Effects of H-bonding and structural constituents on the acidity and potential "anticancer activity" of D-mandelonitrile-
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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 Somayeh Safaei1 · Mohamad Zaman Kassaee1 · Neda Khorshidvand1 · Aliakbar Ahmadi1 Received: 15 December 2019 / Accepted: 26 June 2020 © Springer Nature B.V. 2020
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 H 2O, 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.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116 4-020-04204-w) contains supplementary material, which is available to authorized users. * Mohamad Zaman Kassaee [email protected] 1
Department of Chemistry, Tarbiat Modares University, P. O. Box 14115‑175, Tehran, Iran
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Graphic Abstract
Keywords Laetrile · Amygdalin · Hydrogen bonding · Cancer · Acidity · QTAIM · NBO
Introduction Amygdalin (α-[(6-O-β-D-glucopyranosyl-β-D-glucopyranosyl)oxy]-(αR)benzeneacetonitrile) is still a center of attention for its controversial role in cancer treatment [1, 2]. In 1950s, a semi-synthetic, injectable form of it was developed and patented as laetrile (1COOH, D-mandelonitrile-β-D-glucuronic acid) by Ernst T. Krebs (Scheme 1) [2]. Although 1COOH is frequently used as a synonym for amygdalin, it is structurally different from the natural compound [3]. The 1COOH is an interesting compound whose intramolecular long-range hydrogen bonding (ILRHB(s and pKa values have not been reported. The pKa values are related to a number of properties, such as solubility, extent of binding, the rate of absorption, dosage and the regimes of drugs [4, 5]. There has been a considerable increase in the theoretical works on the calculation of the pKa value in aqueous solution [6–15]. Hydrogen bonding has an important impact on pKa which is highlighted in various articles [16, 17]. Such an interaction increases the stability of the molecular conformation in which it occurs. Several workers have investigated cooperative effects of hydrogen bonding in various molecules, including hydroxyl deri
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