A Chloro-Bridged Heterobimetallic (η 6 ‑Arene)ruthenium-Organotin Complex as an Efficient Topoisomerase Iα Inhibitor Rais Ahmad Khan, † Ahmad Asim, † Rita Kakkar, ‡ Deepti Gupta, ‡ Vivek Bagchi, § Farukh Arjmand, † and Sartaj Tabassum* ,† † Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India ‡ Department of Chemistry, University of Delhi, Delhi 110007, India § Department of Chemistry, University of Missouri, Rolla, Missouri 65409, United States * S Supporting Information ABSTRACT: The chloro-bridged heterobimetallic complex (η 6 - hexamethylbenzene)Ru(dmp)(μ-Cl) 2 Sn(CH 3 ) 2 Cl 2 was designed, synthesized, and characterized by various spectroscopic methods, viz. IR, 1 H and 13 C NMR, and ESI MS, and single-crystal X-ray crystallography as an approach toward multitargeting metal-based potential anticancer drug candidates. In vitro DNA binding studies confirmed the binding affinity of the complex toward the minor groove of DNA, which is further validated by docking studies. Furthermore, the complex exhibited significant inhibitory effects on topoisomerase Iα at a very low concentration (∼8 μM). The cytotoxicity of the complex against HeLa and HepG2 cancer cell lines was evaluated, which revealed significant regression in cancerous cells in comparison with the standard drug. T he serendipitous discovery of the simple inorganic complex cisplatin (i.e., cis-[PtCl 2 (NH 3 ) 2 ]) as an anti- cancer agent has stimulated extensive investigations in the field of metal-based chemotherapeutic agents. 1 Since then, a number of metal-based chemotherapeutic agents have been designed and tested for their biomedical applications. 2 However, serious adverse effects, such as dose limiting, nephrotoxicity, peripheral neuropathy, tinnitus, and hearing loss, are known. 3 These serious limitations have prompted the search for unconven- tional chemotherapeutic strategies. Numerous approaches have been adopted; among these, the concept of multitargeted anticancer agents is quite captivating, showing potential prospects over classical chemotherapeutics. 4 Ruthenium compounds have attracted special interest due to their favorable properties, such as lower toxicity toward healthy tissues, high cytotoxicity against cancer cells, various oxidation states under physiological conditions, and higher coordination number and ligand exchange kinetics similar to those of platinum complexes. 5 Therefore, ruthenium complexes emerged as the most promising alternatives to platinum-based substances for the development of new metallo-pharmaceut- icals. The ruthenium complexes exhibit cytotoxic effects following numerous mechanisms, such as inhibition of metastases, DNA damage, production of reactive oxygen species, interactions with proteins, activation of genes of the endoplasmic reticulum stress pathway, and triggering of apoptosis. 5a,c Extraordinary promise in chemotherapy and photodynamic therapy has been shown by a number of ruthenium complexes in in vitro and in vivo studies; for example, NAMI-A and KP1019 are currently undergoing clinical trials. 6 Among these, ruthenium complexes coordinated by arene ligands have also gained remarkable interest by exhibiting promising anticancer activities, especially against cisplatin-resistant cancer cells, as some compounds are in the advanced preclinical development stage. 6a Alternatively, chemo- therapeutic investigation of other metal complexes established that organotin(IV) compounds have high in vitro antitumor activity in a wide variety of human tumors. In particular, cancer cells do not develop resistance against organotin complexes, well-known for cisplatin and its analogues. 7 Heterobimetallic complexes are bifunctional agents containing two or more active metal entities which exhibit preferential intrinsic DNA interactions. These bimetallic complexes enhance the chemo- therapeutic action manyfold, as they provide a dual mode of binding at the target site and also exhibit novelty in preferential selectivity inside the cell. This strategy has resulted in promising approaches, with compounds exhibiting novel modes of action. 8,9 The design of metal-based pharmaceuticals depends on the choice of ligand framework. One of the conventional ways is to link the metal to a bioactive ligand. 7a,9 Numerous platinum and ruthenium complexes with N-heterocyclic ligands have been reported, a few exhibited of which significant activities and are undergoing clinical trials. 6 Pyrazoles, five-membered N-hetero- cycles, have long been applied in agrochemical and pharmaceutical industries as herbicides and active pharmaceut- icals. Antimicrobial, anticancer, ACE (angiotensin-converting- Received: December 20, 2012 Article pubs.acs.org/Organometallics © XXXX American Chemical Society A dx.doi.org/10.1021/om301223k | Organometallics XXXX, XXX, XXX-XXX