Synthesis and Pharmacological Effects of Diosgenin-Betulinic Acid Conjugates

0531907 - ÚEB 2021 RIV CH eng J - Journal Article
Özdemir, Zülal - Rybková, M. - Vlk, Martin - Šaman, David - Rárová, Lucie - Wimmer, Zdeněk
Synthesis and Pharmacological Effects of Diosgenin-Betulinic Acid Conjugates.
Molecules. Roč. 25, č. 15 (2020), č. článku 3546. E-ISSN 1420-3049
R&D Projects: GA MPO(CZ) FV10599; GA MPO(CZ) FV30300
Institutional support: RVO:61389030 ; RVO:61388963
Keywords : adaptogen * ADME parameters * betulinic acid * catalytic hydrogenation * conjugate * cytotoxicity * diosgenin * Huisgen copper(I)-catalyzed 1,3-dipolar cycloaddition
OECD category: Organic chemistry
Impact factor: 4.412, year: 2020
Method of publishing: Open access
http://doi.org/10.3390/molecules25153546

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.
Permanent Link: http://hdl.handle.net/11104/0310539