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.

Synthesis, Structural Elucidation, and Cytotoxicity Studies of New Triazolyl Half‐Sandwich RuII, OsII, RhIII and IrIII Complexes

“…This might explain its high in vitro cytotoxicity compared to other tested complexes when coupled with its ability to easily cross the cell membrane as conferred by its BPh 4 counterion. [37,38] This is also in line with previous reported results for N ^N bidentate triazolyl complexes [31] and although such an interaction is indiscriminate with imidazole containing biomolecules, it is possible to control the cytotoxicity of this class of complexes by controlling their cellular uptake. This can be achieved through ligand modification or change of counterion.…”

“…This suggests ring angle strain within a cationic complex can be relieved by using a bigger counterion as previously reported. [31] Crystallographic parameters, bond angles and bond lengths for C9 can also be seen in Table S2 and S3.…”

“…Any possible interaction might throw light into the possible mechanism of action (MOA) of C7 and confirm previous reported results for such systems. [30,31] To achieve this, a mixture of DMSO-d 6 : MeOH : D 2 O or DMSO-H 6 : MeOH : H 2 O were used whenever applicable to account for solubility and suitable NMR or UV-VIS observation as detailed in the experimental section.…”

“…Considering the ease of synthesis of 1,2,3-triazole and uniquely interesting properties in biological conditions, we previously synthesized and reported a series of N ^C, N ^N, and N ^O triazolyl Ru II , Os II , Rh III , and Ir III complexes as potential anticancer candidate. [30,31] The observed non-toxicity of most of the N ^N complexes towards normal cells, selectivity against specific cancer cells, and ability to interact with biological molecules led to the synthesis of novel N ^N triazolyl complexes in our continued effort to produce effective and selective metal complexes for anticancer chemotherapy. In this study, nine cationic complexes based on 1-benzyl-4-(aminomethyl)-1H-1,2,3-triazole (L1) and 1-picolyl-4-phenyl-1H-1,2,3-triazole (L2) were prepared (Scheme 1 & Scheme 2) and evaluated for potential anticancer activities.…”

“…Considering the ease of synthesis of 1,2,3‐triazole and uniquely interesting properties in biological conditions, we previously synthesized and reported a series of $${{\rm{N}}^ \wedge {\rm{C}}}$$ , $${{\rm{N}}^ \wedge {\rm{N}}}$$ , and $${{\rm{N}}^ \wedge {\rm{O}}}$$ triazolyl Ru II , Os II , Rh III , and Ir III complexes as potential anti‐cancer candidate [30,31] . The observed non‐toxicity of most of the $${{\rm{N}}^ \wedge {\rm{N}}}$$ complexes towards normal cells, selectivity against specific cancer cells, and ability to interact with biological molecules led to the synthesis of novel $${{\rm{N}}^ \wedge {\rm{N}}}$$ triazolyl complexes in our continued effort to produce effective and selective metal complexes for anticancer chemotherapy.…”