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Synthesis and Pharmacological Effects of Diosgenin–Betulinic Acid Conjugates

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-catalyz...

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Autores principales: Özdemir, Zülal, Rybková, Michaela, Vlk, Martin, Šaman, David, Rárová, Lucie, Wimmer, Zdeněk
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435711/
https://www.ncbi.nlm.nih.gov/pubmed/32756514
http://dx.doi.org/10.3390/molecules25153546
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author Özdemir, Zülal
Rybková, Michaela
Vlk, Martin
Šaman, David
Rárová, Lucie
Wimmer, Zdeněk
author_facet Özdemir, Zülal
Rybková, Michaela
Vlk, Martin
Šaman, David
Rárová, Lucie
Wimmer, Zdeněk
author_sort Özdemir, Zülal
collection PubMed
description 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 (IC(50) = 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.
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spelling pubmed-74357112020-08-28 Synthesis and Pharmacological Effects of Diosgenin–Betulinic Acid Conjugates Özdemir, Zülal Rybková, Michaela Vlk, Martin Šaman, David Rárová, Lucie Wimmer, Zdeněk Molecules Article 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 (IC(50) = 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. MDPI 2020-08-03 /pmc/articles/PMC7435711/ /pubmed/32756514 http://dx.doi.org/10.3390/molecules25153546 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Özdemir, Zülal
Rybková, Michaela
Vlk, Martin
Šaman, David
Rárová, Lucie
Wimmer, Zdeněk
Synthesis and Pharmacological Effects of Diosgenin–Betulinic Acid Conjugates
title Synthesis and Pharmacological Effects of Diosgenin–Betulinic Acid Conjugates
title_full Synthesis and Pharmacological Effects of Diosgenin–Betulinic Acid Conjugates
title_fullStr Synthesis and Pharmacological Effects of Diosgenin–Betulinic Acid Conjugates
title_full_unstemmed Synthesis and Pharmacological Effects of Diosgenin–Betulinic Acid Conjugates
title_short Synthesis and Pharmacological Effects of Diosgenin–Betulinic Acid Conjugates
title_sort synthesis and pharmacological effects of diosgenin–betulinic acid conjugates
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435711/
https://www.ncbi.nlm.nih.gov/pubmed/32756514
http://dx.doi.org/10.3390/molecules25153546
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