Advances in the Chemistry of Natural and Semisynthetic Topoisomerase I/II Inhibitors

The search for new, effective, and low-toxic anticancer agents is one of the most important tasks of modern medicinal chemistry. In general, the solution to this problem comes down to finding new compounds that would act on molecular targets, the targets that play an important role in carcinogenesis. Numerous studies in this field have shown that topoisomerases I and II are one of the main molecular targets in the development of modern anticancer agents. A large number of compounds belonging to different classes are known as capable of inhibiting topoisomerases, including the ones isolated from the natural objects; for example, camptothecin, podophyllotoxin, anthracyclines, polyene acids, and many others. However, along with their efficacy, some of these compounds have a number of substantial disadvantages; chief among these are high toxicity and low solubility, low selectivity of action against malignant tumors, and development of multidrug resistance. The way of overcoming these shortcomings is to create anticancer drugs with improved properties and to study the mechanism of their action within the cell. Therefore numerous groups of researchers carry out an intensive search and selection of natural topoisomerase inhibitors, as well as work on the creation of new synthetic analogs and semisynthetic derivatives of known anticancer compounds capable of altering catalytic activity of ferment by stabilizing the covalent DNA-protein complexes. The present review summarizes the achievements of the past 5–10 years in finding new natural compounds, effective topoisomerase inhibitors, their modification aimed at improving the properties, the study of mechanisms of action, and antitumor activity.