Triazolyl Ru II , Rh III , Os II , and Ir III Complexes as Potential Anticancer Agents: Synthesis, Structure Elucidation, Cytotoxicity, and DNA Model Interaction Studies Charles K. Rono, † William K. Chu, † James Darkwa, † Debra Meyer, ‡ and Banothile C. E. Makhubela* ,† † Department of Chemistry, University of Johannesburg, Kingsway Campus, 2006 Auckland Park, South Africa ‡ Department of Biochemistry, University of Johannesburg, Kingsway Campus, 2006 Auckland Park, South Africa * S Supporting Information ABSTRACT: Novel conjugated ruthenium(II), rhodium- (III), and iridium(III) organometallic complexes of triazoles 1 and 2 synthesized and evaluated for anticancer activity against cervical (HeLa), kidney (HEK293), nonsmall lung cancer (A549), and leukemia (MT4) cancer cell lines are reported herein. The complexes are κ 2 -N,C coordinated and have the formula [ML(Ar)Cl] (where L is 1-benzyl-4-phenyl- 1H-1,2,3-triazole for 1 and 1-benzyl-4-hydroxymethyl-1H- 1,2,3-triazole for 2, Ar is p-cymene for Ru II and Os II and Cp* for Rh III and Ir III , and M is metal). NMR studies, including HMBC and NOESY, were employed to unambiguously elucidate their structures and provide their conformational information in solution. Single-crystal X-ray diffraction data have been used to establish the solid-state structures of selected complexes, which further confirm the structural elucidation by NMR. Dynamic NMR studies, such as differential transferred NOE, have been employed to distinguish between isomers 1a_I and 1a_II of ruthenium(II) complexes of triazole 1. The rhodium(III) (1b) and iridium(III) (1c) complexes exhibited good cytotoxic activities (CC 50 =4-6 μM) comparable to that of the drug auranofin against lung cancer A549 cell lines (CC 50 = 4.69 μM). While triazole 1 based ruthenium(II) (1a) and osmium(II) (1d) complexes displayed modest anticancer activities against HeLa and HEK293 cell lines, the analogous rhodium(III) and iridium(III) complexes exhibited good potential (CC 50 =9-54 μM versus auranofin (3-9 μM)) against these cancer cell lines. Insightful NMR studies on the interaction between the DNA model guanosine 5′-GMP and the complexes 1b,c reveal a possible mode of action of the aquated complexes involving carbenylation with DNA bases or purines through the triazolyl proton H-5. From the findings, these complexes could possibly confer their cytotoxic activities through intercalation with the DNA of pathological cells. Therefore, carbenylation of the triazolylrhodium(III) and iridium(III) complexes by DNA guanosine 5′-GMP is proposed as a novel mode of DNA intercalation of these complexes in cancer cells. ■ INTRODUCTION Cancer is a group of diseases with enormous socioeconomic burden in addition to being the second and third leading causes of death in developed and developing nations, respectively. The discovery of cisplatin as a cancer regimen in combination with pre-cisplatin-era therapeutic organic compounds greatly improved the cure rate for cancer from 10% to an average of at least 90% in most types of cancers and a 100% cure rate in particular for testicular cancer. However, the clinical use of cisplatin as an antitumor drug is limited by dose-limiting side effects (such as neurotoxicity, hepatotoxicity, and nephrotoxicity) and inherent or acquired resistance following repeated treatment. This is often associated with platinum-based drugs. 1 There is continuous effort being made in the design and synthesis of novel anticancer agents with the desired efficacy, selectivity, and broad spectrum activity. 2 This includes metallodrugs capable of inducing apoptosis to tumor cells with no or minimal toxicity to the host in comparison to platinum-based drugs. 2,3 Transition metals other than platinum such as ruthenium, 1,4 palladium, 5 and gold 6 have also been studied for their anticancer activities. These non-platinum-based drugs have shown remarkable cytotoxic results on several cancer cell lines (such as HeLa-cervical, C6-glioma, and Chinese Hamster Ovarian-Ovarian cancer cell lines) with minimal side effects in comparison to platinum-based drugs. 7, 8 Compounds of ruthenium are highly promising drugs and have been identified to be less toxic in comparison to platinum drugs and capable of overcoming resistance induced by platinum drugs on cancer cells. 3, 9 These observed activities in arene ruthenium compounds have been attributed to transportation by transferrin to tumor cells, although at binding sites different Received: July 5, 2019 Article pubs.acs.org/Organometallics Cite This: Organometallics XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.organomet.9b00440 Organometallics XXXX, XXX, XXX-XXX Downloaded via NOTTINGHAM TRENT UNIV on August 16, 2019 at 04:31:49 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.