexes Featuring Atropisomerism. Polyhedron

2013, 51, 168−179.

(22) (a) Rau, T.; Alsfasser, R.; Zahl, A.; van Eldik, R. Structural and

Kinetic Studies on the Formation of Platinum(II) and Palladium(II)

Complexes with ^L-Cysteine-Derived Ligands. Inorg. Chem. 1998, 37,

4223−4230. (b) Barnham, K. J.; Djuran, M. I.; Murdoch, P. d. S.;

Ranford, J. D.; Sadler, P. J. Ring-Opened Adducts of the Anticancer

Drug Carboplatin with Sulfur Amino Acids. Inorg. Chem. 1996, 35,

1065−1072.

(23) Renfrew, A. K. Transition Metal Complexes with Bioactive

Ligands: Mechanisms for Selective Ligand Release and Applications

for Drug Delivery. Metallomics 2014, 6, 1324−1335.

(24) Tie, C.; Gallucci, J. C.; Parquette, J. R. Helical Conformational

Dynamics and Photoisomerism of Alternating Pyridinedicarboxamide/

m-(Phenylazo)azobenzene Oligomers. J. Am. Chem. Soc. 2006, 128,

1162−1171.

(25) (a) Sipos, G.; Drinkel, E. E.; Dorta, R. The Emergence of

Sulfoxides as Efficient Ligands in Transition Metal Catalysis. Chem.

Soc. Rev. 2015, 44, 3834−3860. (b) Trost, B. M.; Rao, M.

Development of Chiral Sulfoxide Ligands for Asymmetric Catalysis.

Angew. Chem., Int. Ed. 2015, 54, 5026−5043. (c) Calligaris, M.

Structure and Bonding in Metal Sulfoxide Complexes: an Update.

Coord. Chem. Rev. 2004, 248, 351−375. (d) Davies, J. A.; Hartley, F. R.

Complexes of the Platinum Metals Containing Weak Donor Ligands.

Chem. Rev. 1981, 81, 79−90.

(26) (a) Aleksanyan, D. V.; Churusova, S. G.; Aysin, R. R.;

Klemenkova, Z. S.; Nelyubina, Yu. V.; Kozlov, V. A. The First Example

of Mechanochemical Synthesis of Organometallic Pincer Complexes.

Inorg. Chem. Commun. 2017, 76, 33−35. (b) Aleksanyan, D. V.;

Klemenkova, Z. S.; Vasil’ev, A. A.; Gorenberg, A. Ya.; Nelyubina, Yu.

V.; Kozlov, V. A. Solid-Phase Cyclopalladation in S,C,S’-Pincer

Systems: Rising Alternative for Synthesis in Solution. Dalton Trans.

2015, 44, 3216−3226. (c) Kozlov, V. A.; Aleksanyan, D. V.; Korobov,

M. V.; Avramenko, N. V.; Aysin, R. R.; Maloshitskaya, O. A.;

Korlyukov, A. S.; Odinets, I. L. The First Solid Phase Synthesis of

Pincer Palladium Complexes. Dalton Trans. 2011, 40, 8768−8772.

(27) Naumann, K. Influence of Chlorine Substituents on Biological

Activity of Chemicals: a Review. Pest Manage. Sci. 2000, 56, 3−21.

(28) Hoogwater, D. A.; Peereboom, M. Kinetics of the Alkaline

Hydrolysis of Several n-Benzyloxycarbonyldipeptide Methyl and Ethyl

Esters. Tetrahedron 1990, 46, 5325−5332.

(13) (a) Ari, F.; Ulukaya, E.; Sarimahmut, M.; Yilmaz, V. T.

Palladium(II) Saccharinate Complexes with Bis(2-pyridylmethyl)-

amine Induce Cell Death by Apoptosis in Human Breast Cancer

Cells in Vitro. Bioorg. Med. Chem. 2013, 21, 3016−3021. (b) Guney,

E.; Yilmaz, V. T.; Ari, F.; Buyukgungor, O.; Ulukaya, E. Synthesis,

Characterization, Structures and Cytotoxic activity of Palladium(II)

and Platinum(II) Complexes Containing Bis(2-pyridylmethyl)amine

and Saccharinate. Polyhedron 2011, 30, 114−122.

(14) Frik, M.; Jimen

́

ez, J.; Vasilevski, V.; Carreira, M.; de Almeida, A.;

Gascon, E.; Benoit, F.; Sanau, M.; Casini, A.; Contel, M. Luminescent

́

Iminophosphorane Gold, Palladium and Platinum Complexes as

Potential Anticancer Agents. Inorg. Chem. Front. 2014, 1, 231−241.

(15) Higgins, J. D., III; Neely, L.; Fricker, S. Synthesis and

Cytotoxicity of Some Cyclometallated Palladium Complexes. J. Inorg.

Biochem. 1993, 49, 149−156.

(16) Ilic,

Harhaji-Trajkovic,

Trajkovic, V.; Trifunovic,

Antimicrobial Activities of 3-((5-Phenyl-1,3,4-oxadiazol-2-yl)methyl)-

2-thioxothiazolidin-4-one Derivatives. Eur. J. Med. Chem. 2014, 74,

502−508.

́

D. R.; Jevtic,

́

V. V.; Radic,

́

G. P.; Arsikin, K.; Ristic,

́

B.;

O.;

́

L.; Vukovic,

́

N.; Sukdolak, S.; Klisuric,

S. R. Synthesis and Evaluation of the

́

(17) Yan, L.; Wang, X.; Wang, Y.; Zhang, Y.; Li, Y.; Guo, Z.

Cytotoxic Palladium(II) Complexes of 8-Aminoquinoline Derivatives

and the Interaction with Human Serum Albumin. J. Inorg. Biochem.

2012, 106, 46−51.

(18) Fong, T. T.-H.; Lok, C.-N.; Chung, C. Y.-S.; Fung, Y.-M. E.;

Chow, P.-K.; Wan, P.-K.; Che, C.-M. Cyclometalated Palladium(II) N-

Heterocyclic Carbene Complexes: Anticancer Agents for Potent in

vitro Cytotoxicity and in vivo Tumor Growth Suppression. Angew.

Chem., Int. Ed. 2016, 55, 11935−11939.

(19) (a) The Privileged Pincer−Metal Platform: Coordination Chemistry

and Applications; van Koten, G., Gossage, R. A., Eds.; Topics in

Organometallic Chemistry;Springer, 2016; Vol. 54, DOI: 10.1007/

978-3-319-22927-0. (b) Pincer and Pincer-Type Complexes: Applications

in Organic Synthesis and Catalysis; Szabo, K., Wendt, O. F., Eds.;

Wiley−VCH: Weinheim, Germany, 2014;. (c) Organometallic Pincer

Chemistry, van Koten, G., Milstein, D., Eds.; Topics in Organometallic

Chemistry; Springer, 2013, Vol. 40 DOI: 10.1007/978-3-642-31081-2.

(d) The Chemistry of Pincer Compounds; Morales-Morales, D.; Jensen,

C. M., Eds.; Elsevier: New York, 2007.

(20) (a) Albrecht, M. Cyclometalation Using d-Block Transition

Metals: Fundamental Aspects and Recent Trends. Chem. Rev. 2010,

110, 576−623. (b) Dupont, J.; Consorti, C. S.; Spencer, J. The

Potential of Palladacycles: More Than Just Precatalysts. Chem. Rev.

2005, 105, 2527−2571. (c) Albrecht, M.; van Koten, G. Platinum

Group Organometallics Based on Pincer Complexes: Sensors,

Switches, and Catalysts. Angew. Chem., Int. Ed. 2001, 40, 3750−3781.

(21) (a) Churusova, S. G.; Aleksanyan, D. V.; Vasil’ev, A. A.;

Nelyubina, Yu. V.; Novikov, V. V.; Pavlov, A. A.; Denisov, G. L.;

Klemenkova, Z. S.; Kozlov, V. A. 5,6- and 6,6-Membered Palladium-

(II) Pincer Complexes Based on Functionalized Carboxamides with

Ancillary Sulfur and Nitrogen Donors. Eur. J. Inorg. Chem. 2016, 2016,

5271−5280. (b) Churusova, S. G.; Aleksanyan, D. V.; Klemenkova, Z.

S.; Nelyubina, Yu. V.; Artyushin, O. I.; Vasil’ev, A. A.; Kozlov, V. A.;

Sudarikov, D. V.; Rubtsova, S. A. Functionalized Mercaptoacetic and

Propionic Acid Amides: Synthesis, Cyclopalladation Features, and

Catalytic Activity of Metal Complexes. Russ. Chem. Bull. 2015, 64,

2678−2689. (c) Aleksanyan, D. V.; Nelyubina, Yu. V.; Klemenkova, Z.

(29) West, C. W.; Estiarte, M. A.; Rich, D. H. New Methods for Side-

Chain Protection of Cysteine. Org. Lett. 2001, 3, 1205−1208.

(30) Climie, I. J. G.; Evans, D. A. ¹³C-Nuclear Magnetic Resonance

Spectroscopy as a Probe of Enzyme EnvironmentII: Effect of

Solvent and pH on ¹³C-Chemical Shifts in Derivatized Amino-Acid

Models. Tetrahedron 1982, 38, 697−711.

(31) Gauthhier, J. Y. Prodrugs of inhibitors of Cathepsin S. Patent

no. WO 2008/028301 A1 (2008). https://worldwide.espacenet.com/

publicationDetails/originalDocument?CC=WO&NR=

2008028301A1&KC=A1&FT=D&ND=2&date=20080313&DB=

&locale=en_EP.

(32) Bellamy, L. J. The Infrared Spectra of Complex Molecules; Wiley:

New York, 1975.

(33) Moriuchi, T.; Nishiyama, M.; Yoshida, K.; Ishikawa, T.; Hirao,

T. Chiral Helicity Induced by Hydrogen Bonding and Chirality of

Podand Histidyl Moieties. Org. Lett. 2001, 3, 1459−1461.

P

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

(34) Sheldrick, G. M. A short history of SHELX. Acta Crystallogr.,

Sect. A: Found. Crystallogr. 2008, 64, 112−122.

Q

DOI: 10.1021/acs.inorgchem.7b01348

Inorg. Chem. XXXX, XXX, XXX−XXX

Article Doi

Highly Cytotoxic Palladium(II) Pincer Complexes Based on Picolinylamides Functionalized with Amino Acids Bearing Ancillary S-Donor Groups

DOI: 10.1021/acs.inorgchem.7b01348

Source and publish data:

Authors:

Article abstract of DOI:10.1021/acs.inorgchem.7b01348

Full text of DOI:10.1021/acs.inorgchem.7b01348

Products guided by the article

R&D Labs maybe for 29745-44-6

Relevant to this article

Hot Product