Human Topoisomerase I mediated cytotoxicity profile of L-valine-quercetin diorganotin(IV) antitumor drug entities

摘要

New chiral L-ID-valine-quercetin diorganotin(IV) complexes [(CH3)(2)Sn(Q)(val)I 1(L/D), [(C6H5)(2)Sn(Q)(val)i 2(L/D), were synthesized and thoroughly characterized by elemental analysis, mass spectrometry, IR, H-1 NMR,Sn-119 NMR spectroscopy. Preliminary comparative DNA binding studies on enantiomeric complexes 1(L/D) and 2(L/D) were carried out by UV vis, fluorescence titrations, thermal denaturation and circular dichroic techniques to ascertain their DNA binding propensity. Thermal denaturation studies of complexes in the absence and presence of CT DNA have been carried out and Delta T-m, was calculated to be 2 3 degrees C depicting electrostatic mode of binding corroborated well with the results of UV vis and fluorescence studies. The intrinsic binding constant, K-b and binding constant, K values revealed that both Lenantiomers of complexes 1 and 2 exhibited exceptionally high binding propensity as compared to their D-enantiomers and between L-enantiomers 2(L) exhibited greatest binding affinity and followed the trend: 2(L)> 1(L)> 2(D) > 1(D). The cytotoxicity profile of 1(L) and 2(L), was studied on four different human cancer cell lines; HeLa, MCF7, Hep-G2, MIA-Pa-Ca-2 by SRB assay which revealed remarkably good cytotoxic activity (with GI(50) values of <10 mu g mL(-1)) and 2(L) exhibited better cytotoxic activity than 1L. Furthermore, the chemotherapeutic action of drug entities was found to be mediated by human Topoisomerase I enzymatic inhibition. (C) 2016 Elsevier B.V. All rights reserved.