TY - JOUR

T1 - Synthesis of fully functionalized spirostanic 1,2,3-triazoles by the three component reaction of diosgenin azides with acetophenones and aryl aldehydes and their biological evaluation as antiproliferative agents

AU - Mironov, Maksim E

AU - Rybalova, Tatyana V

AU - Pokrovskii, Mikhail A

AU - Emaminia, Fatemeh

AU - Gandalipov, Erik R

AU - Pokrovskii, Andrey G

AU - Shults, Elvira E

N1 - Acknowledgements: This work was performed under financial support in part from the Russian Science Foundation (Grant Number 18-13-00361). Authors would like to acknowledge the Multi-Access Chemical Research Center SB RAS for spectral and analytical measurements. Copyright © 2022. Published by Elsevier Inc.

PY - 2023/2

Y1 - 2023/2

N2 - Diosgenin is of significant interest due to its biological activity and synthetic application. In this study, we report the synthesis of a series of spirostanic 1,4,5-trisubstituted 1,2,3-triazoles by the three component reaction of (25R)-6-azidospirostan-3,5-diols with acetophenones and aryl aldehydes. The one-pot two step synthesis proceeds through the in situ formation of (E)-chalcones and copper catalyzed reaction with organic azides in DMF medium. Structural diversity was achieved by varying the aldehyde and acetophenone nature as well as the spirostanic azide stereochemistry. The results of in vitro biological assays showed that fully decorated spirostanic 1,2,3-triazoles exerted significant and selective antiproliferative activity against MCF-7, glioblastoma (SNB-19, T98G, A-172) and neuroblastoma (IMR-32, SH-SYSY) (HCT116) cell lines (GI50 in the single-digit micromolar range). The data revealed that benzoyl and aryl substitutions in the triazole ring introduced at the 6β-position significantly improved the anti-tumor activity of (25R)-6-azidospirostan-3β,5α-diols. This position on the spirostan core may be the favourable to synthesize of potent anticancer leads from diosgenin.

AB - Diosgenin is of significant interest due to its biological activity and synthetic application. In this study, we report the synthesis of a series of spirostanic 1,4,5-trisubstituted 1,2,3-triazoles by the three component reaction of (25R)-6-azidospirostan-3,5-diols with acetophenones and aryl aldehydes. The one-pot two step synthesis proceeds through the in situ formation of (E)-chalcones and copper catalyzed reaction with organic azides in DMF medium. Structural diversity was achieved by varying the aldehyde and acetophenone nature as well as the spirostanic azide stereochemistry. The results of in vitro biological assays showed that fully decorated spirostanic 1,2,3-triazoles exerted significant and selective antiproliferative activity against MCF-7, glioblastoma (SNB-19, T98G, A-172) and neuroblastoma (IMR-32, SH-SYSY) (HCT116) cell lines (GI50 in the single-digit micromolar range). The data revealed that benzoyl and aryl substitutions in the triazole ring introduced at the 6β-position significantly improved the anti-tumor activity of (25R)-6-azidospirostan-3β,5α-diols. This position on the spirostan core may be the favourable to synthesize of potent anticancer leads from diosgenin.

KW - Diosgenin/chemistry

KW - Azides/chemistry

KW - Aldehydes/chemistry

KW - Triazoles/chemistry

KW - Antineoplastic Agents/chemistry

KW - Acetophenones

KW - Spirostanes

KW - Diosgenin

KW - Cytotoxicity

KW - Click chemistry

KW - Steroids

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85144798413&origin=inward&txGid=b3dcfe94f7cb1c72284172e9aca556e9

UR - https://www.mendeley.com/catalogue/1a94620f-7342-3848-82e5-5c96eb2cfd94/

U2 - 10.1016/j.steroids.2022.109133

DO - 10.1016/j.steroids.2022.109133

M3 - Article

C2 - 36328088

VL - 190

JO - Steroids

JF - Steroids

SN - 0039-128X

M1 - 109133

ER -