A Quantitative Structure Activity Relationship (QSAR) Study on Anthrapyrazoles anticancer agents

Abstract

Agents that complex DNA have been established as one of the most effective classes of anticancer agents in clinical use today, with broad application against a number of malignant diseases. The anthracyclines, primarily Daunorubicin and doxorubicin, are representative of this class and are widely utilized clinically. Cumulative cardio toxicity, however, has limited their use. Subsequently, a considerable effort has been made to develop newer anthracycline analogues and other types of DNA- complexing agents in the hope that high levels of broad spectrum anticancer activity might be retained with a relatively low potential for cardio toxicity. Among these latter agents under clinical evaluation are the anthrapyrazoles, a novel class of chromophore-modified anthracenediones related to Mitoxantrone. In this thesis an approach to develop a quantitative structure-activity relationship (QSAR) model (s) that could correlate (s) the structural features of anthrapyrazole (AP) based compounds with their physicochemical, steric, electronic, and structural molecular descriptors was attempted. A set of 18 desoxy anthrapyrazole and 18 dihydroxy anthrapyrazole compounds were used in the models development,’ where 12 of these compounds were in the training set and the remaining 6 compounds of each were used as cross validation (external) sets. The development of the QSAR models involved the use of the multiple linear regression analysis (MLRA) method. Based on the method, two models were chosen to be the best ones for prediction purposes, a desoxy model with r2 value, r2 (CV) value and r2 prediction value of 0.87, 0.71 and 0.70 and a dihydroxy model with r2 value, r2 (CV) value and r2 prediction value of 0.674, 0.586 and 0.213 were obtained.