Computational study of the ring opening mechanism of substituted temolozolomide, TMZ-R (R = Cl, OH, CF3) in water solvent

Abstract

MP2/6-311 + G(d,p) was employed to study the mechanism of the initial step of ring opening of temozolomide (TMZ-H) and its substituted, TMZ-R (R = Cl, OH, CF3) analogues. The study reveals that the difference formation energies of substituted MTIC acids with respect to MTIC acid are ranging between 0.44 and 1.58 kcal/mol. The ring opening of TMZ-R along pathway-2 leads to the lowest conformer (D), whereas reactions along pathway-1 give rise to lower transition states. The barrier energies of TMZ-R are 1.60-3.75 kcal/mol larger than TMZ-H. The conformational analysis reveals that intramolecular hydrogen bonds do not have a stabilizing effect in water solvent.