(<i>E</i>)-1-(3-(3-Hydroxy-4-Methoxyphenyl)-1-(3,4,5-Trimethoxyphenyl)allyl)-1<i>H</i>-1,2,4-Triazole and Related Compounds: Their Synthesis and Biological Evaluation as Novel Antimitotic Agents Targeting Breast Cancer

(<i>E</i>)-1-(3-(3-Hydroxy-4-Methoxyphenyl)-1-(3,4,5-Trimethoxyphenyl)allyl)-1<i>H</i>-1,2,4-Triazole and Related Compounds: Their Synthesis and Biological Evaluation as Novel Antimitotic Agents Targeting Breast Cancer

<b>Background/Objectives:</b> The synthesis of (<i>E</i>)-1-(1,3-diphenylallyl)-1<i>H</i>-1,2,4-triazoles and related compounds as anti-mitotic agents with activity in breast cancer was investigated. These compounds were designed as hybrids of the microtubule-targ...

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Main Authors: Gloria Ana, Azizah M. Malebari, Sara Noorani, Darren Fayne, Niamh M. O’Boyle, Daniela M. Zisterer, Elisangela Flavia Pimentel, Denise Coutinho Endringer, Mary J. Meegan
Format: Article
Language:English
Published: MDPI AG 2025-01-01
Series:Pharmaceuticals
Subjects:
breast cancer
tubulin polymerization inhibitor
hybrid molecule
dual targeting molecule
1,2,4-triazole
aromatase inhibitor
Online Access:https://www.mdpi.com/1424-8247/18/1/118
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Summary:<b>Background/Objectives:</b> The synthesis of (<i>E</i>)-1-(1,3-diphenylallyl)-1<i>H</i>-1,2,4-triazoles and related compounds as anti-mitotic agents with activity in breast cancer was investigated. These compounds were designed as hybrids of the microtubule-targeting chalcones, indanones, and the aromatase inhibitor letrozole. <b>Methods</b>: A panel of 29 compounds was synthesized and examined by a preliminary screening in estrogen receptor (ER) and progesterone receptor (PR)-positive MCF-7 breast cancer cells together with cell cycle analysis and tubulin polymerization inhibition. <b>Results</b>: (<i>E</i>)-5-(3-(1<i>H</i>-1,2,4-triazol-1-yl)-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)-2-methoxyphenol <b>22b</b> was identified as a potent antiproliferative compound with an IC<sub>50</sub> value of 0.39 mM in MCF-7 breast cancer cells, 0.77 mM in triple-negative MDA-MB-231 breast cancer cells, and 0.37 mM in leukemia HL-60 cells. In addition, compound <b>22b</b> demonstrated potent activity in the sub-micromolar range against the NCI 60 cancer cell line panel including prostate, melanoma, colon, leukemia, and non-small cell lung cancers. G<sub>2</sub>/M phase cell cycle arrest and the induction of apoptosis in MCF-7 cells together with inhibition of tubulin polymerization were demonstrated. Immunofluorescence studies confirmed that compound <b>22b</b> targeted tubulin in MCF-7 cells, while computational docking studies predicted binding conformations for <b>22b</b> in the colchicine binding site of tubulin. Compound <b>22b</b> also selectively inhibited aromatase. <b>Conclusions</b>: Based on the results obtained, these novel compounds are suitable candidates for further investigation as antiproliferative microtubule-targeting agents for breast cancer.
ISSN:1424-8247

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