Design and synthesis of heterobimetallic topoisomerase I and II inhibitor complexes: in vitro DNA binding, interaction with 5'-GMP and 5'-TMP and cleavage studies.
New potential cancer chemotherapeutic complexes Cu-Sn(2)/Zn-Sn(2) 3 and 4 were designed and prepared as topoisomerases inhibitors; their in vitro DNA binding studies were carried out which reveal strong electrostatic binding via phosphate backbone of DNA helix, in addition to other binding modes viz. coordinate covalent and partial intercalation. To throw insight to molecular binding event at the target site, UV-vis titrations of 3 and 4 with mononucleotides of interest, viz, 5'-GMP and 5'-TMP were carried out, (in case of 4) by (1)H and (31)P NMR. Cleavage studies employing gel electrophoresis demonstrate both the complexes 3 and 4 are efficient cleavage agents and are specific groove binders (complex 3 binds to both major and minor groove while complex 4 is specifically minor groove binder only). In addition, the complexes show high inhibition activity against topoisomerase I and II. However, complex 4 exhibits significant inhibitory effects on the Topo I activity at a very low concentration approximately 2.5 microM.
Arjmand
Farukh
F
Department of Chemistry, Aligarh Muslim University, Aligarh 202 002, India. farukh_arjmand@yahoo.co.in
Muddassir
Mohd
M
D001665:Binding Sites; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D053837:DNA Cleavage; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D006157:Guanosine Monophosphate / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013055:Spectrophotometry, Infrared; D055672:Static Electricity; D013938:Thymidine Monophosphate / Q000737:chemistry*; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D056831:Coordination Complexes; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D013938:Thymidine Monophosphate; D006157:Guanosine Monophosphate; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II