A chemoselective procedure for MCPBA oxidation of 26-thiodiosgenin to corresponding sulfoxides and sulfone was elaborated. An unusual equilibration of sulfoxides in solution was observed. Moreover, α-alkylation of sulfoxide and sulfone was investigated. Finally, the biological activity of obtained compounds was examined.
- MeSH
- Diosgenin * MeSH
- Oxidation-Reduction MeSH
- Sulfur chemistry MeSH
- Sulfones MeSH
- Sulfoxides chemistry MeSH
- Publication type
- Journal Article MeSH
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.
- 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
The target diosgenin-betulinic acid conjugates are reported to investigate their ability to enhance and modify the pharmacological effects of their components. The detailed synthetic procedure that includes copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (click reaction), and palladium-catalyzed debenzylation by hydrogenolysis is described together with the results of cytotoxicity screening tests. Palladium-catalyzed debenzylation reaction of benzyl ester intermediates was the key step in this synthetic procedure due to the simultaneous presence of a 1,4-disubstituted 1,2,3-triazole ring in the molecule that was a competing coordination site for the palladium catalyst. High pressure (130 kPa) palladium-catalyzed procedure represented a successful synthetic step yielding the required products. The conjugate 7 showed selective cytotoxicity in human T-lymphoblastic leukemia (CEM) cancer cells (IC50 = 6.5 ± 1.1 µM), in contrast to the conjugate 8 showing no cytotoxicity, and diosgenin (1), an adaptogen, for which a potential to be active on central nervous system was calculated in silico. In addition, 5 showed medium multifarious cytotoxicity in human T-lymphoblastic leukemia (CEM), human cervical cancer (HeLa), and human colon cancer (HCT 116). Betulinic acid (2) and the intermediates 3 and 4 showed no cytotoxicity in the tested cancer cell lines. The experimental data obtained are supplemented by and compared with the in silico calculated physico-chemical and absorption, distribution, metabolism, and excretion (ADME) parameters of these compounds.
- MeSH
- Cycloaddition Reaction MeSH
- Diosgenin chemistry MeSH
- Hydrogenation MeSH
- Catalysis MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Palladium chemistry MeSH
- Pentacyclic Triterpenes chemistry MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Drug Screening Assays, Antitumor MeSH
- Pressure MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Addison Disease drug therapy MeSH
- Adrenal Insufficiency drug therapy MeSH
- Aldosterone * history pharmacokinetics pharmacology isolation & purification MeSH
- Diosgenin isolation & purification therapeutic use MeSH
- Fludrocortisone pharmacology therapeutic use MeSH
- Publication type
- Historical Article MeSH
Potatoes are a source of glycoalkaloids (GAs) represented primarily by alpha-solanine and alpha-chaconine (about 95%). Content of GAs in tubers is usually 10-100 mg/kg and maximum levels do not exceed 200 mg/kg. GAs can be hazardous for human health. Poisoning involve gastrointestinal ailments and neurological symptoms. A single intake of >1-3 mg/kg b.w. is considered a critical effect dose (CED). Probabilistic modelling of acute and chronic (usual) exposure to GAs was performed in the Czech Republic, Sweden and The Netherlands. National databases on individual consumption of foods, data on concentration of GAs in tubers (439 Czech and Swedish results) and processing factors were used for modelling. Results concluded that potatoes currently available at the European market may lead to acute intakes >1 mg GAs/kg b.w./day for upper tail of the intake distribution (0.01% of population) in all three countries. 50 mg GAs/kg raw unpeeled tubers ensures that at least 99.99% of the population does not exceed the CED. Estimated chronic (usual) intake in participating countries was 0.25, 0.29 and 0.56 mg/kg b.w./day (97.5% upper confidence limit). It remains unclear if the incidence of GAs poisoning is underreported or if assumptions are the worst case for extremely sensitive persons.
- MeSH
- Humans MeSH
- Eating MeSH
- Solanine analogs & derivatives analysis MeSH
- Solanum tuberosum chemistry MeSH
- Models, Statistical MeSH
- Environmental Exposure analysis MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Europe MeSH
- MeSH
- Solanaceous Alkaloids classification toxicity MeSH
- Atropine pharmacology chemistry MeSH
- Witchcraft history MeSH
- Adult MeSH
- Hallucinogens adverse effects MeSH
- Hyoscyamus MeSH
- Humans MeSH
- Plant Extracts MeSH
- Plants MeSH
- Scopolamine pharmacology chemistry MeSH
- Solanaceae drug effects MeSH
- Solanine toxicity MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
