Topoisomerase inhibitors as anticancer agents: a patent update.

BACKGROUND

Topoisomerases (topos) are nuclear enzymes that resolve topological problems associated with DNA during various genetic processes. The essential role of topos in vital processes of the cell, their elevated level in solid tumors and cell death due to their inhibition make topos inhibitors as a potent class of antineoplastic agents.

METHODS

This review specifically summarizes patents embracing topo I, topo I and II inhibitors. The review covers topos inhibitors which are structurally close to camptothecin (CPT), natural products such as lamellarins and synthetic trisubstituted pyridines. It largely focuses on chemical entities developed by systematic structure-activity relationship (SAR) studies of natural benzo[c]phenanthridine (nitidine) and synthetic protoberberine (coralyne) established as antineoplastic agents targeting topo(s). In addition, indenoisoquinolines and evodiamines initially discovered through COMPARE analysis and receptor-based virtual screening (VS) respectively have been discussed.

CONCLUSIONS

Along with conventional techniques, computer-aided VS, molecular modeling and docking studies have been applied for drug design, discovery and development. Computer-aided tools provide a rational way to explain pharmacological activities of topos inhibitors under study. Comparative study of crystal structures of topo I/II-DNA-drug ternary complex and use of appropriate pharmacological screening methods will lead to potential anticancer drugs in the coming days.