We present an extensive and diverse dataset of bond separation energies associated with the homolytic cleavage of covalently bonded molecules (A-B) into their corresponding radical fragments (A. and B.). Our dataset contains two different classifications of model structures referred to as “Existing” (molecules with associated experimental data) and “Hypothetical” (molecules with no associated experimental data). In total, the dataset consists of 4502 datapoints (1969 datapoints from the Existing and 2533 datapoints from the Hypothetical classes). The dataset covers 49 unique X-Y type single bonds (except H-H, H-F, and H-Cl), where X and Y are H, B, C, N, O, F, Si, P, S, and Cl atoms. All the reference data was calculated at the (RO)CBS-QB3 level of theory. The reference bond separation energies are non-relativistic ground-state energy differences and contain no zero-point energy corrections. This new dataset of bond separation energies (BSE49) is presented as a high-quality reference dataset for assessing and developing computational chemistry methods.
Two pathways for the degradation of the anticancer agent, temozolomide, were investigated, in which the most energy-favoured mechanism was a combination of the two possible pathways.
The calculations transpired that the isomerization mechanism of thiosemicarbazones is influenced by the solvents, in which the inversion and tautomerization path is the likely mechanisms in aprotic and protic solvents, respectively.
The electronic features of anti-tumor agent, temozolomide, and its degradation products (MTIC and metabolite AIC) have been traced by means of UV absorption spectroscopy in vacuo and aqueous media. For comparison, electronic spectra of related structures and drugs (e.g., dacarbazine) were also investigated. These investigations were carried out using time-dependent density functional theory (TD-DFT) method while the conductor like screening model (COSMO) were applied for the inclusion of solvent effects in electronic spectra. From functional benchmarking, two methods; B3LYP and O3LYP were selected among several other methods with 6-311+G(2d,p) basis set aiming to get the best results in accord with the experimental values. An assessment of the obtained spectra has shown that O3LYP functional gives a mean absolute error (MAE) from experimental absorption peaks of 4.3 nm compared to the 7.2 nm MAE value at B3LYP level in aqueous media. Furthermore, since the structural and tautomeric conformers affect the electronic spectra, conformational preferences have been analyzed in temozolomide, dacarbazine, and their related structures. Temozolomide structure possesses two rotamers that differ in the orientation of carboxamide moiety with a small energy difference (energy difference of 1.39 kcal mol in vacuo and 0.35 kcal mol in aqueous media at B3LYP/6-311++G(2df,3pd). The more stable and meta-stable TMZ rotamer have shown their absorption maxima at 329-334 nm, respectively, at O3LYP level in aqueous media. Applying statistical calculation according to Boltzmann population formula at 25 °C and computed weighed mean estimates the λ of temozolomide at 331 nm, which is in notable agreement with the experimental value (330 nm). Moreover, molecular orbital composition analysis has been conducted in order to interpret these findings. Graphical Abstract Temozolomide and dacarbazine.
This work provides a comprehensive computational study on the oxidative degradation of prodrug procarbazine as a symmetrically disubstituted hydrazine (SDSH) by the active species of cytochrome P450 enzymes, compound I (Cpd I). Two model compounds, R‐CH2‐NH‐NH‐CH3 (R= Me and Ph), were selected for this study and all possible enzymatic and non‐enzymatic phases of their oxidative degradation were simulated. Procarbazine activation has three enzymatic processes. Dehydrogenation is the first step which leads to the release of azo compound. This step is either spontaneous (R=Me) or has very low barrier high (R=Ph). Azo system has another tautomer, hydrazo, which despite its more stability is not considered hitherto. Second enzymatic phase is the production of azoxy compound from either azo or hydrazo compound. The calculations revealed that the transition state of hydrazo oxidation to form azoxy compound (4.09/8.23 kcal.mol−1 for Me/Ph substituents), is almost half of the N2‐azo oxidation. In final enzymatic step the azoxy converts to hydroxyl‐azoxy compound. The transition state barrier of the third enzymatic phase is also lower for the hydrazo tautomer in comparison to the azo tautomer (6.55 vs. 19.39 kcal.mol−1 for R=Ph). The more stability and lower barrier energy showed very high importance of hydrazo tautomer in the catabolism of SDSH derivatives. The hydroxyl‐azoxy is not stable and undergoes decomposition to generate the metabolites.
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