Advancement Towards Tin-based Anticancer Chemotherapeutics: Structural Modification and Computer Modeling Approach to Drug-Enzyme Interactions

Tushar      S. Basu Baul; Dhrubajyoti      Dutta; Dick      de Vos; Herbert      Hopfl; Pooja; Palwinder      Singh

Abstract

Three new triphenyltin(IV) complexes, viz., triphenylstannyl 2-((E)-(4-hydroxy-3-((E)-((4-(methoxycarbonyl) phenyl)imino)methyl)phenyl)-diazenyl)benzoate (Ph3SnL2H: 2), methyl 2-((E)-(4-hydroxy-3-((E)-((4- (((triphenylstannyl)oxy)carbonyl)phenyl)imino)methyl)phenyl)diazenyl)benzoate (Ph3SnL3H: 3), and triphenylstannyl 2- ((E)-(4-hydroxy-3-((E)-((4-(((triphenylstannyl)oxy)carbonyl)phenyl)imino)methyl)phenyl)diazenyl)benzoate ((Ph3Sn)2 L4H: 4) were synthesized and characterized by spectroscopic (1H, 119Sn NMR and IR) techniques in combination with elemental analysis. The 119Sn NMR spectral data were recorded in a non-coordinating solvent and indicate tetrahedral coordination geometry in solution. In the solid state, a single-crystal X-ray diffraction analysis of the dinuclear complex (Ph3Sn)2L4H (4) revealed a monocapped tetrahedral coordination geometry with anisobidentate coordination modes of the carboxylate groups with average bond angles around the Sn atoms of 113.5 and 112.2°, respectively. In vitro cytotoxicity studies were performed with all three complexes 2-4, along with a previously reported parent aquatriphenylstannyl complex, 2-((3-formyl-4-hydroxyphenyl)diazenyl)benzoate (Ph3SnL1H.OH2 (1)) across a panel of human tumor cell lines, viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The screening results were compared with those from related triphenyltin(IV) carboxylates containing (i) imino (11-16) and (ii) diazenyl frameworks (1, 5-10). In general, complexes 2-4 exhibited good cytotoxic activity and among them, compound 4 was found to be the best performer, particularly for EVSA-T and MCF-7 cell lines. Additionally, 4 scored better activity than cisplatin (2-15 folds), 5-fluorouracil and etoposide across a panel of cell lines. Docking studies indicated that the diazenyl and imino nitrogen atoms, and the oxygen atoms of triphenyltin ester, methyl ester and phenolic group play an important role for the complexation of the organotin compounds in the active sites of enzymes such as ribonucleotide reductase (pdb ID: 4R1R), thymidylate synthase (pdb ID: 2G8D), thymidylate phosphorylase (pdb ID: 1BRW) and topoisomerase II (pdb ID: 1QZR).

Keywords: Organotin carboxylates, dinuclear tin(IV) complex, cancer chemotherapy, cell lines, docking studies

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