A Combined 2D‐ and 3D‐QSAR Study on Analogues of ARC‐111 with Antitumor Activity

Abstract

Two-Dimensional (2D) and Three-Dimensional (3D) Quantitative Structure–Activity Relationships (QSARs) of a series of analogues of ARC-111 with antitumor activity expressed as pIC50, which is defined as the negative value of the logarithm of necessary molar concentration of these compounds to cause 50% growth inhibition against tumor cell lines P388, have been studied by using a combined method of the DFT, MM2, and statistics for 2D, as well as the Comparative Molecular Field Analysis (CoMFA) for 3D. The established 2D-QSAR model shows not only significant statistical quality, but also predictive ability, with the square of adjusted correlation coefficient of 0.869 and the square of the crossvalidation coefficient q2 of 0.834 as well as the square of predictive correlation coefficient of 0.867 for the test set. The 3D-QSAR model also shows good correlative and predictive capabilities in terms of R2 (0.993) and q2 (0.674) when CoMFA fields are used for the whole studied compounds. The results from 2D- and 3D-QSAR analyses conformably show that the steric interaction plays a crucial role in determining the cytotoxicity of the compounds and that selecting a moderate-size substituent R as well as increasing the negative charge of C28 at the same time are advantageous to improving the antitumor activity. Such results might offer some useful theoretical references for understanding the action mechanism and directing the molecular design of this kind of compound with antitumor activity.