Theoretical Study of Adiabatic and Vertical Electron Affinity of Radiosensitizers in Solution Part 2: Analogues of Tirapazamine

Abstract

Tirapazamine is a radiosensitizer, whose biological activity is associated to its electron affinity (EA). The electron affinity can be divided in two main processes: Vertical and Adiabatic. In this work, we calculated the EAs of nitroimidazoles ( Fig. 2) using HF and DFT methods and evaluated solvent effects (water and carbon tetrachloride) on EAs. For water, we combined the Polarized Continuum Model (PCM) and free energy perturbation (Finite Difference Thermodynamic Integration, FDTI) methods. For carbon tetrachloride, we used the FDTI method. The values of adiabatic EA obtained are in agreement with experimental data (deviations of 13.25 meV). The vertical EA were calculated according to Cederbaum's Outer Valence Green Function (OVGF) method. This study, which relays on theoretical aspects of free energy calculations on charged molecules in solution, could be helpful in the rational design of new and more selective bioreductive anticancer drugs.

Probing NMR parameters, structure and dynamics of 5-nitroimidazole derivatives. Density functional study of prototypical radiosensitizers

“…That the dynamic effects are larger on 15 N than on 13 C chemical shifts is in part related to the general observation that the former responds more sensitively than the latter to changes in the chemical environment, as reflected in the different chemical shift ranges of both nuclei. In addition, the presence of a lone pair adjacent to unsaturated bonds at N-3 gives rise to a small energy gap between magnetically coupled MOs, thus producing large paramagnetic contributions to the magnetic shielding constant of this nucleus, 43 and it is usually these paramagnetic contributions that are sensitive to structural and electronic effects.…”

“…For the equilibrium chemical shifts, we found changes of about 2 and 10 ppm for υ 13 C and υ 15 N , respectively, on going from the gas-phase geometry to that optimized in a continuum with the dielectric parameters of water fcompare υ e (//BP86) and υ e [//BP86/PCM(H 2 O)] entries in Table 3g. On the other hand, when the solvent effect is, in addition, introduced in the NMR calculation, the differences increase to about 6 ppm for υ 13 Table 3g. Upon inspection of the structural parameters, we did not find significant effects of a surrounding continuum: on going from gas to solution phase we noted just a slight decrease in the N-1-C-2 and N-1-C-10 bonds lengths fcompare r e (//BP86) and r e [//BP86/PCM(H 2 O)] data in Table 4g.…”

“…13 C and 15 N NMR spectra were recorded under standard conditions on a Bruker DMX 600 spectrometer equipped with an inverse 5 mm probehead, using ca 1.0 M samples in DMSO-d 6 at 300 K. 13 C chemical shifts are given relative to TMS using the signal of the deuterated lock solvent (at υ D 39.5) as internal reference. The 15 N resonances were detected indirectly via 1 H using the HMBC protocol 28 and are given relative to nitromethane as an external standard.…”

“…No bulk solvent effects using PCM methods were evaluated for these reference compounds, as they are used in neat form experimentally, rather than dissolved in a polar solvent. The resulting 13 C chemical shifts were converted to the usual TMS scale using the experimental value for benzene of υ 13 C D 128.5 ppm. 26 The SSCC calculations were carried out at the B3LYP level employing the EPR-II basis set 44 All NMR calculations were carried out using Gaussian 03.…”

“…The 13 C data have been reported before, 46,47 and are collected in Table 2. For 1, 2 and 4 the carbon C-2 signal is almost invariably around 151 ppm.…”