The synthesis and cholinesterase inhibitory activities of solasodine analogues with seven-membered F ring
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
33130020
DOI
10.1016/j.jsbmb.2020.105776
PII: S0960-0760(20)30301-0
Knihovny.cz E-resources
- Keywords
- Cholinesterase inhibition, Ring expansion, Solasodine, Spiro compounds, Spirostane, Steroidal alkaloids,
- MeSH
- Solanaceous Alkaloids chemical synthesis chemistry pharmacology MeSH
- Cholinesterase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Cholinesterases chemistry drug effects MeSH
- Diosgenin chemistry MeSH
- Nitrogen chemistry MeSH
- Humans MeSH
- Molecular Structure MeSH
- Neuroprotective Agents chemical synthesis chemistry pharmacology MeSH
- Neurotoxicity Syndromes drug therapy enzymology pathology MeSH
- Molecular Docking Simulation MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Solanaceous Alkaloids MeSH
- Cholinesterase Inhibitors MeSH
- Cholinesterases MeSH
- Diosgenin MeSH
- Nitrogen MeSH
- Neuroprotective Agents MeSH
- solasodine MeSH Browser
Solasodine analogues containing a seven-membered F ring with a nitrogen atom placed at position 22a were prepared from diosgenin or tigogenin in a four-step synthesis comprising of the simultaneous opening of the F-ring and introduction of cyanide in position 22α, activation of the 26-hydroxyl group as mesylate, nitrile reduction, and N-cyclization. Solasodine, six obtained 22a(N)-homo analogues, as well as four 26a-homosolasodine derivatives and their open-chain precursors (13 in total) were tested as potential inhibitors of acetyl- and butyryl-cholinesterases and showed activity at micromolar concentrations. The structure-activity relationship study revealed that activities against studied esterases are affected by the structure of E/F rings and the substitution pattern of ring A. The most potent compound 8 acted as non-competitive inhibitors and exerted IC50 = 8.51 μM and 7.05 μM for eeAChE and eqBChE, respectively. Molecular docking studies revealed the hydrogen bond interaction of 8 with S293 of AChE; further rings are stabilized via hydrophobic interaction (ring A) or interaction with Y341 and W286 (rings B and C). Biological experiments showed no neurotoxicity of differentiated SH-SY5Y cells. More importantly, results from neuroprotective assay based on glutamate-induced cytotoxicity revealed that most derivatives had the ability to increase the viability of differentiated SH-SY5Y cells in comparison to galantamine and lipoic acid assayed as standards. The newly synthesized solasodine analogues are able to inhibit and to bind cholinesterases in noncompetitive mode of inhibition and exhibited neuroprotection potential of differentiated neuroblastoma cells after Glu-induced toxicity.
References provided by Crossref.org
Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE
