Advancement towards tin-based anticancer chemotherapeutics: structural modification and computer modeling approach to drug-enzyme interactions.
Three new triphenyltin(IV) complexes, viz., triphenylstannyl 2-((E)-(4-hydroxy-3-((E)-((4-(methoxycarbonyl)phenyl)imino)methyl)phenyl)-diazenyl)benzoate (Ph(3)SnL(2)H: 2), methyl 2-((E)-(4-hydroxy-3-((E)-((4-(((triphenylstannyl)oxy)carbonyl)phenyl)imino)methyl)phenyl)diazenyl)benzoate (Ph(3)SnL(3)H: 3), and triphenylstannyl 2-((E)-(4-hydroxy-3-((E)-((4-(((triphenylstannyl)oxy)carbonyl)phenyl)imino)methyl)phenyl)diazenyl)benzoate ((Ph(3)Sn)(2)L(4)H: 4) were synthesized and characterized by spectroscopic ((1)H, (119)Sn NMR and IR) techniques in combination with elemental analysis. The (119)Sn 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 (Ph(3)Sn)(2)L(4)H (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 (Ph(3)SnL(1)H.OH(2) (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).
Department of Chemistry, North-Eastern Hill University, NEHU Permanent Campus,Umshing, Shillong 793 022, India. basubaul@nehu.ac.in
Tushar S
TS
Basu Baul
Dhrubajyoti
D
Dutta
Dick
D
de Vos
Herbert
H
Höpfl
Pooja
Palwinder
P
Singh
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003198:Computer Simulation; D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D009947:Organotin Compounds / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding
D000970:Antineoplastic Agents; D009947:Organotin Compounds; D005047:Etoposide; D002945:Cisplatin; D005472:Fluorouracil