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Supplementary data for the quantum chemical calculation of free radical substitution reaction mechanism of camptothecin.

ABSTRACT: This data article contains the truncated view of the transition states for methyl radical attacking camptothecin at the site of 9, 10, 11, 12 and 14 in acidic conditions obtained from quantum computation of Gaussian 09 with B3LYP/6-31+G(d,p) level, also the truncated view of transition states for H abstraction by singlet O₂ from sites of 9, 10, 11 and 12 of the intermediates of methyl combination with camptothecin and that by triplet O₂ from site 9 of the intermediate of methyl combination with camptothecin in acidic condition are included. The corresponding parameters of reaction rate constant calculation for the formation of methyl radical from acetaldehyde, the first and second step of radical substitution of camptothecin under acidic conditions are listed. The data of the basic parameters for the computation of the total energy of the spin-projection of singlet oxygen, and the S² values for the reactants, transition states and intermediates in the free radical substitution reaction of camptothecin are also included.

SUBMITTER: Dai Y

PROVIDER: S-EPMC6141799 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Supplementary data for the quantum chemical calculation of free radical substitution reaction mechanism of camptothecin.

Dai Yujie Y Hua Qingyuan Q Ling Jun J Shao Chunfu C Zhong Cheng C Zhang Xiuli X Hu Yanying Y Zhang Liming L Liu Yaotian Y

Data in brief 20180709

This data article contains the truncated view of the transition states for methyl radical attacking camptothecin at the site of 9, 10, 11, 12 and 14 in acidic conditions obtained from quantum computation of Gaussian 09 with B3LYP/6-31+G(d,p) level, also the truncated view of transition states for H abstraction by singlet O<sub>2</sub> from sites of 9, 10, 11 and 12 of the intermediates of methyl combination with camptothecin and that by triplet O<sub>2</sub> from site 9 of the intermediate of me ...[more]

PMID: 30246097

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Project description:This work presents an investigation into the effect of including explicit solvent molecules in DFT (Density Functional Theory) calculations of relative energies (ΔErel) and NMR (Nuclear Magnetic Resonance) chemical shifts for organic molecules in chloroform, water, and dimethyl sulfoxide (DMSO) solution using the PCM (Polarizable Continuum Model) approach. The large and flexible molecule of the antibiotic azithromycin (AZM) containing five OH groups and other polar centers susceptible to interacting with solvent molecules was used here as a working example. An increasing number of explicit solvent molecules was used in the geometry optimization of the supermolecule (n = 5, 15, 25, and 50), which accurately reproduces the first solvation shell. We optimized a large AZM trimer (3AZM-75CHCl3) structure at the ωB97x-D/6-31G(d,p)-PCM level, containing 747 atoms, which may roughly simulate a 0.1 M dilute solution, with a good agreement with experimental NMR data. The supermolecule approach offers a robust description of solute-solvent intermolecular interactions, effectively accounting for both short- and long-range effects, making it a reliable method for selecting the predominant conformer in solution. While the effect of including explicit solvent molecules on the DFT calculation of ΔErel and 1H NMR chemical shifts (OH protons) is remarkable, it is only moderate for the evaluation of 13C NMR spectra, providing support for the use of the continuum solvation model in this case. For highly solvated structures, a degree of arbitrariness in the calculation of relative energies is naturally introduced, mainly due to solvent-solvent interaction, causing a strong dependence of total energies on the initial guess structure used in the geometry optimization procedure, with variation in ΔErel around 70 kcal mol-1 being predicted, and, therefore, it may not be quite suitable as a criterion to find the predominant conformer in solution. This does not happen with the DFT calculation of 1H NMR chemical shifts (RMSD variations less than 0.1 ppm were observed for distinct initial guess structures), which are more strongly influenced by the local chemical environment. This is an interesting result regarding the use of an explicit solvent model in DFT calculations for organic molecules.

Project description:Recently, we showed that peroxynitrite (ONOO(-)) reacts directly and rapidly with aromatic and aliphatic boronic acids (k ≈ 10(6) M(-1)s(-1)). Product analyses and substrate consumption data indicated that ONOO(-) reacts stoichiometrically with boronates, yielding the corresponding phenols as the major product (∼85-90%), and the remaining products (10-15%) were proposed to originate from free radical intermediates (phenyl and phenoxyl radicals). Here, we investigated in detail the minor, free radical pathway of boronate reaction with ONOO(-). The electron paramagnetic resonance (EPR) spin-trapping technique was used to characterize the free radical intermediates formed from the reaction between boronates and ONOO(-). Using 2-methyl-2-nitrosopropane (MNP) and 5-diethoxyphosphoryl-5-methyl-1-pyrroline-N-oxide (DEPMPO) spin traps, phenyl radicals were trapped and detected. Although phenoxyl radicals were not detected, the positive effects of molecular oxygen, and inhibitory effects of hydrogen atom donors (acetonitrile, and 2-propanol) and general radical scavengers (GSH, NADH, ascorbic acid, and tyrosine) on the formation of phenoxyl radical-derived nitrated product, suggest that the phenoxyl radical was formed as the secondary species. We propose that the initial step of the reaction involves the addition of ONOO(-) to the boron atom in boronates. The anionic intermediate undergoes both heterolytic (major pathway) and homolytic (minor pathway) cleavage of the peroxy (O-O) bond to form phenol and nitrite as a major product (via a nonradical mechanism), or a radical pair PhB(OH)(2)O(•-)···(•)NO(2) as a minor product. It is conceivable that phenyl radicals are formed by the fragmentation of the PhB(OH)(2)O(•-) radical anion. According to the DFT quantum mechanical calculations, the energy barrier for the dissociation of PhB(OH)(2)O(•-) radical anion to form phenyl radical is only a few kcal/mol, suggesting rapid and spontaneous fragmentation of the PhB(OH)(2)O(•-) radical anion in aqueous media. Biological implications of the minor free radical pathway are discussed in the context of ONOO(-) detection, using the boronate probes.

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Supplementary data for the quantum chemical calculation of free radical substitution reaction mechanism of camptothecin.

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Supplementary data for the quantum chemical calculation of free radical substitution reaction mechanism of camptothecin.

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