Relationship between the molecular structure and the anticancer activity of N‐(2‐chloroethyl)‐N′‐cyclohexyl‐N‐nitrosoureas: A theoretical investigation

Abstract

AbstractN‐(2‐chloroethyl)‐N′‐cyclohexyl‐N‐nitrosoureas (CCNU) is an important alkylating agent used in the clinical treatment of cancer. The quantitative structure‐activity relationship (QSAR) of CCNU derivatives was investigated using the density functional theory (DFT)‐based descriptors and the n‐octanol/water partition coefficient (milogP). Geometry optimization was performed using the DFT/B3LYP method in conjunction with the 6‐311+G(d,p) basis set. Experimental data of anticancer activity, log(1/C), were used for the QSAR analysis. By stepwise multiple regressions, four optimum descriptors, (milog P)2, E1, EZ/E and BO1Cl8 were found for constructing the QSAR models. Two satisfied models were obtained by multiple linear regressions with the values of R2 higher than 0.9. The (milog P)2 descriptor has the highest correlation to the anticancer activity, indicating that similar improvements to hydrophilicity and lipophilicity are necessary for enhancing anticancer activity. The energy barriers for the decomposition of CCNU derivatives via a retro‐ene reaction (E1) and for the transformation from Z‐tautomers to E‐tautomers (EZ/E) are also considerable descriptors in the QSAR models. The anticancer activity is increased with the decrease of E1 and the increase of EZ/E. The BO1Cl8 descriptor, which requires the inclusion of the other three descriptors in the models, has positive correlation with the anticancer activity of CCNU derivatives. The results indicate that the introduction of the descriptors of activation energies (E1 and EZ/E) is a significant contribution to the methodology of QSAR investigations, because the dynamic descriptors may be more correlated with the biological activity of drugs and toxicants than the static descriptors. Our models shed light on the structure‐activity relationship of CCNU derivatives and may be useful in the development of more effective and less toxic nitrosoureas as anticancer agents. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011