Density Functional Theory Investigation of the Binding of ThioTEPA to Purine Bases: Thermodynamics and Bond Evolution Theory Analysis

Abstract

Density functional theory with the ωB97X-D exchange–correlation functional together with implicit as well as explicit solvation is used to describe the reactions of the adenine and guanine purine bases on N,N′,N″-triethylenethiophosphoramide (thioTEPA), an alkylating agent used as an anticancer drug. This reaction is decomposed into (i) a nucleophilic addition and (ii) a proton “migration” that is mediated by the solvent molecules. The calculations reveal that the first step is rate determining and that the presence of an explicit water molecule to mediate the proton migration has a negligible role on the kinetics of the first step, so that the focus is set on the first step of the reaction. ωB97X-D calculations highlight (i) the activation energy (Gibbs free enthalpy) is smaller for imine nitrogens than amine nitrogens, (ii) for the imine functions, the activation energy is slightly smaller for adenine than for guanine together with a larger exergonicity for the alkylation by adenine, and (iii) among the amine nitrogens, the presence of stabilizing H-bonds in the case of exocyclic amines leads to smaller activation energy than for the endocyclic ones. The reaction mechanisms are unraveled by employing the bond evolution theory, combining the use of electronic localization functions, and their evolution along the intrinsic reaction coordinate, with Thom’s catastrophe theory. These analyses, suitable for highlighting the populations of the major monosynaptic and disynaptic basins, show (i) the reaction with imine nitrogens begins by the cleavage of the C–N aziridine bond and is followed by the simultaneous formation of the new C–N bond and the disappearance of the nitrogen lone pair, (ii) the reaction with the nitrogen atom of an endocyclic or exocyclic amine proceeds first by the formation of the cross-linking C–N bond and then by the cleavage of the C–N aziridine bond and the disappearance of the nitrogen lone pair, and (iii) in case ii, this bond breaking and forming occur before the transition state, which has been correlated to the increased Gibbs enthalpy of activation with respect to the reaction with the nitrogen atom of imine functions.

Extended-sampling QM/MM simulation of biochemical reactions involving P–N bonds

“…They are aromatic nitrogen mustard-based prodrugs for aziridine molecule or aziridinium ions, proposed to induce cancer cell death either by alkylating DNA 90,91 or by the formation of cross-links within DNA. 92 Although it is known that the aziridine or aziridinium binds to guanine in DNA, the exact mechanism is still not quite clear.…”

Investigating the Mechanism of the Catalytic Intramolecular Aza-Wittig Reaction Involved in the Synthesis of 2-Methylbenzothiazole from the Perspective of Bonding Evolution Theory

“…14 A bit later, by combining ELFs 14 with Thom's catastrophe, 15 Krokidis and Silvi developed the Bonding Evolution Theory (BET), 16,17 which, over the years, has been demonstrated to have irrevocable robustness in unraveling the chemical bond-breaking and -forming processes in a diversity of organic synthesis mechanisms. [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] Benzothiazole is a molecule of interest. It belongs to one of the most important classes of heterocyclic compounds, and it plays a significant role in medicinal chemistry.…”

Unveiling the [3+2] cycloaddition between difluoromethyl diazomethane and 3-ylideneoxindole from the perspective of molecular electron density theory

“…Bonding evolution theory 52 (BET) has allowed establishing the molecular mechanism of a great number of organic reactions by means of the analysis of the bonding changes along the reaction path, which is possible due to the straightforward connection between the electron density distribution and the chemical structure. [53][54][55][56][57][58] During BET analysis, the chemical reaction is divided into structural stability domains (SSDs), which represent the portion of chemical path having the same number and types of atomic basins. 23,43 The transition from one SSD to another represents a catastrophe.…”