Synthesis of Estrone Heterodimers and Evaluation of Their In Vitro Antiproliferative Activity

Directed structural modifications of natural products offer excellent opportunities to develop selectively acting drug candidates. Natural product hybrids represent a particular compound group. The components of hybrids constructed from different molecular entities may result in synergic action with...

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Bibliographic Details
Main Authors: Bózsity-Faragó Noémi
Nagy Viktória
Szabó Johanna
Pálházi Balázs
Kele Zoltán
Resch Vivien
Paragi Gábor
Zupkó István
Minorics Renáta
Mernyák Erzsébet
Format: Article
Published: 2024
Series:INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 25 No. 8
Subjects:
doi:10.3390/ijms25084274

mtmt:34789041
Online Access:http://publicatio.bibl.u-szeged.hu/30125
Description
Summary:Directed structural modifications of natural products offer excellent opportunities to develop selectively acting drug candidates. Natural product hybrids represent a particular compound group. The components of hybrids constructed from different molecular entities may result in synergic action with diminished side effects. Steroidal homo- or heterodimers deserve special attention owing to their potentially high anticancer effect. Inspired by our recently described antiproliferative core-modified estrone derivatives, here, we combined them into heterodimers via Cu(I)-catalyzed azide–alkyne cycloaddition reactions. The two trans-16-azido-3-(O-benzyl)-17-hydroxy-13α-estrone derivatives were reacted with 3-O-propargyl-D-secoestrone alcohol or oxime. The antiproliferative activities of the four newly synthesized dimers were evaluated against a panel of human adherent gynecological cancer cell lines (cervical: Hela, SiHa, C33A; breast: MCF-7, T47D, MDA-MB-231, MDA-MB-361; ovarian: A2780). One heterodimer (12) exerted substantial antiproliferative activity against all investigated cell lines in the submicromolar or low micromolar range. A pronounced proapoptotic effect was observed by fluorescent double staining and flow cytometry on three cervical cell lines. Additionally, cell cycle blockade in the G2/M phase was detected, which might be a consequence of the effect of the dimer on tubulin polymerization. Computational calculations on the taxoid binding site of tubulin revealed potential binding of both steroidal building blocks, mainly with hydrophobic interactions and water bridges.
Physical Description:15
ISSN:1661-6596