Chemical Modifications of Cinchona Alkaloids Lead to Enhanced Inhibition of Human Butyrylcholinesterase
| Autor: | Reko Leino, Pravin S. Shinde, Pia Vuorela, Daniela Karlsson, C. Gopi Mohan, Adyary Fallarero, C P Anju, Igor Busygin |
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| Rok vydání: | 2014 |
| Předmět: |
Pharmacology
0303 health sciences Trimethylsilyl biology 010405 organic chemistry Stereochemistry Active site Plant Science General Medicine Cinchonine 01 natural sciences 0104 chemical sciences 3. Good health 03 medical and health sciences chemistry.chemical_compound Complementary and alternative medicine chemistry Docking (molecular) Drug Discovery biology.protein Structure–activity relationship Cinchonidine Cytotoxicity Butyrylcholinesterase 030304 developmental biology |
| Zdroj: | Natural Product Communications. 9:1934578X1400900 |
| ISSN: | 1555-9475 1934-578X |
| Popis: | Butyrylcholinesterase (BChE) inhibitors were identified from a collection containing cinchonine, cinchonidine and synthetic derivatives, and further characterized using cytotoxicity and molecular docking studies. The most active ones were: (10≡)-10,11-dibromo-10,11-dihydrocinchonidine (11), a competitive inhibitor with Ki, = 3.45±0.39 μM, and IC50 BChE = 9.83±0.30 μM/human (h)BChE = 34.47±4.63 and O-(trimethylsilyl)cinchonine (15), a mixed inhibitor with Kiuc = 1.73±0.46 μM and Kic = 0.85±0.26 μM, and IC50 BChE = 0.56±0.14 μM / hBChE = 0.24±0.04. In cytotoxicity experiments, ≥80% of the cells remained viable when exposed to concentrations of up to 80 μM of both inhibitors in four different cell lines, including neurons. Due to the bulkier trimethylsilyl side group of 15, it covered the active site of hBChE better than 11 with an OH-group while not being able to fit into the active site gorge of hAChE, thus explaining the selectivity of 15 towards hBChE. |
| Databáze: | OpenAIRE |
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