Topoisomerase 1B poisons: Over a half-century of drug leads, clinical candidates, and serendipitous discoveries

Abstract

Topoisomerases are DNA processing enzymes that relieve supercoiling (torsional strain) in DNA, are necessary for normal cellular division, and act by nicking (and then religating) DNA strands. Type 1B topoisomerase (Top1) is overexpressed in certain tumors, and the enzyme has been extensively investigated as a target for cancer chemotherapy. Various chemical agents can act as "poisons" of the enzyme's religation step, leading to Top1-DNA lesions, DNA breakage, and eventual cellular death. In this review, agents that poison Top1 (and have thus been investigated for their anticancer properties) are surveyed, including natural products (such as camptothecins and indolocarbazoles), semisynthetic camptothecin and luotonin derivatives, and synthetic compounds (such as benzonaphthyridines, aromathecins, and indenoisoquinolines), as well as targeted therapies and conjugates. Top1 has also been investigated as a therapeutic target in certain viral and parasitic infections, as well as autoimmune, inflammatory, and neurological disorders, and a summary of literature describing alternative indications is also provided. This review should provide both a reference for the medicinal chemist and potentially offer clues to aid in the development of new Top1 poisons.

Keywords: Topoisomerase; alkaloids; camptothecin; cancer; drug discovery; indenoisoquinolines; natural products; semisynthetic derivatives.