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New activation mechanism for half-sandwich organometallic anticancer complexes.

ABSTRACT: The Cp x C-H protons in certain organometallic RhIII half-sandwich anticancer complexes [(?5-Cp x )Rh(N,N')Cl]+, where Cp x = Cp*, phenyl or biphenyl-Me4Cp, and N,N' = bipyridine, dimethylbipyridine, or phenanthroline, can undergo rapid sequential deuteration of all 15 Cp* methyl protons in aqueous media at ambient temperature. DFT calculations suggest a mechanism involving abstraction of a Cp* proton by the Rh-hydroxido complex, followed by sequential H/D exchange, with the Cp* rings behaving like dynamic molecular 'twisters'. The calculations reveal the crucial role of p? orbitals of N,N'-chelated ligands in stabilizing deprotonated Cp x ligands, and also the accessibility of RhI-fulvene intermediates. They also provide insight into why biologically-inactive complexes such as [(Cp*)RhIII(en)Cl]+ and [(Cp*)IrIII(bpy)Cl]+ do not have activated Cp* rings. The thiol tripeptide glutathione (?-l-Glu-l-Cys-Gly, GSH) and the activated dienophile N-methylmaleimide, (NMM) did not undergo addition reactions with the proposed RhI-fulvene, although they were able to control the extent of Cp* deuteration. We readily trapped and characterized RhI-fulvene intermediates by Diels-Alder [4+2] cyclo-addition reactions with the natural biological dienes isoprene and conjugated (9Z,11E)-linoleic acid in aqueous media, including cell culture medium, the first report of a Diels-Alder reaction of a metal-bound fulvene in aqueous solution. These findings will introduce new concepts into the design of organometallic Cp* anticancer complexes with novel mechanisms of action.

SUBMITTER: Banerjee S

PROVIDER: S-EPMC5916112 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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New activation mechanism for half-sandwich organometallic anticancer complexes.

Banerjee Samya S Soldevila-Barreda Joan J JJ Wolny Juliusz A JA Wootton Christopher A CA Habtemariam Abraha A Romero-Canelón Isolda I Chen Feng F Clarkson Guy J GJ Prokes Ivan I Song Lijiang L O'Connor Peter B PB Schünemann Volker V Sadler Peter J PJ

Chemical science 20180301 12

The Cp x C-H protons in certain organometallic RhIII half-sandwich anticancer complexes [(η5-Cp x )Rh(N,N')Cl]+, where Cp x = Cp*, phenyl or biphenyl-Me4Cp, and N,N' = bipyridine, dimethylbipyridine, or phenanthroline, can undergo rapid sequential deuteration of all 15 Cp* methyl protons in aqueous media at ambient temperature. DFT calculations suggest a mechanism involvi ...[more]

PMID: 29732100

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Project description:We report the synthesis, characterization, and antiproliferative activity of 15 iridium(III) half-sandwich complexes of the type [(?5-Cp*)Ir(2-(R'-phenyl)-R-pyridine)Cl] bearing either an electron-donating (-OH, -CH2OH, -CH3) or electron-withdrawing (-F, -CHO, -NO2) group at various positions on the 2-phenylpyridine (2-PhPy) chelating ligand giving rise to six sets of structural isomers. The X-ray crystal structures of [(?5-Cp*)Ir(2-(2'-fluorophenyl)pyridine)Cl] (1) and [(?5-Cp*)Ir(2-(4'-fluorophenyl)pyridine)Cl] (2) exhibit the expected "piano-stool" configuration. DFT calculations showed that substituents caused only localized effects on the electrostatic potential surface of the chelating 2-PhPy ligand of the complexes. Hydrolysis of all complexes is rapid, but readily reversed by addition of NaCl. The complexes show preferential binding to 9-ethylguanine over 9-methyladenine and are active catalysts for the oxidation of NADH to NAD+. Antiproliferative activity experiments in A2780 ovarian, MCF-7 breast, A549 lung, and HCT116 colon cancer cell lines showed IC50 values ranging from 1 to 89 ?M, with the most potent complex, [(?5-Cp*)Ir(2-(2'-methylphenyl)pyridine)Cl] (13) (A2780 IC50 = 1.18 ?M), being 10× more active than the parent, [(?5-Cp*)Ir(2-phenylpyridine)Cl], and 2× more active than [(?5-CpxPh)Ir(2-phenylpyridine)Cl]. Intriguingly, contrasting biological activities are observed between structural isomers despite exhibiting similar chemical reactivity. For pairs of structural isomers both the nature and position of the functional group can affect the hydrophobicity of the complex. An increase in hydrophobicity resulted in enhanced cellular-iridium accumulation in A2780 ovarian cells, which generally gave rise to an increase in potency. The structural isomers [(?5-Cp*)Ir(2-(4'-fluorophenyl)pyridine)Cl] (2) and [(?5-Cp*)Ir(2-phenyl-5-fluoropyridine)Cl] (4) preferentially localized in the cytosol > membrane and particulate > nucleus > cytoskeleton. This work highlights the strong dependence of biological behavior on the nature and position of the substituent on the chelating ligand and shows how this class of organometallic anticancer complexes can be fine-tuned to increase their potency without using extended cyclopentadienyl systems.

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New activation mechanism for half-sandwich organometallic anticancer complexes.

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New activation mechanism for half-sandwich organometallic anticancer complexes.

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