Inhibiteur de topoisomérase

Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerase plays important roles in cellular reproduction and DNA organization, as they mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells. Topoisomerase inhibitors influence these essential cellular processes. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks while others, deemed topoisomerase poisons, associate with topoisomerase-DNA complexes and prevent the re-ligation step of the topoisomerase mechanism. These topoisomerase-DNA-inhibitor complexes are cytotoxic agents, as the un-repaired single- and double stranded DNA breaks they cause can lead to apoptosis and cell death. Because of this ability to induce apoptosis, topoisomerase inhibitors have gained interest as therapeutics against infectious and cancerous cells. In the 1940s, great strides were made in the field of antibiotic discovery by researchers like Albert Schatz, Selman A. Waksman, and H. Boyd Woodruff that inspired significant effort to be allocated to the search for novel antibiotics. Studies searching for antibiotic and anticancer agents in the mid to late 20th century have illuminated the existence of numerous unique families of both TopI and TopII inhibitors, with the 1960s alone resulting in the discovery of the camptothecin, anthracycline and epipodophyllotoxin classes. Knowledge of the first topoisomerase inhibitors, and their medical potential as anticancer drugs and antibiotics, predates the discovery of the first topoisomerase (Escherichia. coli omega protein, a TopI) by Jim Wang in 1971. In 1976, Gellert et al. detailed the discovery of the bacterial TopII DNA gyrase and discussed its inhibition when introduced to coumarin and quinolone class inhibitors, sparking greater interest in topoisomerase-targeting antibiotic and antitumor agents.