Synthesis of New Galanthamine-Peptide Derivatives Designed for Prevention and Treatment of Alzheimer’s Disease

Author(s): Lyubomir T. Vezenkov*, Daniela S. Tsekova*, Ivanka Kostadinova, Rositsa Mihaylova, Nikolay G. Vassilev, Nikolai D. Danchev

Journal Name: Current Alzheimer Research

Volume 16 , Issue 3 , 2019

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Background: Although no effective treatment for the Alzheimer’s disease currently exist, some drugs acting as Acetylcholinesterase inhibitors, like galanthamine have positively affected such patients. β- and/or γ-secretase inhibitors are another type of potential drugs. Here we report synthesis of new peptide-galanthamine derivatives, with expected inhibitory activity against both Acetylcholinesterase and β-secretase.

Objectives: The aim of this work is obtaining new peptide derivatives of galanthamine with decreased toxicity compared to galanthamine.

Methods: Syntheses were conducted in solution using fragment condensation approach. The new derivatives were characterized by melting points, angle of optical rotation, NMR and Mass spectra. Acute toxicity was determined on mice, according to a Standard protocol. All new compounds were tested in vitro for cytotoxic activity in a panel of human (HEP-G2, BV-173) and murine (Neuro-2a) tumor cell lines via a standard MTT-based colorimetric method.

Results: New derivatives of galanthamine containing shortened analogues of β-secretase inhibitor (Boc- Asn-Leu-Ala-Val-OH) and either nicotinic or isonicotinic residue, both connected with a linker (L-Asp) to position 11 of galanthamine were obtained. In vivo toxicity of some new compounds was found up to 1000 mg/kg. Cell toxicity screening against the tumor cell lines showed negligible growth-inhibiting properties of the galanthamine derivatives.

Conclusion: Synthesis of new galanthamine derivatives comprising peptide moiety and nicotinic acid or isonicotinic acid is reported. Acute toxicity studies reveal they are about 100 times less toxic than galanthamine. This effect is due to the peptide fragment. Cytotoxicity studies show good correlation with low toxicity results. These results are encouraging for the application of this class compounds as medicines.

Keywords: Galanthamine, Alzheimer's disease, nicotinic acid, isonicotinic acid, toxicity, cytotoxicity.

(a)Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12(10): 383-8. (1991).; (b)Mudher A, Lovestone S. Alzheimer’s disease-do tauists and baptists finally shake hands? Trends Neurosci 25(1): 22-6. (2002).; (c)Murphy MP, LeVine H. Alzheimer’s Disease and the β-Amyloid Peptide. J Alzheimers Dis 19(1): 311-27. (2010).; (d)Mokhtar SH, Bakhuraysah MM, Cram DS, Petratos S. The beta-amyloid protein of alzheimer’s disease: communication breakdown by modifying the neuronal cytoskeleton. Int J Alzheimers Dis 2013:15 pages. (2013).Article ID 910502
[] ; (e)Vázquez de la Torre A, Gay M, Vilaprinyó-Pascual S, et al. Direct evidence of the presence of cross-linked Aβ dimers in the brains of Alzheimer’s disease patients. Anal Chem (2018).; 90(7): 4552-60.(2018).. releases/2018/04/180417115709.htm
Alzheimer’s Disease Facts and Figures. Ebook. Chicago: Alzheimer’s Association, 2018. Accessed January 3, 2019.
(a)St George-Hyslop PH. Genetic factors in the genesis of Alzheimer’s disease. Ann N Y Acad Sci 924: 1-7. (2000).; bMonczor M. Diagnosis and treatment of Alzheimer’s disease. Curr Med Chem 5(1): 5-13. (2005).
Poirel O, Mella S, Videau C, et al. Moderate decline in select synaptic markers in the prefrontal cortex (BA9) of patients with Alzheimer’s disease at various cognitive stages. Scientific Rep 8: 938. (2018).
(a)Matharua B, Gibsona BG, Parsons R, Huckerby TN, Moore SA, Cooper LJ, et al. Galantamine inhibits β-amyloid aggregation and cytotoxicity. J Neurol Sci 280(1-2): 49-58. (2009).; (b)Folch J, Ettcheto M, Petrov D, Abad S, Pedrуs I, Marin M, et al. Review of the advances in treatment for Alzheimer disease: strategies for combating β-amyloid protein. Neurologia 33(1): 47-58. (2018).
Guillou C, Bernard JL, Gras E, Thai C. An Efficient total synthesis of (+-) galanthamine. Angew Chem 113: 4881-2. (2001).
Paskov DS. Nivalin: pharmacology and clinical applicationMedicina i Fizkultura, Sofia. (1959).
(a)Vezenkov LT, Georgieva M, Danalev DL, Ivanov Tch B, Ivanova GI. Synthesis and characterization of new galanthamine derivatives comprising peptide moiety. Protein Pept Lett 16: 1024-8. (2009).; (b)Vezenkov L, Georgieva M, Danalev D. Ivanov Tch, Bakalova A Hristov et al. Galanthamine derivatives, methods for their obtaining and use, EP2123328-B1. (2011).
Vezenkov L, Sevalle J, Danalev D, Ivanov T, Bakalova A, Georgieva M, et al. Galanthamine-based Hibrid molecules with acetylholinesterase, butyrylholinesterase and γ-secretase inhibition activity. Curr Alzheimer Res 9: 600-5. (2012).
Ivanov I, Danalev DL, Vezenkov LT. New peptide mimetics with potential β-secretase inhibition activity. Bulg Chem Commun 41(2): 143-8. (2009).
Ivanov I, Vezenkov LT, Danalev DL. New peptide analogues of beta-secretase inhibitor OM 99-2, modified in P3-position. Coll Czech Chem Comm Symp Ser 11: 47-50. (2009).
Ivanov I, Danalev DL, Vezenkov LT. Peptides 2008, The Proceedings of the 30-th European Peptide Symposium, 240-241. Available from:
Vezenkov L, Ilieva L, Danalev DL, Bakalova A, Vassilev ND, Danchev N, et al. Synthesis of new peptide derivatives of galanthamine designed for prevention and treatment of Alzheimer’s disease. Protein Pept Lett 22(10): 913-22. (2015).
(a)Lemeignan M, Millart H, Lamiable D, Molgo J, Lechat P. Evaluation of 4-aminopyridine and 3,4-diaminopyridine penetrability into cerebrospinal fluid in anesthetized rats. Brain Res 304: 166-9. (1984).; (b)Hankes LV, Coenen HH, Rota E, Langen KJ, Herzog H, Wutz W. Effect of Huntington's and Alzheimer's diseases on the transport of nicotinic acid or nicotinamide across the human blood-brain barrier Adv Exp Med Biol 294: 675-8. (1991).; (c)Penberthy WT. Nicotinic acid-mediated activation of both membrane and nuclear receptors towards therapeutic glucocorticoid mimetics for treating multiple sclerosisPPAR Res 2009, Article ID 853707, 11pages (2009).
Chen J, Chopp M. Niacin, an old drug, has new effects on central nervous system disease. Open Drug Discov J 2: 181-6. (2010).
OECD Guidelines for the Testing of Chemicals. Acute Oral Toxicity – Up-and-Down-Procedure(UDP) OECD/OCDE 425, Adopted:3 October (2008).
Vidaluc J-L, Calmel F, Bigg D, et al. Novel [2-(4-Piperidinyl)ethyl](thio)ureas:synthesis and antiacetylcholinesterase activity. J Med Chem 37(5): 689-95. (1994).
López-García J, Lehocký M, Humpolíček P, Sáha P. HaCaT Keratinocytes response on antimicrobial atelocollagen substrates: Extent of cytotoxicity, cell viability and proliferation. J Funct Biomater 5: 43-57. (2014).

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Article Details

Year: 2019
Published on: 27 March, 2019
Page: [183 - 192]
Pages: 10
DOI: 10.2174/1567205016666190228123923
Price: $65

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