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

Abstract

N-(2-chloroethyl)-N 0 -cyclohexyl-N-nitrosoureas (CCNU) is an important alkylating agent used in the clinical treatment of cancer. The quantitative structureactivity 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 6-311þG(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 , E 1 , E Z/E and B O1ACl8 were found for constructing the QSAR models. Two satisfied models were obtained by multiple linear regressions with the values of R 2 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 (E 1 ) and for the transformation from Z-tautomers to E-tautomers (E Z/E ) are also considerable descriptors in the QSAR models. The anticancer activity is increased with the decrease of E 1 and the increase of E Z/E . The B O1ACl8 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 (E 1 and E Z/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.

Comparative theoretical investigation of the formation of DNA interstrand crosslinks induced by two kinds of N‐nitroso compounds: nitrosoureas and nitrosamines

“…However, the E structure is energetically favorable than the Z structure by 3.5 kcal/mol. In our previous researches about the structural–activity relationship of nitrosoureas, we also found that the E tautomers were more stable than the Z tautomers. The stability of Z and E structures of N ‐nitroso compounds were compared in a series of experimental and theoretical investigations, which all indicated that the E tautomers were more energetically favorable than the Z tautomers, although there was an intramolecular H‐bond between the oxygen of nitroso group and NH in Z configuration.…”

A density functional theory investigation on the formation mechanisms of DNA interstrand crosslinks induced by chloroethylnitrosoureas

“…The energy barrier from the 1 ‐Gua complex to 2 (6.11 kcal/mol) is similar to the reported energy barrier of O 6 ‐guanine alkylation by the methanediazonium ion (4.2 kcal/mol34). According to our previous investigation of the structure–anticancer activity relationship of CCNU derivatives,36 the energy barrier of the decomposition of CENUs was about 25–27 kcal/mol, which is much higher than the alkylation of guanine. Therefore, it can be hypothesized that guanine alkylation by 1 readily occurs following the decomposition of CENUs.…”

“…The 3/4TS was confirmed by a frequency calculation to have a unique imaginary frequency at 456.0 i cm −1 , corresponding to the vibration mode of the C β atom shift between N1 and Cl, accompanying the stretching vibration of the C β N1 bond. As indicated in Figure 4, the energy barrier of this step is 20.59 kcal/mol, which is clearly higher than the alkylation of guanine by the chloroethyldiazonium ion, but still lower than the decomposition of CENUs 36. The Δ G 298K of the intramolecular cyclization step is −13.42 kcal/mol (Table 1), and the relative energy of 4 is −19.06 kcal/mol.…”

Synthesis and quantitative structure–activity relationships study for phenylpropenamide derivatives as inhibitors of hepatitis B virus replication

“…In order to explore the relationship between structure and antiviral activity, a series of phenylpropenamide derivatives was synthesized and their antiviral activities were then tested. The density functional theory (DFT) and linear regression analysis method were used to construct the 2D-QSAR models [16][17]. Furthermore, three-dimensional quantitative structure-activity relationship (3D-QSAR) method is helpful to extract a relation between biological activity and chemical structure.…”