Topoisomerase II inhibitors

Topoisomerase II (Topo II) is a nuclear protein known to play crucial roles in DNA replication,18 condensation and segregation of chromosomes,19,20 and transcription.21 Topo II catalyzes a number of ATP-dependent reactions, such

Figure 11.1 R = CH3 for Co(acacen)X2; R = COOH for Co(aciden)X2, peptide attached through COOH group

Figure 11.1 R = CH3 for Co(acacen)X2; R = COOH for Co(aciden)X2, peptide attached through COOH group

H3C^O

H OH

Figure 11.2 Chemical structure of cobalt(III) salicylaldoxime (CoSAL)

as relaxation of negative supercoils, knotting and unknotting, and catenation and decatenation of DNA in vitro?2 24

Cobalt(III) salicylaldoxime complex (CoSAL) was found to possess antiproliferative properties (Figure 11.2).25 Recently, through DNA-binding studies and studies of the action of this complex on Topo II catalytic activities, it was found that Topo II is one of the cellular targets of CoSAL and thereby accounts for the anti-proliferative activity. The inhibition of topo II activity by CoSAL is due to the bidirectional mode of interaction with enzyme and DNA which could aid in forming a drug-mediated cleavage complex.26 The 2-furfural semicarbazone and thiosemicarbazone cobalt complexes were also found to suppress human DNA topoisomerase II activity with DNA nicks and DNA fragmentation,27 but they did not alkylate the bases of DNA, cause intercalation between base pairs or cause cross-linking of DNA strands. Cobalt complexes of 2-furaldehyde oximes were also synthesized and examined.28 These cobalt complexes were inhibitors of DNA polymerase a-activity and de novo purine synthesis with marginal inhibition of ribonucleoside reductase and dihydrofolate reductase activities with DNA fragmentation, but they did not inhibit L1210 DNA Topo II activity, except reducing thymidylate synthetase activity.

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