Original article New modulated design, docking and synthesis of carbohydrate-conjugate heterobimetallic Cu II eSn IV complex as potential topoisomerase II inhibitor: In vitro DNA binding, cleavage and cytotoxicity against human cancer cell lines Sartaj Tabassum * , Mohd Afzal, Farukh Arjmand Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India article info Article history: Received 18 May 2013 Received in revised form 9 September 2013 Accepted 14 September 2013 Available online 25 September 2013 Keywords: Heterobimetallic complexes T4 ligase DNA cleavage Molecular docking abstract New carbohydrate-conjugate heterobimetallic complexes [C 22 H 50 N 6 O 13 CuSnCl 2 ](3) and [C 22 H 58 N 6 O 17- NiSnCl 2 ] (4) were synthesized from their monometallic analogs [C 22 H 52 N 6 O 13 Cu] (1) and [C 22 H 60 N 6 O 17 Ni] (2) containing N-glycoside ligand (L). In vitro DNA binding studies of L and complexes (1 e4) with CT DNA were carried out by employing various biophysical and molecular docking techniques which revealed that heterobimetallic complex 3 strongly binds to DNA in comparison to 4, monometallic complexes (1 and 2) and the free ligand. Complex 3 cleaves pBR322 DNA via hydrolytic pathway (confirmed by T4 DNA ligase assay) and inhibited Topo-II activity in a dose-dependent manner. Furthermore, complex 3 was docked into the ATPase domain of human-Topo-II in order to probe the possible mechanism of inhibition. Ó 2013 Elsevier Masson SAS. All rights reserved. 1. Introduction Cancer or malignant neoplasm, the uncontrolled and patho- logical proliferation of abnormal cells, is the second leading cause of human death after cardiovascular diseases in the world, and the number of new cases increases each year [1,2]. Although there are many therapeutic strategies, including chemotherapy and radio- therapy, high systemic toxicity and drug resistance limit their successful outcomes in most cases. Cancer chemotherapy based on metal complexes has gained momentum after the serendipitous discovery of cisplatin [cis-diamminedichloroplatinum (II)], and re- mains a front-line treatment for most aggressive solid tumors [3]. Therefore, novel treatments are urgently needed for cancer therapy. DNA and enzymes represent the most targeted bioreceptors for small molecules as various regulatory processes such as gene expression, gene transcription, mutagenesis, carcinogenesis [4e6]. Most anticancer drugs bind to DNA and proteins either in a reversible or irreversible manner suggesting a direct relationship between their interactions with macromolecules, hence, leading to their therapeutic effect [7]. Design of new metal-based drug candidate depends on the ligand scaffold having multihydroxy functionality and well-defined stereochemistry suitable for metal coordination which can modu- late the reactivity, lipophilicity, oral/systematic bioavailability of metal ions, stabilization of the oxidation state and substitutional inertness depending on the requirements for chemotherapy [8]. In this regard, the biocompatibility of carbohydrates and its ability to recognized by cell-surface receptors indicate their potential utility as ligands in targeted drug delivery for therapeutic applications. Therefore, considerable efforts have been directed toward carbo- hydrate recognition by synthetic receptors in relation to the important roles of saccharides in biological processes, such as celle cell recognition, signal transduction, tumor metastasis, and build- ing blocks for nucleic acids [9,10]. Moreover, carbohydrates are one of the major energy sources for living beings through the pro- cessing of glucose inside the cells. The energy requirement in cancer cells are significantly higher than the normal cells for their uncontrolled growth and altered metabolism resulting in the over expression of transmembrane proteins mediating the transport of glucose to the cells [11]. The recent emerging themes in the chemotherapeutic regime are the development of bifunctional architectures, one of them Abbreviations: UVevis, UVevisible; CT DNA, calf thymus DNA; Tris, Tris(hy- droxymethyl)aminomethane; EB, ethidium bromide; DMSO, dimethyl sulfoxide; LNT, liquid nitrogen temperature; TCNE, tetracyanoethylene. * Corresponding author. E-mail address: tsartaj62@yahoo.com (S. Tabassum). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2013.09.036 European Journal of Medicinal Chemistry 74 (2014) 694e702