Effects of H-bonding and structural constituents on the acidity and potential "anticancer activity" of D-mandelonitrile-β-D-glucuronic acid by density functional theory

Abstract

Laetrile (D-mandelonitrile-β-D-glucuronic acid, 1COOH) is being promoted, more and more, as an alternate cancer treatment, in many countries. Here we show how intramolecular long-range hydrogen bonding (ILRHB) affects proton affinity (PA) of 1COOH and turns it into a rather strong acid at M06/6–311 + + G(d,p) level of theory. The ILRHB between carboxylate and the –CN of 1COOH activates the cyanide and provides a form of neighboring group participation (anchimeric assistance) in which the rate of the cyanide release is increased. The released cyanide is reported to kill cancer cells more rigorously than the normal ones. Constituents (–CN, –ph and –OH) effects on 1COOH acidity are probed. The –OH groups show the highest impact on increasing the relative acidity in H2O, DMSO and gas phase. The 1COOH and its derivatives appear more acidic in DMSO than in water. Quantum theory of atoms in molecules (QTAIM), natural bond orbital (NBO) analysis and the polarized continuum mode (PCM) are used for calculation of the pKa values.