Title:Advancement Towards Tin-based Anticancer Chemotherapeutics: Structural Modification and Computer Modeling Approach to Drug-Enzyme Interactions
Volume: 12
Issue: 24
Author(s): Tushar S. Basu Baul, Dhrubajyoti Dutta, Dick de Vos, Herbert Hopfl, Pooja and Palwinder Singh
Affiliation:
Keywords:
Organotin carboxylates, dinuclear tin(IV) complex, cancer chemotherapy, cell lines, docking studies
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).
