Quantitative Structure–Activity Relationships of Heterocyclic Topoisomerase Iand II Inhibitors

Deoxyribonucleic acid (DNA) topoisomerases are ubiquitous enzymes that are involved in diverse cellularprocesses, such as replication, recombination, transcription, and chromosome segregation. These enzymessolve topological problems related to DNA double helical structure by breaking and rejoining DNA strands.There are two major classes of topoisomerases: topoisomerase I (topo I), which breaks and resealsone strand of DNA, and topoisomerase II (topo II), which alters DNA topology by catalyzing thepassage of an intact DNA double helix through a transient double stranded break made in a secondhelix. A variety of heterocyclic antitumor agents currently used in chemotherapy or evaluated in clinicaltrials are known to inhibit either DNA topo I or II. The clinical use of these inhibitors is limiteddue to sever toxic effects on normal cells. Therefore, there has been increasing interest in discoveringand developing novel heterocyclic molecules that inhibit topo I or II or both, and which have the abilityto spare normal cells. Interest in the application of the quantitative structure–activity relationship(QSAR) has steadily increased in recent decades because it has repeatedly proven itself to be a low-cost,high-return investment. Potential use of QSAR models for screening of chemical databases or virtual librariesbefore their synthesis appears equally attractive to chemical manufacturers, pharmaceutical companies, andgovernment agencies. We hope it may also be useful in the design and development of new heterocyclic topo Ior II inhibitors. In this chapter, an attempt has been made to collect the inhibitory data on differentseries of heterocyclic compounds against topos I and II, and to discuss it in terms of QSAR to understandthe chemical–biological interactions.