The synthesis and cholinesterase inhibitory activities of solasodine analogues with seven-membered F ring. Issue 205 (January 2021)

• Record Type: Journal Article
• Authors: Kiełczewska, Urszula; Jorda, Radek; Gonzalez, Gabriel; Morzycki, Jacek W.; Ajani, Haresh; Svrčková, Katarína; Štěpánková, Šárka; Wojtkielewicz, Agnieszka
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 205(2021)
• Publication Date: 2021-01
• Subjects: Ring expansion -- Solasodine -- Spiro compounds -- Spirostane -- Steroidal alkaloids -- Cholinesterase inhibition; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2020.105776
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: A series of solasodine analogues with 5/7 spiroether unit were synthesized. Solasodine, 22a( N )-homo-, and 26a-homosolasodine analogues were tested for cholinesterase inhibition. The most potent compounds acted as non-competitive inhibitors with IC50 < 10μm. Their binding mode was evaluated by molecular docking studies. The examined derivatives show no neurotoxicity of SH-SY5Y neuroblastoma cell lines. Abstract: 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.