QSAR AND ACTION MECHANISM OF TROXACITABINE PRODRUGS WITH ANTITUMOR ACTIVITY
Si Yan Liao, Lian Xu, Qian Li, KANG CHENG ZHENG · Journal of Theoretical and Computational Chemistry · 2007
The quantitative structure–activity relationship (QSAR) of troxacitabine prodrugs with antitumor activity has been studied by using the density functional theory (DFT), molecular mechanics (MM2), and statistical methods. The established QSAR model shows not only significant statistical quality, but also predictive ability, with the square of adjusted correlation coefficient [Formula: see text] and the square of the cross-validation coefficient (q2 = 0.807). The antitumor activity is expressed as p IC50, which is defined as the negative value of the logarithm of necessary molar concentration of a compound to cause 50% growth inhibition against the human non-small-cell lung cancer cell line SW1573. It appears to be mainly governed by two factors (or original variables), i.e. the calculated hydrophobic coefficient (C log P) of whole molecule and the net charges of the first atom of substituent R (Q FR ), although three descriptors, i.e. C log P, (C log P)2, and Q FR , were selected in our multiple linear regression model. The factor C log P shows parabolic relation to p IC50 and its suitable range is around 5.6, and the other factor Q FR shows a significant negative correlation with p IC50. In this paper, a detailed discussion on these two factors was carried out, and their close correlation with the action mechanism of these prodrugs was reasonably revealed. Such results can offer some useful theoretical references for understanding the action mechanism and directing the molecular design of this kind of compound with antitumor activity.