New Triazolyl N^N Bidentate Rh(III), Ir(III), Ru(II) and Os(II) Complexes: Synthesis and Characterization, Probing Possible Relations between Cytotoxicity with Transfer Hydrogenation Efficacy and Interaction with Model Biomolecules

Abstract

Cisplatin and other metallodrugs have realised great success in clinical chemotherapeutic applications as anticancer drugs. However, severe toxicity to healthy cells and non-selectivity to cancer cells remains a challenge, warranting the further search for alternative agents. Herein, we report the anticancer potential of a series of complexes of the general formula [MCl(p-cym)(k2-N^N-L)]+ X− and [MCl(Cp*)(k2-N^N-L)]+ X−, where M is the metal centre (Ru(II), Os(II), Rh(III) or Ir(III)), L = 1-benzyl-4-pyridinyl-1-H-1,2,3-triazole for L1 and 1-picolyl-4-pyridinyl-1-H-1,2,3-triazole for L2 and X− = Cl−, BF4−, BPh4−. When evaluated for activity against some cancerous and non-cancerous cell lines (namely, HeLa, HEK293, A549 and MT4 cancer cells and the normal healthy kidney cells (BHK21)), most of the compounds displayed poor cytotoxicities against cancer cells except for complexes C2 ([RuCl(p-cym)(k2-N^N-L1)]+ BPh4−, EC50 = 9–16 µM and SI = 14), C7 ([RuCl(p-cym)(k2-N^N-L2)]+ BPh4−, EC50 = 17–53 µM and SI = 4) and C11 ([IrCl(Cp*)(k2-N^N-L2)]+ BF4−, EC50 < 5 µM and SI > 10). Selected complexes C1 ([RuCl(p-cym)(k2-N^N-L1)]+ BF4−), C5 ([IrCl(Cp*)(k2-N^N-L1)]+ BF4−) and C11 showed significant interactions with model biomolecules such as guanosine-5′-monophosphate (5′-GMP), bovine serum albumin (BSA) and amino acids under physiological conditions, possibly through carbenylation and N-coordination with 5′-GMP, N-coordination with L-Histidine and L-proline. While the compounds showed good activities in reducing pyruvate to lactate, there was no direct correlation between catalytic transfer hydrogenation of pyruvate and the observed cytotoxic activities. As observed in this work, the marked influence of single atom replacement in ligand may provide a pivotal approach to improving the cytotoxicity and fine-tuning the selectivity to cancer cells.