Other Anticancer Drugs Targeting DNA and DNA-Associated Enzymes

TL;DR: The chapter shows the relevance of the Top2 poisons because they represent the largest group of approved agents among these targets, especially the anthracycline antibiotics previously discussed in Chapter 4 as precursors of radical species.

Abstract: Chapter 7 describes the chemical basis of the DNA intercalation process and several multimodal anticancer agents that exert their biological activity via intercalation with DNA and inhibition of topoisomerase II, other DNA-associated enzymes, or transcription factors that control genes involved in processes important for tumor progression and metastasis. It briefly discusses the role of topoisomerase I (Top1) and topoisomerase II (Top2), their mechanisms, and their inhibitors, discussing in detail structure modifications attempting to overcome the spontaneous and rapid inactivation of most camptothecin derivatives, the role of Top1 targeted agents as interfacial inhibitors, and the basis of Top1 inhibitors’ inherent resistance. The chapter shows the relevance of the Top2 poisons because they represent the largest group of approved agents among these targets, especially the anthracycline antibiotics previously discussed in Chapter 4 as precursors of radical species. It also discusses other Top2 poisons, particularly those related to the natural lignan podophyllotoxin, as well as the most relevant Top2 catalytic inhibitors. Among DNA-associated enzymes, telomerase inhibitors such as G-quadruplex stabilizers, inhibitors of telomerase reverse transcriptase (hTERT), and the RNA domain template are described (telomerase-based immunotherapy is discussed in Chapter 12). Finally, inhibitors of DNA repair processes, such as the nucleotide excision repair, are only enunciated because these agents are discussed in detail in Chapter 14.