Title:Synthesis of New Galanthamine-Peptide Derivatives Designed for Prevention and Treatment of Alzheimer’s Disease
Volume: 16
Issue: 3
关键词:
加兰他敏,阿尔茨海默病,烟酸,异烟酸,毒性,细胞毒性。
摘要:
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.