Lyubomir T. Vezenkov*, Daniela S. Tsekova*, Ivanka Kostadinova, Rositsa Mihaylova, Nikolay G. Vassilev and Nikolai D. Danchev Pages 183 - 192 ( 10 )
<P>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. </P><P> Objectives: The aim of this work is obtaining new peptide derivatives of galanthamine with decreased toxicity compared to galanthamine. </P><P> 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. </P><P> 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. </P><P> 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.</P>
Galanthamine, Alzheimer's disease, nicotinic acid, isonicotinic acid, toxicity, cytotoxicity.
Department of Organic Chemistry, University of Chemical Technology and Metallurgy, Sofia 1756, Department of Organic Chemistry, University of Chemical Technology and Metallurgy, Sofia 1756, Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University, Sofia 1000, Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University, Sofia 1000, Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia 1113, Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University, Sofia 1000