Osmium(ii) tethered half-sandwich complexes: pH-dependent aqueous speciation and transfer hydrogenation in cells

Volume 12

Number 27

21 July 2021

Pages 9249–9562

Chemical

Science

rsc.li/chemical-science

ISSN 2041-6539

EDGE ARTICLE

Ana M. Pizarro et al.

Osmium(II) tethered half-sandwich complexes:

pH-dependent aqueous speciation and transfer

hydrogenation in cells

Chemical

Science

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Osmium(II) tethered half-sandwich complexes: pH-

dependent aqueous speciation and transfer

hydrogenation in cells†

Cite this: Chem. Sci., 2021, 12, 9287

All publication charges for this article

have been paid for by the Royal Society

of Chemistry

a

ab

Sonia Infante-Tadeo,

and Ana M. Pizarro

Vanessa Rodrıguez-Fanjul,

Abraha Habtemariam

´

ac

*

Aquation is often acknowledged as a necessary step for metallodrug activity inside the cell. Hemilabile

ligands can be used for reversible metallodrug activation. We report a new family of osmium(^II) arene

complexes of formula [Os(h⁶-C₆H₅(CH₂)₃OH)(XY)Cl]^+/0(1–13) bearing the hemilabile h⁶-bound arene 3-

phenylpropanol, where XY is a neutral N,N or an anionic N,O^ꢀbidentate chelating ligand. Os–Cl bond

cleavage in water leads to the formation of the hydroxido/aqua adduct, Os–OH(H). In spite of being

considered inert, the hydroxido adduct unexpectedly triggers rapid tether ring formation by attachment

of the pendant alcohol–oxygen to the osmium centre, resulting in the alkoxy tethered complex [Os(h⁶-

arene-O-k¹)(XY)]ⁿ⁺

.

Complexes 1C–13C of formula [Os(h⁶:k¹-C₆H₅(CH₂)₃OH/O)(XY)]⁺are fully

characterised, including the X-ray structure of cation 3C. Tether-ring formation is reversible and pH

dependent. Osmium complexes bearing picolinate N,O-chelates (9–12) catalyse the hydrogenation of

pyruvate to lactate. Intracellular lactate production upon co-incubation of complex 11 (XY ¼ 4-Me-

picolinate) with formate has been quantiﬁed inside MDA-MB-231 and MCF7 breast cancer cells. The

tether Os–arene complexes presented here can be exploited for the intracellular conversion of

metabolites that are essential in the intricate metabolism of the cancer cell.

Received 7th April 2021

Accepted 9th June 2021

DOI: 10.1039/d1sc01939b

rsc.li/chemical-science

We^25–28and others^{21–23,29,30}have seen an opportunity in

designing organometallic compounds bearing hemilabile

Introduction

ligands for metallodrug controlled activation. Hemilabile

ligands are dened as bidentate non-symmetric ligands in

which one of the binding groups is rmly attached to the metal

centre. The other coordinated group is weakly bound and

therefore can easily be dissociated.³¹Since the displaced atom

with metal-binding capabilities stays in close proximity to the

metal, the process of opening and closing is reversible. Some

have described hemilabile ligands as “swinging gates” to enable

metal reactivity.^32,33A signicant number of ruthenium(II) half-

sandwich complexes bearing tethered groups containing

C,^34–36N,^23,25,37O,^26,37–39S,^40–42and P^37,43–46donors have been re-

ported. However, the only tethered h⁶-arene–osmium(II)

described to date in the literature is the [3 + 2] annulation

product of osmium hydrido alkenylcarbyne complex [OsH

{^CC(PPh₃)]CHPh}(PPh₃)₂Cl₂]⁺with a substituted allenoate,

which aﬀords a typical three-legged piano-stool structure with

the h⁶-benzene, two PPh₃, and an alkenyl carbon atom (pendant

from the arene) connected to the metal center.⁴⁷In addition,

octahedral complexes of formula [OsCl₂(N^P)₂] have shown

some cis versus trans uxional conversion attributable to the

hemilability of the N^P ligand in solution.⁴⁸

Cisplatin (cis-diamminedichloridoplatinum(II)) is one of the

most well-known anticancer drugs due to its widespread use in

the clinic. Its intracellular mechanism of action is believed to

involve Pt–Cl hydrolysis prior to target interaction.^1,2Following

the success of Pt drugs, a number of new organometallic coor-

dination compounds with labile chlorido ligands have been

synthesized and tested for anticancer activity. New complexes of

Pt,^3,4Au,⁵Ru,^6–8Re,⁹Ir,^10,11and Os^12–14have been reported to be

highly cytotoxic, even circumventing cisplatin-resistance.

Additionally, a search for control over metallodrug activation

has resulted in a variety of interesting selectivity-seeking

approaches, such as photoactivation,^15–17ligand redox-

mediated activation,^11,18–20and pH-dependent activation,^21–26

among others.

^aIMDEA Nanociencia, Faraday 9, 28049 Madrid, Spain. E-mail: ana.pizarro@imdea.

org

^bDepartment of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4

7AL, UK

c

´

Unidad Asociada de Nanobiotecnologıa CNB-CSIC-IMDEA, 28049 Madrid, Spain

Organometallic Os(II) complexes have similar, oen almost

identical, structures to the analogous ruthenium compounds,

† Electronic supplementary information (ESI) available. CCDC 2026997–2027004.

For ESI and crystallographic data in CIF or other electronic format see DOI:

10.1039/d1sc01939b

yet they are oen more inert,⁴⁹a useful feature vis-a-vis exerting

`

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control over metal reactivity. Os(II) half-sandwich compounds of benzoate)Cl₂]₂or other electron withdrawing substituted arene

general formula [Os(h⁶-arene)(XY)Z]ⁿ⁺are less reactive towards Ru(^II) dimers,^25,34,43,45this method proved ineﬀective in the case

hydrolysis —the rate of aquation is oen ca. 100 times slower of osmium, as our arene-exchange reactions repeatedly failed

than for Ru—^50–53and once aquated the aqua ligand is more when using [Os(h⁶-Et-benzoate)Cl₂]₂as

a suitable dimer

acidic, ca. ꢀ1.5 pK_aunits.^49,51Slowing down metal reactivity, precursor. It was thus deemed necessary to reduce the specied

which can also be achieved by replacing chlorido by iodido arene ligand to the corresponding cyclohexadiene. To obtain 3-

ligand, has indeed been related to high cytotoxic potency.^14,18,54(1,4-cyclohexadien-1-yl)-1-propanol, the Birch reduction of 3-

For iridium complexes we have recently reported that stabilis- phenylpropanoic acid was carried out, following an experi-

ing a closed tether structure in complexes [Ir(h⁵:k¹-C₅Me₄CH₂- mental procedure similar to that described by Habtemariam

py)(C,N)]PF₆, and thus delaying metal reactivity towards et al.⁶⁸The reduced cyclohexadiene carboxylic acid was further

substitution reactions, increases cytotoxicity by up to two orders reduced to the corresponding alcohol by the addition of LiAlH₄.

of magnitude.²⁸

Osmium(^II) dimer [Os(h⁶-C₆H₅(CH₂)₃OH)(m-Cl)Cl]₂was then

Transfer hydrogenation (TH) by transition metal compounds synthesized by the reaction of 3-(1,4-cyclohexadien-1-yl)-1-

of Ru(^II),^8,26,55–57Rh(III),⁵⁸and Ir(III),^8,10,27are attracting much propanol with OsCl₃$3H₂O, as reported previously (Chart

attention in bioinorganic chemistry since they have demon- S1A†).⁴⁹Microwave synthetic methods reported by Tonnemann

¨

strated the potential of catalytically consuming or producing et al.⁶⁹were used to improve the yield and reaction times.

important metabolites, such as NADH, that are vital for

All chlorido complexes 1–13 were synthesized from the

a number of cellular processes.^59–62In particular, lactate and reaction of the dimeric precursor, [Os(h⁶-C₆H₅(CH₂)₃OH)(m-Cl)

pyruvate are key cell metabolites that the tumour cell requires to Cl]₂, with the corresponding chelating ligand using similar

promote cancer invasion as they help circulating tumour cells to procedures to those reported for other half-sandwich arene

survive by enhancing their resistance against oxidative stress.⁶³complexes (Chart S1B†).^13,52,64Chart 1 shows the compounds

Osmium(II) arene [Os(h⁶-p-cymene)(impy-NMe₂)Cl/I]PF₆obtained with general formula [Os(h⁶-C₆H₅(CH₂)₃OH)(XY)Cl]^+/0

,

(impy ¼ iminopyridine) can oxidize NADH to NAD⁺by Os-driven where XY ¼ ethylenediamine, en (1), bipyridine, bipy (2), phe-

hydride abstraction.⁶⁴Importantly, chiral 16-electron complex nanthroline, phen (3), 1-(2-pyridinyl)methanamine, ampy (4), N-

[Os(h⁶-p-cymene)(TsDPEN)], (TsDPEN ¼ N-(p-toluenesulfonyl)- phenyl-1-(pyridin-2-yl)methanimine, Ph-impy (5), N-(4-(tert-

1,2-diphenylethylenediamine), inspired by the Noyori-type of butyl)phenyl)-1-(pyridin-2-yl)methanimine, tBuPh-impy (6), N-

catalysts for asymmetric transfer hydrogenation,⁶⁵is capable of

catalysing asymmetric reduction of pro-chiral pyruvate to

lactate using non-toxic doses of sodium formate as a hydride

donor inside cells.^66,67

Herein we describe the synthesis of thirteen osmium(II)

complexes 1–13, of formula [Os(h⁶-C₆H₅(CH₂)₃OH)(XY)Cl]^+/0

,

bearing the hemilabile h⁶-bound arene 3-phenylpropanol and

where XY is a neutral N,N or an anionic N,O^ꢀbidentate

chelating ligand. We report for the rst time Os(^II) tethered half-

sandwich complexes in their closed-tether form, 1C–13C,

including the X-ray structure of cation 3C, where the hemilabile

arene ligand chelates the osmium centre by simultaneous h⁶-

C(arene) and k¹-O(R) binding. We show how the high stability of

Os(^II) h⁶-arene and the exceptional lability of alcohol oxygen as

a coordinating group appear as the ideal combination to allow

for control over metal reactivity in aqueous solution throughout

the biologically relevant pH range. Aiming to unravel speciation

in aqueous solution we have been surprised by the unexpected

reactivity of the hydroxido adduct (the Os–OH bond), and the

highly reversible open/close nature of the Os–O(tether) ring.

Finally, we evaluate the reactivity of these complexes toward

catalytic transfer hydrogenation of pyruvate using formate as

hydride-source, nding that compounds reported here are

capable of producing quantiable excess lactate inside cancer

cells.

Results and discussion

Synthesis and characterization

Chart

1 Open and closed tethered osmium(II) arene complexes

studied in this work of the general formulae [Os(h⁶-C₆H₅(CH₂)₃-

While a common synthetic method to introduce variations in

Ru(^II) arenes involves arene-exchange reactions in [Ru(h⁶-Et/Me- OH)(XY)Cl]^+/0and [Os(h⁶:k¹-C₆H₅(CH₂)₃OH/O)(XY)]⁺.

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(2-bromophenyl)-1-(pyridin-2-yl)methanimine, BrPh-impy (7),

N-phenethyl-1-(pyridin-2-yl)methanimine, PhEt-impy (8), pico-

linate, pico (9), 6-methylpicolinate, 6-Me-pico (10), 4-methyl-

picolinate, 4-Me-pico (11), 4-carboxy-2-pyridinecarboxylate, 4-

COOH-pico (12), and 8-quinolinate, quinol (13). Cationic

complexes 1–8 were isolated as chloride salts while 9–13 as

neutral. All complexes were isolated in good yields (56–94%).

The corresponding closed tether complexes of formula

[Os(h⁶:k¹-C₆H₅(CH₂)₃OH/O)(XY)]⁺(1C–13C; Chart 1) were syn-

thesised using silver nitrate to abstract the chlorido ligand of

the open-tether monomer in water or methanol (Chart S1B†). In

several cases it was necessary to modify the pH of the aqueous

solution for the intramolecular rearrangement (closure of the

tether-ring) to occur (vide infra). Closed-tether complexes 2C,

3C, 4C, 8C, 10C, 11C and 13C were synthesised and obtained as

nitrate salts in good yields (56–99%). Complexes 1C, 5C, 6C, 7C,

9C and 12C were characterized in solution as isolation was

unsuccessful due to the fast interconversion dynamics with

their open-tether counterparts. The ¹H NMR spectra of open-

and close-tether complexes display in all cases distinct patterns

for the resonances of the h⁶-bound arene protons. In complexes

1–13, Dd(bound arene) spans 0.14–0.54 ppm, and in the closed-

tether counterparts, 1C–13C, spans 0.34–1.02 ppm (Table S1†),

that is, the increment of chemical shi between the most

deshielded and most shielded h⁶-bond arene proton signals

was larger for closed-tether complexes than that of their open

tether counterparts, attributable to restricted h⁶-bound arene

rotation along the Os-centroid axis for closed tether complexes.

1

This is in agreement with the observed diﬀerences of H NMR

shis corresponding to closed vs. open Ru(^II) tether

compounds.^25,26,37

Ruthenium open and closed tether complexes bearing bipy

and phen 2Ru, 2CRu, 3Ru and 3CRu and complex [Ru(h⁶:k¹-

C₆H₅(CH₂)₃OH)Cl₂] have been reported before,^37,70,71and are

included for comparis_ꢀon purposes. The cations were isolated as

their chloride or BF₄salts while the dichlorido complex is

neutral.

Fig.

1

ORTEP diagrams and atom numbering schemes for

compounds: (A) 5$PF₆, (B) 8$PF₆, (C) 9, (D) 10, (E) 11, (F) 13, (G) 3C$PF₆,

and (H) dichlorido complex [Os(h⁶:k¹-C₆H₅(CH₂)₃OH)Cl₂] (50% prob-

ability ellipsoids). The H atoms (with the exception of the alcohol

hydrogens), the solvent molecules, and the counterions have been

omitted for clarity. Complex 10 in (D) shows disorder of the tethered

oxygen occupying two diﬀerent positions, resulting in a lower quality

of structural determination.

Details of the synthesis and full characterization of all

complexes are given in the ESI (Fig. S1–S23†).

Interestingly, while N,N-chelating ligands aﬀorded Os

closed-tether complexes with an alkoxy group coordinatively

bound to the metal (deprotonated tethered alcohol), complexes

bearing N,O-chelating ligands produced complexes with the

alcohol attached to the metal. All our closed complexes are

therefore +1 cations. Conductivity measurements supported the

observation, giving values in the range ca. 100 S cm²mol^ꢀ1

corresponding to 1 : 1 electrolytes.⁷²The ¹H NMR signal of such

an alcohol proton can indeed be identied in the N,O closed

tether structures when the spectrum is recorded in DMSO-d₆

(see for example spectrum of 10C in Fig. S17†), contrariwise the

proton signal cannot be found in DMSO-d₆solutions of N,N-

chelated complexes.

stool” geometry, with osmium(^II) p-bonded to the h⁶-arene

ligand. Open tether complexes are s-bonded to a chlorido and

a bidentate chelating ligand, while in closed tether complexes

one of the three “legs” is occupied by the s-bonded alcohol/

alkoxy pendant from the h⁶-arene, aﬀording an h⁶-Os-k¹six-

membered chelate ring in the structure (Fig. 1G and 1H).

The crystal structures presented in this work are the rst to

be reported with a pendant alcohol function attached to the h⁶-

bound arene in complexes of general formula [Os(h⁶-arene)(XY)

Z]ⁿ⁺. Moreover, no X-ray structures of osmium closed tether

complexes of formula [Os(h⁶-arene-O-k¹)(XY)]ⁿ⁺, where a coor-

dinating tethered oxygen is bound to the metal centre, have

been previously reported. In fact, tethered h⁶-arene–osmium(II)

compounds are extremely rare; we only found complex [Os(h⁶-

benzene-C-k¹)(PPh₃)₂]⁺, with a tethered alkenyl pendant from

the derivatised arene,⁴⁷in the Cambridge Database.

The X-ray crystal structures of chlorido complexes 5$PF₆,

8$PF₆, 9, 10, 11, 13, and closed tether complexes 3C$PF₆and

dichlorido [Os(h⁶:k¹-C₆H₅(CH₂)₃OH)Cl₂] (Fig. 1), unambigu-

ously supported our structural determination. All complexes

present the familiar pseudo-octahedral “three-legged piano-

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Closed-tether structures feature a strong oﬀset of C7 (rst literature.^53,73However, the chlorido ligand of complexes 9–12

carbon in the tether chain attached to the arene) toward the dissociates readily in water, surpassing ca. 40% Os–Cl cleavage

osmium atom with regard to the plane that contains the h⁶- in the rst 24 h. Quinolinate complex 13 fully hydrolyses within

ꢀ

bound arene, with calculated values of 0.138 and 0.193 A, the rst minutes of dissolution in water, ruling out hydrolysis

respectively, for both 3C$PF₆and dichlorido [Os(h⁶:k¹- rate determination by ¹H NMR, which mirrors the hydrolysis of

C₆H₅(CH₂)₃OH)Cl₂] (Table S2†). Another interesting feature in reported quinolinate compound [Os(h⁶-p-cym)(oxine)Cl].⁵³

all the X-ray structures is the extensive hydrogen bonding of the

The relatively faster hydrolysis of the Os–Cl species in

oxygen pendant from the arene, especially strong in the case of complexes 9–12, containing picolinate ligands, is in agreement

cation 3C between the tethered O-alkoxy and a water molecule with previous reports.^13,49,53It may be explained on the basis of

of crystallization (Fig. S24 and Table S3†).

an increased electron density at the metal centre due to the

Full crystallographic analysis, selected bonds and angles anionic chelating ligand, possibly aided by the stabilising

(Table S2†), p–p intermolecular interactions, directionality, interaction between hydrogen atoms of the coordinated water

angles and distances of hydrogen-bonding interactions in the aqua species and the oxygen atom of the tethered alcohol

(Fig. S24 and Table S3†), and detailed crystallographic data group. Indeed, the X-ray structures of complexes 9, 11 and 13

(Table S4†), are included in the ESI† of this manuscript. CCDC indicate strong hydrogen bonding of the tethered alcohol

2026997–2027004 contain the ESI crystallographic data for this oxygen with neighbouring Os(^II) molecules with strong covalent

paper.

character (Fig. S24 and Table S3†).⁷⁴

The rate of hydrolysis in D₂O of picolinate compounds 9–12

was monitored by ¹H NMR at 300, 310 and 320 K at various time

intervals. The percentage of disappearance of chlorido adduct

for 9–12 (based on peak integration) was plotted against time

and tted to pseudo-rst order kinetics, and their half-life times

were calculated. For all four complexes hydrolysis reaches

equilibrium within the rst hour even at the lowest temperature

(Table 1 and Fig. S25–S27†).

Arrhenius activation energies (E_a) and activation enthalpies

(DH^‡) of hydrolysis of compounds 9, 10 and 12 (Table 1 and

Fig. S26–S27†) are lower than those previously found for similar

picolinate Os–arenes, which are reported to be ca. 90 kJ mol^ꢀ1

for both parameters.^13,53However, activation entropies (DS^‡) are

Aqueous solution studies

Metallodrug activity inside the cell is believed to be triggered by

aquation. The hydrolysis rate of Os(^II) arene compounds of the

type [Os(h⁶-arene)(XY)Cl]ⁿ⁺is highly aﬀected by the nature of

the chelating ligand.^13,49,52,53pK_a^*It has been proven that

compounds with N,O-chelated ligands display aqueous behav-

iour intermediate between those bearing N,N- and O,O-chelates,

the former being too slow for the complex to have an impact on

cell survival, and the latter being too fast, resulting in the loss of

the XY ligand and leading to the formation of inert di-osmium

OH-bridged species.⁵³Following Os–Cl cleavage, the aqua

adduct is formed. Above the pK_a^*corresponding to the Os–OH₂/

OH equilibria, the hydroxido Os–OH species will predominate.

This is believed to render the complex inactive towards substi-

tution reactions,⁴⁹including potential intracellular targets, and

thus negatively impacting their biological eﬀectivity.⁵³

Hydrolysis of the Os–Cl bond. The Os–Cl bond hydrolyses in

all cases at 310 K within 24 h to diﬀerent extents (Fig. 2), as

determined by ¹H NMR. Although speciation evolves over

several days, the main changes occur within 24 h. Fig. 2 shows

that the extent of the Os–Cl bond cleavage in water is indeed

highly dependent on the nature of the XY ligand.^13,49,52,53

Complexes 1–8, bearing N,N-chelating ligands, barely undergo

hydrolysis of the Os–Cl bond within the rst 24 h (hydrolysis

ranges between 0–19%) in agreement with previous

similar to those determined for similar complexes varying from

ꢀ70 to ꢀ50 J K^ꢀ1mol^ꢀ1

.

The large negative activation

13,53

entropies (DS^‡) found for the hydrolysis of 9, 10, 11 and 12

indicate that entropy decreases on forming the transition state,

which suggests that an associative mechanism is involved, in

which two reaction partners form a single activated complex.

The fastest hydrolysing compound, 11, presents the most

negative entropy, ꢀ131.7 J K^ꢀ1mol^ꢀ1, a value more than two-

fold of its analogue [Os(h⁶-C₆H₅C₆H₅)(4-Me-pico)Cl]⁺, with an

entropy of ꢀ55.6 ꢁ 1.6 J K^ꢀ1mol^ꢀ1

.

¹³Complex 11 also requires

the lowest DH^‡towards hydrolysis.

pH-dependent speciation. Hydrolysis of the osmium–chlor-

ido bond in complexes 1–13 is not an isolated event. As depicted

in Chart 2, speciation in aqueous solution of the complexes

reported here involves: (i) hydrolysis of the Os–Cl bond to form

the Os-aqua adduct, that is, the chlorido ligand is substituted by

a water molecule forming an Os–OH(H) bond; and (ii) intra-

molecular rearrangement, i.e., a further substitution reaction of

the aqua/hydroxido ligand by the tethered alcohol/alkoxy,

prompting tether ring closure through formation of an Os–

O(H)R s-bond.

Such a three-way speciation of complexes 1–13 was rst

detected by ¹H NMR in unbuﬀered D₂O (Fig. S28†). Addition of

excess sodium chloride to the mixture of species at equilibrium

conrmed the assignment of the aqua adduct by H NMR (by

conversion of the aqua to the chlorido species). Addition of

Fig. 2 Hydrolysis of the Os–Cl bond for complexes 1–13. The bars

represent the percentage of remaining open-tether chlorido

complexes 1–13 over time in unbuﬀered D₂O as determined by ¹H

NMR. Equilibrium is mostly reached in the ﬁrst 24 h. Complex 13 is fully

1

hydrolysed from the ﬁrst data recording (t # 15 min upon dissolution). AgNO₃to solutions of complexes 2, 3, 8, 10 and 11 aided the

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Table 1 Rate data for the aquation of complexes 9, 10, 11 and 12 at 300, 310 and 320 K

T (K)

k_hyd(min^ꢀ1

)

t_1/2(min)

E_a(kJ mol^ꢀ1

)

DH^‡(kJ mol^ꢀ1

64.4 ꢁ 1.0

)

DS^‡(J K^ꢀ1mol^ꢀ1

ꢀ51.5 ꢁ 3.1

)

9

300

310

320

300

310

320

300

310

320

300

310

320

0.08

0.19

0.48

0.06

0.09

0.29

0.20

0.26

0.54

0.05

0.11

0.28

8.6

3.7

1.4

11.9

7.5

2.4

3.5

2.7

1.3

13.2

6.1

2.5

67.0 ꢁ 0.9

10

11

12

63.9 ꢁ 15.5

40.8 ꢁ 11.1

67.0 ꢁ 4.7

61.4 ꢁ 15.5

38.3 ꢁ 11.0

64.4 ꢁ 4.7

ꢀ65.0 ꢁ 49.9

ꢀ131.7 ꢁ 35.6

ꢀ55.0 ꢁ 15.1

8 show more than 60% of closed tether structure at basic pH

aer 24 h. Even fully aquated complex 13 shows a clear pref-

erence for the closed tether species 13C at pH 10 even at t ¼

15 min.

pK_a^*determination. Following hydrolysis rate determination

and nding reversible interconversion of open and closed

tether complexes in a pH-dependent manner, we endeavour to

determine the pK_as of the species in solution. Both aqua (1A–

13A) and closed tether (1C–13C) species are subjected to acid–

base equilibria (Chart 2). Alcohol coordination to osmium(^II) in

Chart 2 Aqueous speciation of open and closed tether complexes,

including acid–base equilibria (n ¼ 1 for complexes 1–8; n ¼ 0 for 9–

13).

unambiguous characterization of the closed tether species.

Furthermore, Ag⁺-mediated choride sequestration indicated

that Os–Cl bond cleavage favours tether-ring closure.

Peacock et al. have shown pH to be important in the aqueous

behaviour and thus the biological impact of hydrolysable Os–

arenes as potential anticancer agents.^{13,49,52,53,75}We aimed to

assess the eﬀect of pH on interconversion of species in aqueous

solution of the Os(^II) half-sandwich OH-tethered complexes.

Selected compounds 1, 2, 5, 8, 9, 10, 11 and 13 were dissolved in

D₂O (at [Os] ¼ 5 mM) in four unbuﬀered pH solutions (pH 1, 4, 7

and 10). Fig. 3 shows how our complexes undergo speciation,

whereby the aqua (or hydroxido) species seemingly evolve to the

closed tether complex until reaching equilibria where coexis-

tence of the three species (chlorido, aqua/hydroxido and closed

tether species) occurred upon 24 h of incubation.

The percentage of hydrolysis-triggered species is similar at

pH 1 and 4, i.e., pH-variation when the proton concentration is

high has no impact in the speciation of these complexes. The

predominant species are chlorido and aqua species (Chart 2). At

pH 10, however, most complexes show a remarkable preference

Fig. 3 Speciation of chlorido complexes (A) 1, (B) 2, (C) 5, (D) 8, (E) 9,

for intramolecular rearrangement, as seen by the evolution over (F) 10, (G) 11, and (H) 13 at time ca. 15 min and after 24 h in unbuﬀered

aqueous solutions at pH 1, 4, 7 and 10. The arrow represents time

forward, from t ¼ 15 min to t ¼ 24 h.

time towards the closed tether species. All but complexes 2 and

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the closed tether complexes renders the s-bonded alcohol the lack of (de)protonatable positions in the structure, with the

proton highly acidic, favouring deprotonation of an otherwise exception of complex 12, which bears a carboxylic acid in the

largely basic group (estimated pK_aof 3-phenyl-1-propanol ca. picolinate ligand (Fig. S31F†).

16).

Since the pK_a^*₁data is below 7.4 (physiological pH) for all Os–

Complexes 1–13 were treated with AgNO₃in water or alco- arenes, in a live cell environment, the complexes are expected to

holic aqueous solutions to ensure the formation of both the be present in the hydroxido form rather than the aqua species.

aqua and subsequently the closed tether species. Compounds Yet in our complexes the hydroxido species readily evolves to

2Ru and 3Ru were synthesised^37,70and included for comparison the closed tether complex. Contrary to previous reports on Os–

purposes. The pK_a^*₁values for the aqua/hydroxido (OH₂/OH) arene aquation,^49,53,75inert hydroxido-bridged dimers have not

adduct of formula [M(h⁶-C₆H₅(CH₂)₃OH)(XY)(OH₂/OH)]ⁿ⁺, for been detected throughout this work. In fact, the species re-

complexes 1A, 2A, 2ARu, 3A, 3ARu, 8A, 12A and 13A, and the ported here are interconvertible in a reversible manner over the

pK_a^*₂values for the coordinated alcohol/alkoxy group (ROH/RO) pH range. The formation of closed tether species presents a very

in closed tether complexes of formula [M(h⁶:k¹-C₆H₅(CH₂)₃OH/ exciting turn of events due to their strong predominance at

O)(XY)]ⁿ⁺, for complexes 1C, 2C, 2CRu, 3C, 3CRu, 8C and 12C, pH . pK_a^*₁; preventing deactivation of the Os(II) compound.

were determined and are presented in Table 2 and Fig. S29.† ¹H

Speciation proved indeed highly dependent on pH (Fig. 3),

NMR peaks corresponding to coordinated arene protons in clearly favouring tether ring closure even at pH . pK_a^*₂; that is,

closed and aqua adducts 1C–3C, 3CRu, 1A–3A and 3ARu, or the pK_a^*of the Os-bound alcohol. We postulate a concerted

chelating ligand protons in 8A, 8C, 12A, 12C and 13A, were associative mechanism for intramolecular rearrangement

followed as they shied to high eld on increasing pH* resulting in tether ring formation by which an incoming ligand,

(Fig. S30† contains the titration of a mixture containing 3, 3A the tethered alcohol, likely assisted by H-bonding, transfers its

and 3C, as an example). Changes in the ¹H NMR chemical shis proton to the hydroxido ligand (favoured by pK_a^*₁. pK_a^*₂),

of closed tether and aqua species were recorded at 298 K over thereby facilitating the release of a water molecule from the

the 0–12 pH range by the addition of NaOD or DNO₃as osmium rst coordination sphere (Chart 3). This is supported

appropriate. The chemical shi-versus-pH plots and pK_a^*values by extensive hydrogen-bonding by the pendant oxygen as

obtained from the titrations are compiled in Fig. S31.†

observed upon X-ray analysis, especially strong for closed tether

The nature of the chelating ligand (N,N, N,O or O,O) shows cation 3C (Fig. S24 and Table S3†).

a great inuence on the pK_a^*values of the M–OH₂group (basicity

Hydrolysis of the Os–O bond for the closed tether complexes.

increasing N,N < N,O < O,O, with better p-acceptors, such as Solutions of closed complexes 2C, 10C and 13C were prepared

1

phen, aﬀording more acidic metal centres, which resulted in in D₂O and their speciation was evaluated by H NMR in three

lower pK_a^*s for the aqua adduct).^{13,26,49,51–53,76}The high acidity of diﬀerent solutions at pH 1, 7, 12 (Fig. S32†). The three

osmium arene aqua complexes has been previously attributed complexes favour the aqua species at equilibrium at pH 1.

to increased mixing of the ds* (Os) / s (OH^ꢀ) orbitals.^77,78The However, at pH 7 and more signicantly at pH 12, even complex

higher acidity of Os versus Ru can also explain the acidity of the 10C, which initially undergoes major cleavage of the Os–O bond

coordinated hemilabile alcohol/alkoxy (Fig. S29†).^23,49,77

(up to 70%), reverts to the closed tether complex over time (ca.

Closed-tether and aqua species identication was conrmed 80% closed tether aer 24 h) showing a clear preference for the

1

by the H NMR pH titration associated with both pK_a^*s: The tether-ring formation at basic equilibrium highlighting the

chlorido species are devoid of chemical shi variation due to reversibility of the process. The pH in all the samples dropped

aer 24 h, the samples prepared in unbuﬀered pH 12 solutions

showed the most signicant change. There is a clear correlation

Table 2 pK_a^*values of the aqua ligand in complexes 1A, 2A, 2ARu, 3A,

3ARu, 8A, 12A and 13A, and the tethered alcohol in complexes 1C, 2C,

2CRu, 3C, 3CRu, 8C and 12C

between these data and those of speciation of chlorido

complexes 2, 10 and 13 as described in Fig. 3.

pK_a^*₁

pK_a^*₂

[Os(h⁶-C₆H₅(CH₂)₃OH)(en)(OH₂)]²⁺(1A)

[Os(h⁶:k¹-C₆H₅(CH₂)₃OH)(en)]²⁺(1C)

5.83

—

5.81

—

7.28

—

5.62

—

7.18

—

5.69

—

6.64

—

7.01

—

5.46

—

4.23

—

5.78

—

4.26

—

6.39

—

4.41

—

5.63

—

[Os(h⁶-C₆H₅(CH₂)₃OH)(bipy)(OH₂)]²⁺(2A)

[Os(h⁶:k¹-C₆H₅(CH₂)₃OH)(bipy)]²⁺(2C)

[Ru(h⁶-C₆H₅(CH₂)₃OH)(bipy)(OH₂)]²⁺(2ARu)

[Ru(h⁶:k¹-C₆H₅(CH₂)₃OH)(bipy)]²⁺(2CRu)

[Os(h⁶-C₆H₅(CH₂)₃OH)(phen)(OH₂)]²⁺(3A)

[Os(h⁶:k¹-C₆H₅(CH₂)₃OH)(phen)]²⁺(3C)

[Ru(h⁶-C₆H₅(CH₂)₃OH)(phen)(OH₂)]²⁺(3ARu)

[Ru(h⁶:k¹-C₆H₅(CH₂)₃OH)(phen)]²⁺(3CRu)

[Os(h⁶-C₆H₅(CH₂)₃OH)(PhEt-impy)(OH₂)]²⁺(8A)

[Os(h⁶:k¹-C₆H₅(CH₂)₃OH)(PhEt-impy)]²⁺(8C)

[Os(h⁶-C₆H₅(CH₂)₃OH)(4-COOH-pico)(OH₂)]⁺(12A)

[Os(h⁶:k¹-C₆H₅(CH₂)₃OH)(4-COOH-pico)]⁺(12C)

[Os(h⁶-C₆H₅(CH₂)₃OH)(quinol)(OH₂)]⁺(13A)

Chart 3 Suggested mechanism of tether-ring closure as dependent

on pH, given that pK_a^*₁. pK_a^*₂

:

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Speciation of closed tether complexes 2C, 10C and 13C in the

Complex 11, selected on the basis of its fast hydrolysis and

presence of chloride ions was also investigated. Since water- catalytic performance was probed as a catalyst at three diﬀerent

mediated speciation is highly dependent on pH, the behav- temperatures (300, 310, and 320 K) and concentrations of

iour of 2C, 10C and 13C was evaluated in 0.1 M DCl and 0.1 M hydride source (100, 200 and 400 mM sodium formate; Table 3).

DClO₄solutions (Fig. S33†) at 310 K over 24 h. These solutions TOF values increased with temperature. For example, an

were selected because the concentration of protons is equiva- increment of 20 K resulted in ca. 11-fold increase in TH rate.

lent in both, yet the chloride concentration varies from 100 mM This is a similar increment to that reported for other Ru–arene

Cl^ꢀin DCl (similar to that in plasma) to nil in DClO₄. The complexes bearing N,O-chelates, in which a similar variation of

results indicate that the tether-ring opening occurs to approxi- temperature (increase of 23 K) resulted in an increment of 7-fold

mately the same extent, clarifying that pH dominates speciation in the TOF value.⁸⁴Compound 11 has a maximum TOF value of

over chloride concentration.

0.20 h^ꢀ1at pH 4 (Os/pyr/for; 1 : 2 : 100), which is comparable to

pyruvate reduction by the reported 16-electron species [Os(h⁶-p-

cymene)(TsDPEN)], for which the TOF_maxin PBS is 1.5 h^ꢀ1(for

Os/pyr/for, 1 : 200 : 400).⁸⁵The percentage of conversion from

Catalytic reduction of pyruvate to lactate

Osmium(^II) arenes have been reported to carry out catalytic pyruvate to lactate aer 1 h incubation shows that an increment

transfer hydrogenation reactions.^64,66A screening of selected of 10 K doubled the percentage of conversion (Fig. S37†).

complexes 1, 3, 5, 6, 9, 10, 11, 12, 13 was carried out to evaluate

Complexes 9–13 are, to the best of our knowledge, the rst

the conversion of pyruvate (pyr) to lactate using formate (for) as 18-electron Os arene complexes to achieve catalytic TH of

the hydride source, at ratios 1 : 2 : 100 (Os catalyst/pyr/for) at pyruvate. Such an activity, in conjunction with the high solu-

1

pH 4 and 310 K, by means of H NMR.

bility in aqueous media and the protective nature of the

Complexes 1, 3, 5 and 6 with N,N ligands did not transform dynamic tether ring formation, prompted us to investigate the

pyruvate to lactate over 48 h, even aer formation of the Os- potential of carrying out TH inside cells by selected complex 11.

formate adduct for complexes 1 and 5 was observed by ¹H

NMR. The formate adduct is believed to precede hydride Production of lactate inside cells

abstraction by the metal centre during the catalytic cycle.^55,56,66,79It

The majority of the Os(^II) complexes reported here had no

has been reported that chlorido removal increases the activity of

impact on cell survival of MDA-MB-231 and HCT116 cells up to

catalytic metal complexes by generating species that can bind to

a concentration of 200 mM (Fig. S38 and Table S5†), largely in

agreement with data reported for similar Os–arenes in other

formate.⁵⁶Hydrolysis of complexes 9–13, bearing N,O-chelating

ligands, could thus be in their favour to mediate the trans-

cancer cell lines.^12,49,52,64Only complexes 11 and 11C appear to

1

formation of pyruvate to lactate. In the H NMR spectra of the

be an exception regarding cytotoxic potential, presenting the

lowest IC₅₀value in the series in colon cancer cells HCT116 (IC₅₀

hydrogenation reactions by 9, 11, 12 and 13 two new sets of peaks

were attributed to the Os–aqua (Os–OH₂) and the Os–formate (Os–

OOCH) adducts. A sharp singlet at ca. 7.9 ppm was attributed to

the Os-bound formate (free formate appears at ca. 8.4 ppm), in

values 30.5 ꢁ 3.3 and 19.5 ꢁ 0.6 mM, respectively). Intracellular

accumulation experiments in MDA-MB-231 and HCT116 cells

showed that uptake for 11C was high, as determined by ICP-MS

(Table S6†). These results, together with the catalytic capabil-

ities of 11 for transfer hydrogenation, encouraged us to probe

this complex for osmium intracellular reactivity as a potential

accordance with analogous Ru(^II) arene formate complexes

(Fig. S34†).^26,80Although the species (h⁶-arene)Os–H in TH catal-

ysis has been reported to appear around ꢀ4 ppm by ¹H NMR,⁶⁴in

our experiments the hydrido species was elusive.^26,81The intensity

metabolite-modulating tool.

of the signals of free pyruvate (3H, singlet, 2.36 ppm) decreased

We investigated whether direct detection of Os-mediated

and a new peak assignable to lactate (3H, doublet, 1.33 ppm)

lactate production was possible inside cancer cells. One

concern was the lack of structural compromise that could

promote enantiomeric enrichment in the reduction of pro-

appeared. Compound 11 mediated total reduction of pyruvate to

lactate aer 18 h (Fig. S35†) whereas 13 barely achieved stoi-

chiometric conversion aer 2 days (Fig. S36A†). Since more than

one mol equiv. of pyruvate was reduced per mol equiv. of osmium

complexes 9, 11 and 12, a catalytic mechanism is implied.

Table 3 Catalytic data on the reduction of pyruvate (2 mM) to lactate

of 1 mM 9, 11–13 in D₂O at pH 4 as determined by ¹H NMR

We further explored the catalytic capabilities of complex 9,

bearing the unsubstituted picolinate, by varying the pH as well spectroscopy

as increasing the amount of H-source and the temperature.

TON_tand TOF_maxdata are compiled in Fig. S36B.† The most

favourable pH in the range 3–7 was 5 (reaction almost 4ꢂ faster

HCOONa

(mM)

Compound

T (K)

TOF_max(h^ꢀ1

)

R²

than at pH 3), which could be rationalized by considering that

the pK_aof formic acid is 3.75 and that the formation of the

formate adduct holds a central role in the catalytic trans-

formation.^55,56Lack of stability of pyruvate at low pH^82,83could

be aﬀecting the eﬃciency of our catalysts in acidic solutions.

Both an increase in the amount of formate and of temperature

resulted in higher TON_tand TOF values as anticipated.

9

11

310

300

310

320

300

310

100

200

400

100

0.049

0.037

0.200

0.417

0.052

0.061

0.050

0.140

0.992

0.989

0.990

0.985

0.998

0.983

0.967

0.970

12

13

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chiral pyruvate by 11. Our complex is synthesized as a racemic

mixture, and it is only reasonable to think that the product of

the reaction, lactate, would also be obtained as a racemic

mixture.

We rst optimized a UV-vis-based assay for lactate determi-

nation, examining whether complex 11 is capable of producing

a valid substrate for enzymatic quantication from pro-chiral

pyruvate (Fig. S39†). We used in this experiment ^L-lactate

deshydrogenase (^L-LDH) as L-lactate is produced from pyruvate

during anaerobic glycolysis and is present in humans at

concentrations 100 times greater than ^D-lactate. L-Lactate

generated by 11 was conrmed by reaction with ^L-LDH enzyme,

a process accompanied by concomitant production of UV-vis-

active NADH (Fig. S39†). As anticipated, osmium-produced

lactate increased with increase in reaction time from 0 to 4 h

in the presence of formate (Fig. S39B†).

Next we carried out lactate determination in cells. The choice

of cell line to demonstrate whether it would be possible for 11 to

produce measurable lactate inside cancer cells was carefully

considered. MDA-MB-231 and MCF7 were selected on the basis

of their growth media composition (non-pyruvate and pyruvate

containing, respectively). The low cytotoxic eﬀect of 11 in these

Fig. 4 Lactate generated (nmol) per million cells determined in MDA-

MB-231 and MCF7 breast cancer cell lines at 12 and 24 h. In yellow,

lactate in cells exposed to 11 (lactate background level resulting from

Os-stimulated cell metabolism only). In grey, lactate produced upon

co-incubation of osmium, formate and pyruvate (0.3, 10, and 2 mM,

respectively) in MDA-MB-231 cells. In green, lactate determined upon

co-incubation of osmium, formate and pyruvate (0.3, 10, and 1 mM,

respectively) in MCF7 cells.

cell lines (IC₅₀90.6 ꢁ 4.0 and 105.1 ꢁ 10.6 mM in MDA-MB-231 intracellular tool to target the metabolic plasticity of the cancer

cell.

and MCF7, respectively) was also advantageous as it allowed us

to expose the cells to a relatively high osmium concentration

(300 mM). Pyruvate (2 mM) and formate (10 mM) were added to

the MDA-MB-231 cells media whereas only formate (10 mM) was

Conclusions

added to the MCF7 cells (media from commercial sources Water-mediated processes in Os–arenes (such as conversion of

already contain 1 mM pyruvate). Controls were stimulated only the Os–chlorido bond into the Os–aqua bond) are either inef-

with the osmium compound (we also included double-negative cient or tend to result in species with low reactivity. We have

controls; detailed protocol in the ESI†). Upon exposing the overcome this issue by introducing a pendant arm primed with

drugs to 11 for either 12 or 24 h, the cells were washed, lysed, a terminal alcohol functionality attached to the arene ligand.

deproteinated and centrifuged. The lysate supernatants were The h⁶-bound arene behaves now as hemilabile, with a weakly

then tested for ^L-lactate determination and quantication. The k¹-bound alcohol group. Strikingly, this ligand furnishes the Os

results are shown in Fig. 4. Lactate increases when cells are complex with an entirely new reactivity prole. Osmium–arenes

exposed to 11 and formate, in comparison to those exposed to oen generate Os–OH inactive species due to the acidity of the

osmium alone. The impact of formate and Os in lactate gener- metal.^52,53In our compounds, the hydroxido adduct (Os–OH)

ation in MCF7 at 24 h is the most noticeable and the diﬀerences triggers intramolecular rearrangement culminating in the

are signicate (p-value < 0.01) when compared to the same binding of the pendant oxygen to the metal centre (formation of

experiment lacking formate, and despite being exposed to half a closed tether complex), protecting the complex towards irre-

of the amount of exogenous pyruvate (1 mM in MCF7 and 2 mM versible inactivation. The ligand exchange uxionality of the

in MDA-MB-231). We tentatively attribute the diﬀerent results in hemilabile ligand thus ensures the kinetic reactivation of the

both cell lines to the readiness of MCF7 cells to internalize metal centre. We reported here reversible formation of Os–

pyruvate, since it is a media component.

arene tether complexes in water. Our results imply the

Our results indicate that the tether Os–arene complexes unprecedented reactivation of the otherwise inert hydroxido

presented here can be exploited for the conversion of metabo- Os(^II)–arene complexes.

lites that are essential in the demanding metabolism of the

cancer cell. Depletion of the enantiomeric excess of the hydro- cells is

Finding metallodrugs that can exert catalytic activity inside

challenging task. Alcohol-tethered Os(^II)–arene

a

genated product (racemic lactate as opposed to ^L-lactate) might complexes have demonstrated to carry out transfer hydrogena-

also have an impact on intracellular activity and warrants tion reactions inside cells. The combination of tether-ring

further exploration. Additionally, articial non-enzymatic TH of protection towards excessive metal reactivity in the intracel-

pyruvate inside cells can aﬀect the activity of lactate dehydro- lular nucleophile-rich microenvironment (protection towards

genase (LDH) in converting pyruvate to lactate and vice versa, catalyst poisoning), their high-water solubility, and the readi-

which in turn is intimately ligated to the generation of NAD⁺ness towards catalytic transformations when exposed to the

and NADH for a number of intracellular processes. An organo- appropriate sacricial agent, makes them strong contenders as

metallic complex capable of modulating metabolites pyruvate/ intracellular catalysts. Tumour cell metabolism is considered

lactate (and consequently NADH/NAD⁺) can be a powerful an exploitable vulnerability in cancer therapy,⁸⁶where lactate

9294 | Chem. Sci., 2021, 12, 9287–9297

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and pyruvate have central, yet not completely unveiled, roles.⁸⁷Habtemariam was supported by the Comunidad Autonoma de

We have demonstrated that catalytic tethered Os–arenes can be Madrid (Professorship of Excellence 2016-T3/IND-2054).

extraordinary candidates for modulating such an aspect of

´

cancer progression in foreseeable therapies.

References

As whether the pH-dependent aqueous dynamics of this new

class of Os compounds will have an impact on the anticancer

capabilities of these complexes, further work is necessary to

understand such subtleties. Internal pH (pH_i) in heterogeneous

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diﬀerent stages of metabolic reprogramming, and also varies

from tumour to tumour depending on malignity.^63,88We

hypothesize that the cancer cell exceptional metabolism, which

results in cytosolic and intra-organelle pH disruption will

impact metallodrug speciation and thus tune its anticancer

eﬀect. In other words, diﬀerent drugs will exert diﬀering

degrees of lethality to pre-selected tumours based on their pH-

responsiveness, highlighting an additional structural advantage

by the Os-tether design presented here.

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´

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Conﬂicts of interest

There are no conicts to declare.

Acknowledgements

´

We thank Dr J. Perles and Dr M. Ramırez (Universidad

´

Autonoma de Madrid) for the analysis of X-ray data. Dr Z. Pardo 17 S. Alonso-deCastro, A. L. Cortajarena, F. Lopez-Gallego and

´

and Dr A. Arnaiz and Ms C. Leis (IMDEA Nanociencia) are

L. Salassa, Angew. Chem., Int. Ed., 2018, 57, 3143–3147.

gratefully acknowledged for assistance with NMR experiments 18 Y. Fu, A. Habtemariam, A. M. Pizarro, S. H. van Rijt,

and cell culture techniques, respectively. We acknowledge

funding from the EC (FP7-PEOPLE-2013-CIG, no. 631396), from

D. J. Healey, P. A. Cooper, S. D. Shnyder, G. J. Clarkson

and P. J. Sadler, J. Med. Chem., 2010, 53, 8192–8196.

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2016-0686, and CTQ2017-84932-P), and the Comunidad

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4625–4638.

´

Autonoma de Madrid (Scholarship PEJD-2016/IND-2608). Dr A.

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Osmium(ii) tethered half-sandwich complexes: pH-dependent aqueous speciation and transfer hydrogenation in cells

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