Quantitative Structure-Cytotoxicity Relationships of Sesquiterpene Lactones derived from partial charge (Q)-based fractional Accessible Surface Area Descriptors (Q_frASAs)

Abstract

In continuation of a previous QSAR study on the cytotoxicity of 20 sesquiterpene lactones (STLs) of the helenanolide type towards a mouse tumour cell line where a very strong correlation of activity with only two indicator variables encoding the nature of the present α,β-unsaturated carbonyl structure elements (cyclopentenone and α-methylene-γ-lactone structure) was found, it was the major goal of this study to establish a QSAR model for a set of STLs with wider structural variability. Cytotoxicity towards the human KB cervix carcinoma cell line was experimentally determined for a set of 40 STLs representing five different structural groups (2 germacranolides, 6 guaianolides, 23 pseudoguaianolides, 8 eudesmanolides and 1 carabranolide (cyclopropane type xanthanolide) and the resulting IC50 values were submitted to a QSAR study using the molecular modelling program MOE. As major result it could be shown that variance in STL cytotoxicity data can be explained to a high degree by electronic and surface properties. QSAR models of considerable internal and external predictivity could be obtained by PCR and PLS analysis of a descriptor set representing fractional accessible molecular surface areas (Q_frASAs). This set of descriptors is calculated by partitioning the molecular surface accessible to a spheric probe of radius 1.4 Å into fractions attributable to atoms within 14 charge intervals from −0.3 to 0.3 e. The applicability of such Q_frASA descriptors is validated by analysis of several sets of literature data, yielding QSAR models of good statistical quality. It is therefore assumed that Q_frASA descriptors may be of wider applicability in QSAR and QSPR.