Nitrosation Chemistry of Pyrroline, 2-Imidazoline, and 2-Oxazoline:  Theoretical Curtin−Hammett Analysis of Retro-Ene and Solvent-Assisted C−X Cleavage Reactions of α-Hydroxy-<i>N</i>-Nitrosamines

J of Physical Organic Chem

Zhong

2012

Nitrosamines and nitrosoureas are two families of N‐nitroso compounds (NNCs) with a common nitroso group connected to the nitrogen atom; however, the two types of analogs often exhibit distinct bioactivities when they have similar substructures in the side chains. Nitrosamines are usually considered to be potent carcinogens to various organs and species, whereas nitrosoureas can inhibit cancer cell growth. This distinction between the two types of compounds complicates our understanding of the structure–bioactivity relationship of NNCs. In this work, the mechanisms for the formation of DNA interstrand crosslinks induced by nitrosoureas and nitrosamines, which are an important DNA damage related to the cytotoxicity of NNCs, were compared using the density functional theory method. 1,3‐Bis‐(2‐chloroethyl)‐1‐nitrosourea (BCNU) and the bifunctional metabolite of diethylnitrosamine, N‐nitrosoethyl‐(2‐hydroxyethyl)amine sulfonate (NEHEAS), were used as the computational models. Four pathways for the formation of G–C crosslinks induced by BCNU and NEHEAS were compared. The results show that the crosslinking mechanisms initiated by α‐alkylation are energetically feasible for both BCNU and NEHEAS, and the decompositions of BCNU and NEHEAS represent the rate‐limiting steps. However, for the crosslinking mechanisms initiated by β‐alkylation, BCNU and NEHEAS exhibit different preferences. The energy barrier for the decomposition of the BCNU‐induced β‐alkylation product is much higher than that of NEHEAS. Such an energy barrier may inhibit the mechanism of BCNU initiated by β‐alkylation. Consequently, it is postulated that BCNU and NEHEAS induce DNA interstrand crosslinks via different mechanisms, which may distinguish the bioactivity of the two types of NNCs. Copyright © 2012 John Wiley & Sons, Ltd.

Section: Resultsmentioning

confidence: 99%

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

J of Physical Organic Chem

Zhong

2012

“…1), such as 1,3‐bis‐(2‐chloroethyl)‐1‐nitrosourea (BCNU), 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea (CCNU), and 1‐(2‐chloroethyl)‐3‐(4‐methylcyclohexyl)‐1‐nitrosourea (MeCCNU), are an important family of antineoplastic agents used in the clinical treatment of various human malignancies, including brain tumors, melanoma, lymphoma, and other solid tumors 1–4. CENUs are unstable in aqueous media, and rapidly decompose to yield chloroethyldiazonium (1) via a retro‐ene mechanism,5, 6 as indicated in Figure 1. Faustino et al7 found that the half‐life of N ′‐benzoyl‐ N ‐nitrosourea was less than 50 min in phosphate buffer and only 15 min in blood plasma.…”

Section: Introductionmentioning

confidence: 99%

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

Int J of Quantum Chemistry

Zhong

2012

Chloroethylnitrosoureas (CENUs) are an important family of alkylating agents used in the clinical treatment of cancer. Their anticancer mechanism primarily involves the formation of DNA interstrand crosslinks (ICLs) induced by the chloroethyldiazonium ion derived from the decomposition of CENUs. In this work, the mechanism for the formation of ICLs was investigated by density functional theory (DFT) with B3LYP, wB97XD, and M062X functinoals using conductor-like polarizable continuum model solvent model. Three pathways leading to the formation of three types of G-C crosslinks were compared. G(N1)-C(N3) crosslink is predicted to be the dominant crosslinking product other than G(O 6 )-C(N 4 ) and G(N 2 )-C(O 2 ) crosslinks, which is consistent with the previous results obtained from QM/MM computations. The results indicate that the formation of the G(N1)-C(N3) crosslink via pathway A is the most favorable mechanism from both kinetic and thermodynamic standpoints. In this pathway, the chloroethyldiazonium ion alkylates guanine on the O 6 site followed by intramolecular cyclization to form O 6 ,N1ethanoguanine (4). The cytosine then reacts with intermediate 4 on the C a atom to yield the G(N1)-C(N3) crosslink. This work provides reasonable explanations for the supposed mechanism of CENUs-induced ICLs formation obtained from experimental investigations.the reaction was plotted to confirm the rate-determining step and to provide explanations for the experimental observations. Models and ComputationsAs demonstrated in previous research efforts, [20] DNA ICLs induced by N-nitroso compounds (NNCs) were formed between complementary guanine and cytosine, because the ethidenes generated from NNCs exactly matched with the distance between the paired negative atoms. Therefore, three pathways (see Fig. 2) leading to three kinds of DNA ICLs, that is, G(O 6 )-C(N 4 ), G(N1)-C(N3), and G(N 2 )-C(O 2 ), were compared by DFT calculations. The geometric structures of all reactants, transition states (TSs), intermediates, and products were optimized with the DFT methods, using B3LYP, [21,22] wB97XD, [23] and M062X [24] functionals, respectively, with a 6-31þG(d,p) basis set. As all DNA damage events involved in anticancer or carcinogenic processes were supposed to take place in aqueous solution, the solvent effect of water on all reactions was taken into account. On the basis of the optimized geometries obtained in the gas phase, all structures were further optimized using self-consistent reaction field computations using the conductor-like polarizable continuum model (CPCM) [25,26] using the B3LYP, wB97XD, and M062X functionals, respectively, at the 6-31þG(d,p) theoretical level. Universal force field radii was used for all structures to evaluate the solvent effects of water, which is the default for the Gaussian 09 program package. The TSs were located by the Synchronous Transit-Guided Quasi-Newton method [27,28] with the QST2 or QST3 options to the Opt keyword. The analytical computations of the vibrational frequencies were performe...

“…Besides all these static descriptors, three activation energies were considered as dynamic descriptors. The first energetic parameter ( E 1 ) is the activation energy for CCNU derivatives decomposing to 1‐(2‐chloroethyl)‐2‐hydroxydiazene and isocyanate by a retro‐ene reaction52, 53. This retro‐ene reaction was demonstrated to be the rate‐limiting step for nitrosoureas degrading to the final alkylating agents, 2‐chloroethyl cations, through pathway 154–56.…”

Section: Models and Computationsmentioning

confidence: 99%

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

Cao

Int J of Quantum Chemistry

Jin

et al. 2011

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.