Topoisomerases: Features of the Action, Classification, Cell Functions, Inhibition, Anthrafurandion

Abstract

Introduction. Topoisomerases influence on DNA topology and are capable of running down their super spiraling molecules by importation of one- or two-chained ruptures with the subsequent restitution and also the negative super rounds or catenae’s. Topoisomerases are known to be targets for antineoplastic therapy. Inhibitors of these enzymes of various nature and chemical structure are widely used for the suppression of tumor Topoisomerase I and/or II activity with the blocking cells in the phase G2 and a delay of their introduction in mitosis. Such difficult curable tumors as colorectal cancer, carcinoma of the stomach, non-small cell lung cancer and so forth are the most sensitive to these drugs. The search of perspective antineoplastic inhibitors is implemented generally in ranks of the non-camptothecin agents among which heterocyclic condensed nitrogenous compounds, in particular, anthrafurandiones show the most significant results. The review of thematic literature from 2011 to 2018 is devoted to the description of properties of topoisomerase as targets and their inhibitors from perspective classes. Objectives: 1. The analysis of signal characteristics of topoisomerases as targets for anticancer non-camptothecin inhibitors. 2. Identification of structure-activity relationship in the ranks of potential inhibitors of topoisomerases. 3. The choice of the most perspective non-camptothecin topoisomerase inhibitors among heterocyclic condensed nitrogenous compounds on the basis of the comparative analysis of structure and properties. Material and methods. Materials of 79 scientific articles published in the leading biological, biochemical and chemical journals of the different countries within the 8 last years are subjected to the analysis. The structure of the review meets the purpose and tasks of the scientific analysis. Results. The analysis of the thematic literature showed topoisomerases to be relevant targets for antineoplastic therapy of severe oncological pathology. In this regard, intensive search of various pharmaceuticals among topoisomerase inhibitors is performed in recent years. Researchers modify the known basic structures as well as synthesize new compounds. The discovery of a top-directional effect of the known medicines expands the data on their mechanism of the action. To identify the topoisomerase inhibitory activity of the drug the methods with the use of plasmid DNA is applied. The cytotoxic activity, apoptosis induction, including the caspases activation, modification of mitochondrial potential, influence on p53 and others are examined in parallel studies. The research directed on the identification of new effective non-camptothecin oral topoisomerase inhibitors among the anthracyclines derivatives are of undoubted relevance. Such agents, in contrast to Doxorubicin (anthracycline antibiotic widely used for tumor therapy), have moderate toxicity and allow to control the growth of solid tumors and leukemia in mono-therapy mode. Conclusion. In terms of searching of original antineoplastic agents, a class of heterocyclic condensed nitrogenous compounds, first of all, the anthraquinones showing properties of topoisomerase inhibitors is one of the most promising. The results of chemical and biological research of the compounds of this series were laid in a basis of the design of medicinal substances and their drug formulations. Prognostically significant data obtained in preclinical testing allow us to hope that obtained antitumor agents will be highly effective on a clinical stage of trials.

Antitumor Drugs Based on Indolocarbazol Derivatives

“…On the basis of rebeccamycin, a glycosyl-dichloroindolocarbazole analogue with the improved water solubility denoted as becatecarin (BMS-181176, BMY-27557, NSC-655649, XL 119, XL-119, XL119) (National Cancer Institute, USA) (Fig. 12) 15 was obtained [99]. Becatecarin is an antitumor antibiotic with an inhibitory activity against topoisomerase I and topoisomerase II, as well as the ability to intercalate DNA [100,104].…”

“…Edothecarin (J-107088, J-107088, PF-804950, 14 Isoenmers are not specified. 15 PHA-782615) (Banyu Co., Japan) (Fig. 14) is a NB-506 derivative with a broad spectrum of antitumor activity, it is a topoisomerase I inhibitor that induces cleavage of single-stranded DNA more effectively than original indolocarbazole or camptothecin.…”

“…Topoisomerases affect the topology of DNA and are able to relax their supercoiled molecules by introducing single-or double-stranded breaks followed by their DSB repair, as well as negative supercoils, or catenans. Inhibitors of these enzymes are widely used to suppress the activity of type I and / or type II tumor topoisomerases, blocking cells in the G2 phase and delaying their entry into mitosis [15].…”