QSAR AND MOLECULAR DESIGN OF BENZO[B]ACRONYCINE DERIVATIVES AS ANTITUMOR AGENTS

Abstract

Quantitative structure-activity relationship (QSAR) studies of a series of benzo[b]acronycine derivatives as a novel class of antitumor agents have been carried out using the density functional theory (DFT), molecular mechanics (MM+) and statistical methods. Some calculated parameters of geometric structures, electronic structures and molecular properties of the compounds were adopted as generalized descriptors (variables). Via a stepwise regression analysis, some main independent factors affecting the activities of the compounds were selected out, and then the quantitative structure-activity relationship (QSAR) equation was established. The results suggest that the energy difference (Δ ε L-H ) between the lowest unoccupied molecular orbital and the highest occupied molecular orbital, the net charges of the nitrogen atom N 11 and the first atom of the substituent R 2 , and the hydrophobic parameter (log P 1 ) of the substituent R 1 are the main independent factors contributing to the antitumor activities of the compounds. The fitting correlation coefficient (r 2 ) and the cross-validation coefficient (q 2 ) for the model established by this study are 0.865 and 0.721, respectively, showing this model with a good predictability. The QSAR equation can be used to estimate unknown antitumor activity of this kind of compound, and thus design new compounds with high antitumor activities. Here, based on this QASR study, 4 new compounds with predicted high antitumor activities have been theoretically designed and they are expecting experimental verification.