Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Theoretical Analysis for the Safe Form and Dosage of Amygdalin Product

Author(s): Vasil Tsanov* and Hristo Tsanov

Volume 20, Issue 7, 2020

Page: [897 - 908] Pages: 12

DOI: 10.2174/1871520620666200313163801

Price: $65


Indroduction: This article presents a theoretical analysis of the safe form and dosage of the amygdalin derivative. By making a precise socio-anthropological analysis of the life of the ancient people of Botra (Hunza people, Burusho/Brusho people), a hypothesis has been postulated through a number of modern quantum-mechanical, molecular-topological and bio analytical checks, and has also been confirmed by two proofs.

Methods: The proposed hypothesis underwent theoretical and logical analysis to confirm and/or reject it. The methodological scheme was: determining the optimal chemical formula, determination of the pharmaceutical molecular form and determination of the drug dose.

Results: A convenient, harmless, form of amygdalin derivative is available that has the same biological and chemical activity and could be used in conservative clinical oncology. The article also presents a theoretical comparative analysis of biochemical reactivity in in vivo and in vitro media, by which we also determine the recommended dosage for patient administration. A comparative analysis of the data, obtained in published clinical studies of amygdalin, is presented, summarizing a scheme of the anti-tumor activity of the proposed molecular form.

Conclusion: The hydrolyzed to amide / carboxylic acid cyano / nitrile glycosides are potential drugs. Their biological activity remains unchanged, but their toxicity is many times lower than unmodified native molecules. We claim that this study we have conducted on amygdalin / dhurrin-derived amide is the only study on this molecular form. Other substances in these groups with pronounced biological activity (including anti-tumor) are the hydrolyzed nitrile groups by Prunasin, Lucumin, Vicianin, Sambunigrin, Dhurrin, Taxiphyllin, Zierin, Preteacin, p-Glucosyloxymandelonitrile, Linamarin, Lotaustralin, Acaciapetalin, Triglochinin, Dejdaclin, Tetraphyllin A, Tetrallin B, Gynocardin etc., to their amide/carboxylic acid.

Keywords: Oncology, amygdalin, PM6, PM7, TD-DFT, pharmacological activity.

Graphical Abstract
Ahmed, Mr. Ethnicity, identity and group vitality: A study of Burushos of Srinagar. J. Ethnic Cultural Stud., 2016, 3(1), 1-10.
Chang, L.W.; Zhu, H.P.; Li, W.B.; Liu, H.C.; Zhang, Q.S.; Chen, H.B. [Protective effects of amygdalin on hyperoxia-exposed type II alveolar epithelial cells isolated from premature rat lungs in vitro.]. Zhonghua Er Ke Za Zhi, 2005, 43(2), 118-123.
[PMID: 15833168]
Do, J.S.; Hwang, J.K.; Seo, H.J.; Woo, W.H.; Nam, S.Y. Antiasthmatic activity and selective inhibition of type 2 helper T cell response by aqueous extract of semen armeniacae amarum. Immunopharmacol. Immunotoxicol., 2006, 28(2), 213-225.
[] [PMID: 16873091]
Holland, J. Why patients seek unproven cancer remedies: a psychological perspective. CA Cancer J. Clin., 1982, 32(104)
Zhu, Y.; Su, Z.; Li, C. Analgesic effect and no physical dependence of amygdalin. Zhongguo Zhong Yao Za Zhi,, 1994, 19(128)
Hwang, H.J.; Kim, P.; Kim, C.J.; Lee, H.J.; Shim, I.; Yin, C.S.; Yang, Y.; Hahm, D.H. Antinociceptive effect of amygdalin isolated from Prunus armeniaca on formalin-induced pain in rats. Biol. Pharm. Bull., 2008, 31(8), 1559-1564.
[] [PMID: 18670089]
Hwang, H.J.; Lee, H.J.; Kim, C.J.; Shim, I.; Hahm, D.H. Inhibitory effect of amygdalin on lipopolysaccharide-inducible TNF-alpha and IL-1beta mRNA expression and carrageenan-induced rat arthritis. J. Microbiol. Biotechnol., 2008, 18(10), 1641-1647.
[PMID: 18955812]
Yang, H.Y.; Chang, H.K.; Lee, J.W.; Kim, Y.S.; Kim, H.; Lee, M.H.; Shin, M.S.; Ham, D.H.; Park, H.K.; Lee, H.; Kim, C.J. Amygdalin suppresses lipopolysaccharide-induced expressions of cyclooxygenase-2 and inducible nitric oxide synthase in mouse BV2 microglial cells. Neurol. Res., 2007, 29(Suppl. 1), S59-S64.
[] [PMID: 17359643]
Paoletti, I.; De Gregorio, V.; Baroni, A.; Tufano, M.A.; Donnarumma, G.; Perez, J.J. Amygdalin analogues inhibit IFN-γ signalling and reduce the inflammatory response in human epidermal keratinocytes. Inflammation, 2013, 36(6), 1316-1326.
[] [PMID: 23933845]
Wei, Y.; Xie, Q.; Ito, Y. Preparative separation of axifolin-3-glucoside, hyperoside and amygdalin from plant extracts by high-speed countercurrent chromatography. J. Liq. Chromatogr. Relat. Technol., 2009, 32(7), 1010-1022.
[] [PMID: 20046896]
Shim, S.M.; Kwon, H. Metabolites of amygdalin under simulated human digestive fluids. Int. J. Food Sci. Nutr., 2010, 61(8), 770-779.
[] [PMID: 20528582]
Guo, J.; Wu, W.; Sheng, M.; Yang, S.; Tan, J. Amygdalin inhibits renal fibrosis in chronic kidney disease. Mol. Med. Rep., 2013, 7(5), 1453-1457.
[] [PMID: 23525378]
Jiagang, D.; Li, C.; Wang, H.; Hao, E.; Du, Z.; Bao, C.; Lv, J.; Wang, Y. Amygdalin mediates relieved atherosclerosis in apolipoprotein E deficient mice through the induction of regulatory T cells. Biochem. Biophys. Res. Commun., 2011, 411(3), 523-529.
[] [PMID: 21756879]
Baroni, A.; Paoletti, I.; Greco, R.; Satriano, R.A.; Ruocco, E.; Tufano, M.A.; Perez, J.J. Immunomodulatory effects of a set of amygdalin analogues on human keratinocyte cells. Exp. Dermatol., 2005, 14(11), 854-859.
[] [PMID: 16232308]
Perez, J. Amygdalin analogs for the treatment of psoriasis. Future Med. Chem., 2013, 5, 799-808.
Mirmiranpour, H.; Khaghani, S.; Zandieh, A.; Khalilzadeh, O.O.; Gerayesh-Nejad, S.; Morteza, A.; Esteghamati, A. Amygdalin inhibits angiogenesis in the cultured endothelial cells of diabetic rats. Indian J. Pathol. Microbiol., 2012, 55(2), 211-214.
[] [PMID: 22771646]
Heikkila, R.E.; Cabbat, F.S. The prevention of alloxan-induced diabetes by amygdalin. Life Sci., 1980, 27(8), 659-662.
[] [PMID: 7412494]
Kwon, H.Y.; Hong, S.P.; Hahn, D.H.; Kim, J.H. Apoptosis induction of Persicae Semen extract in human promyelocytic leukemia (HL-60) cells. Arch. Pharm. Res., 2003, 26(2), 157-161.
[] [PMID: 12643594]
Fukuda, T.; Ito, H.; Mukainaka, T.; Tokuda, H.; Nishino, H.; Yoshida, T. Anti-tumor promoting effect of glycosides from Prunus persica seeds. Biol. Pharm. Bull., 2003, 26(2), 271-273.
[] [PMID: 12576693]
Barwina, M.; Wiergowski, M.; Sein Anand, J. [Accidental poisoning with peach seeds used as anticancer therapy--report of two cases]. Przegl. Lek., 2013, 70(8), 687-689.
[PMID: 24466722]
Howard-Ruben, J.; Miller, N.J. Unproven methods of cancer management. Part II: Current trends and implications for patient care. Oncol. Nurs. Forum, 1984, 11(1), 67-73.
[PMID: 6318190]
Yang, D.; Qiu, M.; Zou, L.Q.; Zhang, W.; Jiang, Y.; Zhang, D.Y.; Yan, X. The role of palliative chemotherapy for terminally ill patients with advanced NSCLC. Thorac. Cancer, 2013, 4(2), 153-160.
[] [PMID: 28920200]
Milazzo, S.; Ernst, E.; Lejeune, S.; Boehm, K.; Horneber, M. Laetrile treatment for cancer. Cochrane Database Syst. Rev.,., 2011, 11, CD005476
[PMID: 22071824]
Fenselau, C.; Pallante, S.; Batzinger, R.P.; Benson, W.R.; Barron, R.P.; Sheinin, E.B.; Maienthal, M. Mandelonitrile beta-glucuronide: synthesis and characterization. Science, 1977, 198(4317), 625-627.
[] [PMID: 335509]
Davignon, J.P.; Trissel, L.A.; Kleinman, L.M. Pharmaceutical assessment of amygdalin (Laetrile) products. Cancer Treat. Rep., 1978, 62(1), 99-104.
[PMID: 627001]
Karabulutlu, E.Y. Coping with stress of family caregivers of cancer patients in Turkey. Asia Pac. J. Oncol. Nurs., 2014, 1(1), 55-60.
[] [PMID: 27981084]
Ellison, N.M.; Byar, D.P.; Newell, G.R. Special report on Laetrile: the NCI Laetrile Review. Results of the National Cancer Institute’s retrospective Laetrile analysis. N. Engl. J. Med., 1978, 299(10), 549-552.
[] [PMID: 683212]
Bolarinwa, I.F.; Orfila, C.; Morgan, M.R. Amygdalin content of seeds, kernels and food products commercially-available in the UK. Food Chem., 2014, 152, 133-139.
[] [PMID: 24444917]
Newmark, J.; Brady, R.O.; Grimley, P.M.; Gal, A.E.; Waller, S.G.; Thistlethwaite, J.R. Amygdalin (Laetrile) and prunasin beta-glucosidases: distribution in germ-free rat and in human tumor tissue. Proc. Natl. Acad. Sci. USA, 1981, 78(10), 6513-6516.
[] [PMID: 6796962]
Syrigos, K.N.; Rowlinson-Busza, G.; Epenetos, A.A. In vitro cytotoxicity following specific activation of amygdalin by beta-glucosidase conjugated to a bladder cancer-associated monoclonal antibody. Int. J. Cancer, 1998, 78(6), 712-719.
[<712:AID-IJC8>3.0.CO;2-D] [PMID: 9833764]
Chen, Y.; Ma, J.; Wang, F.; Hu, J.; Cui, A.; Wei, C.; Yang, Q.; Li, F. Amygdalin induces apoptosis in human cervical cancer cell line HeLa cells. Immunopharmacol. Immunotoxicol., 2013, 35(1), 43-51.
[] [PMID: 23137229]
Bitting, T.H. Drugs--Federal Drug Administration ban on Laetrile treatments for terminally ill cancer patients is arbitrary and capricious. Tulsa Law J., 1978, 14, 222-225.
[PMID: 11662799]
Moertel, C.G.; Fleming, T.R.; Rubin, J.; Kvols, L.K.; Sarna, G.; Koch, R.; Currie, V.E.; Young, C.W.; Jones, S.E.; Davignon, J.P. A clinical trial of amygdalin (Laetrile) in the treatment of human cancer. N. Engl. J. Med., 1982, 306(4), 201-206.
[] [PMID: 7033783]
Miller, K.W.; Anderson, J.L.; Stoewsand, G.S. Amygdalin metabolism and effect on reproduction of rats fed apricot kernels. J. Toxicol. Environ. Health, 1981, 7(3-4), 457-467.
[] [PMID: 7288898]
Park, H.J.; Yoon, S.H.; Han, L.S.; Zheng, L.T.; Jung, K.H.; Uhm, Y.K.; Lee, J.H.; Jeong, J.S.; Joo, W.S.; Yim, S.V.; Chung, J.H.; Hong, S.P. Amygdalin inhibits genes related to cell cycle in SNU-C4 human colon cancer cells. World J. Gastroenterol., 2005, 11(33), 5156-5161.
[PMID: 16127745]
Unproven methods of cancer management. Laetrile. CA Cancer J. Clin., 1991, 41(3), 187-192.
[] [PMID: 1902140]
Shishkovsky, K.R. Administrative law... Laetrile and other drugs to be used by the terminally ill are not exempt from the safety and effectiveness requirements of the Federal Food, Drug, and Cosmetic Act of 1938. J. Urban Law, 1980, 57(2), 364-388.
[PMID: 11662840]
Liao, Z.G.; Ling, Y.; Zhong, Y.; Ping, Q.N. [The simultaneous determination of laetrile, paeoniflorin and paeonol in Jingzhi Guizhi Fuling capsule by HPLC]. Zhongguo Zhongyao Zazhi, 2005, 30(16), 1252-1254.
[PMID: 16245901]
Shils, M.E.; Hermann, M.G. Unproved dietary claims in the treatment of patients with cancer. Bull. N. Y. Acad. Med., 1982, 58(3), 323-340.
[PMID: 7052177]
Chang, H.K.; Shin, M.S.; Yang, H.Y.; Lee, J.W.; Kim, Y.S.; Lee, M.H.; Kim, J.; Kim, K.H.; Kim, C.J. Amygdalin induces apoptosis through regulation of Bax and Bcl-2 expressions in human DU145 and LNCaP prostate cancer cells. Biol. Pharm. Bull., 2006, 29(8), 1597-1602.
[] [PMID: 16880611]
Greenberg, D.M. The case against laetrile: the fraudulent cancer remedy. Cancer, 1980, 45(4), 799-807.
[<799:AID-CNCR2820450432>3.0.CO;2-6] [PMID: 6986971]
Herbert, V. Laetrile: the cult of cyanide. Promoting poison for profit. Am. J. Clin. Nutr., 1979, 32(5), 1121-1158.
[] [PMID: 219680]
Louise,, C.;; Elizabeth,, J.;; Markham, A. Transgenic models and cancer treatment. Cancer Treat. Rev., 1995, 21(6)
Milazzo, S.; Lejeune, S.; Ernst, E. Laetrile for cancer: a systematic review of the clinical evidence. Support. Care Cancer, 2007, 15(6), 583-595.
[] [PMID: 17106659]
Questionable cancer practices in Tijuana and other Mexican border clinics. CA Cancer J. Clin., 1991, 41(5), 310-319.
[] [PMID: 1878788]
Curran, W.J. Law-medicine notes. Laetrile for the terminally ill: Supreme Court stops the nonsense. N. Engl. J. Med., 1980, 302(11), 619-621.
[] [PMID: 7351911]
Zhou, C.; Qian, L.; Ma, H.; Yu, X.; Zhang, Y.; Qu, W. Enhancement of amygdalin activated with beta.D.glucosidase on HepG2 cells proliferation and apoptosis. Carbohydr Polym,, 2012, 90, 516-23.
Carter, J.H.; McLafferty, M.A.; Goldman, P. Role of the gastrointestinal microflora in amygdalin (laetrile)-induced cyanide toxicity. Biochem. Pharmacol., 1980, 29(3), 301-304.
[] [PMID: 7362642]
Kousparou, C.A.; Epenetos, A.A.; Deonarain, M.P. Antibody-guided enzyme therapy of cancer producing cyanide results in necrosis of targeted cells. Int. J. Cancer, 2002, 99(1), 138-148.
[] [PMID: 11948505]
Biaglow, J.; Durand, R. The enhanced radiation response of an in vitro tumour model by cyanide released from hydrolysed amygdalin. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med., 1978, 33, 397-401.''
Petrov, G. Organic Chemistry; University Press, Sofia University, 1996/2018. ISBN: 9789540723832
Boshev, N.; Polnarev, B.; Atanasov, K.; Atanasov, N.; Bosheva, M.; Zanzov, I.; Krastanev, I.; Kirin, I.; Popov, I.; Savov, S.; Yanev, P. The Biological Constants in Humans; State Publishing House Medicina i Fizkultura, Sofia,, 1986.
U.S. Department of Agriculture, FDC ID: 168462, NDB Number:11457; ,, 1984/2004.
Petersilka, M.; Gossmann, U.J.; Gross, E.K. Excitation energies from time-dependent density-functional theory. Phys. Rev. Lett., 1996, 76(8), 1212-1215.
[] [PMID: 10061664]
Young, D. Appendix A. A.2.3 GAMESS. Computational Chemistry: A Practical Guide for Applying Techniques to Real World Problems; Wiley-Interscience, 2001, p. 335.
Leach, A. Molecular Modelling: Principles and Applications, 2nd ed; Prentice Hall: Harlow, 2001.
Halgren, T. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J. Comput. Chem., 1996, 17, 490-519.
Liptak, M.; Shields, G. Experimentation with different thermodynamic cycles used for pKa calculations on carboxylic acids using complete basis set and Gaussian-n models combined with CPCM continuum solvation methods. Int. J. Quantum Chem., 2001, 85, 727-741.
Babić, D.; Klein, D.J.; Lukovits, I.; Nikolić, S.; Trinajstić, N. Resistance-distance matrix: A computational algorithm and its applications. Int. J. Quantum Chem., 2002, 90, 166-176.
Balaban, A. Distance Connectivity Index. Chem. Phys. Lett., 1982, 89, 399-404.
Devillers, J.; Balaban, A. Topological Indices and Related Descriptors in QSAR and QSPR; Gordon and Breach: Amsterdam, Netherlands, 1999, pp. 117-119.
Mercader, E.; Castro, E.A.; Toropov, A. Maximum topological distances based indices as molecular descriptors for QSPR. 4. Modeling the enthalpy of formation of hydrocarbons from elements. Int. J. Mol. Sci., 2001, 2, 121-132.
Randić, M. Characterization of molecular branching. J. Am. Chem. Soc., 1975, 97, 6609-6615.
Kier, L.; Hall, L. Molecular Connectivity in Structure-Activity Analysis; J. Wiley & Sons: New York, 1986.
Rouvray, D.H. The rich legacy of half a century of the Wiener index.Topology in Chemistry: Discrete Mathematics of Molecules;; Rouvray,, D.H.; King,, R.B.,, Eds.; Horwood Publishing,, 2002, pp. 16-37.
Todeschini, R.; Consonni, V. Handbook of Molecular Descriptors; Wiley, 2000.
Kwon, Y. “4.2.4: Partition and Distribution Coefficients”. Handbook of Essential Pharmacokinetics, Pharmacodynamics and Drug Metabolism for Industrial Scientists; Kluwer Academic/Plenum Publishers: New York, 2001, p. 44.
Wang, J.; Hou, T. Recent advances on aqueous solubility prediction. Comb. Chem. High Throughput Screen., 2011, 14(5), 328-338.
[] [PMID: 21470182]
Perrin, D.; Dempsey, B.; Serjeant, E. Methods of pKa Prediction”. pKa Prediction for Organic Acids and Bases; Chapman & Hall: London, 1981, pp. 21-26.
Born, M.; Wolf, E. Principles of Optics: Electromagnetic Theory of Propagation, Interference and Diffraction of Light (7th ed.), section 2.3.3;; Cambridge University Press,, 1999. ISBN 0-521-64222-1
Clayden, J. Organometallic Chemistry. Organic chemistry. Clayden, Jonathan; Oxford University Press: Oxford, 2001, pp. 1311-1314.
Bodor, N.; Buchwald, P.; Huang, M. The role of computational techniques in retrometabolic drug design strategies. Theoret. Computat. Chem., 1999, 8, 569-618.
Sander, R. Compilation of Henry’s law constants (version 4.0) for water as solvent. Atmos. Chem. Phys., 2015, 15, 4399-4981.
Young, D. Computational Chemistry, David Young, Wiley-Interscience, 2001. Appendix A. A.3.2; MOPAC, 2001, p. 342.
Stewart, James J. P. Stewart Computational Chemistry, Colorado Springs, CO, USA, HTTP://OpenMOPAC.net2016.
Stewart, J.J.P. Optimization of parameters for semiempirical methods VI: more modifications to the NDDO approximations and re-optimization of parameters. J. Mol. Model., 2013, 19(1), 1-32.
[] [PMID: 23187683]
Nagasawa, T.; Mathew, C.D.; Mauger, J.; Yamada, H. Nitrile hydratase-catalyzed production of nicotinamide from 3-cyanopyridine in Rhodococcus rhodochrous. Appl. Environ. Microbiol., 1988, 54(7), 1766-1769.
[] [PMID: 16347686]
Takano, Y.; Houk, K.N. Benchmarking the Conductor-like Polarizable Continuum Model (CPCM) for aqueous solvation free energies of neutral and ionic organic molecules. J. Chem. Theory Comput., 2005, 1(1), 70-77.
[] [PMID: 26641117]
Song,, Z.;; Xu,, X. Advanced research on anti-tumor effects of amygdalin. J. Cancer Res. Ther., 2014, 10(Suppl. 1), 3-7.
[ PMID: 25207888]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy