Synthesis and Pharmacological Effects of Diosgenin-Betulinic Acid Conjugates.

Zülal Özdemir,Martin Vlk,Zdeněk Wimmer,Lucie Rárová,Michaela Rybková,David Šaman

doi:10.3390/molecules25153546

Abstract

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.

Highlights

Saponins belong among plant products displaying multiple biological and pharmacological activity, and many of them are considered to be adaptogens
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
Diosgenin (1) is unable to bind metal ions, and the change made from more traditional cholesterol/cholesterylamine system to diosgenin could influence the overall conformation of the bivalent structures, modifying the metal ions chelating properties

Summary

Introduction

Saponins belong among plant products displaying multiple biological and pharmacological activity, and many of them are considered to be adaptogens. This term is used to describe a plant product capable of (a) producing a nonspecific response resulting in increasing the power of resistance against multiple (physical, chemical, or biological) stressors; (b) having a normalizing effect, irrespective. Molecules 2020, 25, 3546; doi:10.3390/molecules25153546 www.mdpi.com/journal/molecules displaying non-steroidogenic activity along with other beneficial effects [3]. Chemopreventive and therapeutic effects of diosgenin [4]. Chemoprevention of cancer has Diosgenin, (3β,25R)-spirost-5-en-3-ol (1, Figure 1), is a steroid sapogenin part of the saponin been focused on a regression of multistage process of carcinogenesis. Wright or Trigonella foenum-graecum L. and phytochemicals have been intensively their high low and almost no in numbers of legumes

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Results

Conclusion