Overview of the New Bioactive Heterocycles as Targeting Topoisomerase Inhibitors Useful Against Colon Cancer

Abstract

Colorectal cancer (CRC) is the third most common cancer globally, with high mortality. Metastatic CRC is incurable in most cases, and multiple drug therapy can increase patients' life expectancy by 2 to 3 years. Efforts are being made to understand the relationship between topoisomerase enzymes and colorectal cancer. Some studies have shown that higher expression of these enzymes is correlated to a poor prognosis for this type of cancer. One of the primary drugs used in the treatment of CRC is Irinotecan, which can be used in monotherapy or, more commonly, in therapeutic schemes such as FOLFIRI (Fluorouracil, Leucovorin, and Irinotecan) and CAPIRI (Capecitabine and Irinotecan). Like Camptothecin, Irinotecan and other compounds have a mechanism of action based on the formation of a ternary complex with topoisomerase I and DNA providing damage to it, therefore leading to cell death. Thus, this review focused on the principal works published in the last ten years that demonstrate a correlation between the inhibition of different isoforms of topoisomerase and in vitro cytotoxic activity against CRC by natural products, semisynthetic and synthetic compounds of pyridine, quinoline, acridine, imidazoles, indoles, and metal complexes. The results revealed that natural compounds, semisynthetic and synthetic derivatives showed potential in vitro cytotoxicity against several colon cancer cell lines, and this activity was often accompanied by the ability to inhibit both isoforms of topoisomerase (I and II), highlighting that these enzymes can be promising targets for the development of new chemotherapy against CRC. Pyridine analogs were considered the most promising for this study, while the evaluation of the real potential of natural products was limited by the lack of information in their work. Moreover, the complexes, although promising, presented as the main limitation the lack of selectivity.