(<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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2025-01-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Gloria Ana |
| collection | DOAJ |
| description | <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. |
| format | Article |
| id | doaj-art-a2fba876f7134359b8172862dbf084ba |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-a2fba876f7134359b8172862dbf084ba2025-01-24T13:45:27ZengMDPI AGPharmaceuticals1424-82472025-01-0118111810.3390/ph18010118(<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 CancerGloria Ana0Azizah M. Malebari1Sara Noorani2Darren Fayne3Niamh M. O’Boyle4Daniela M. Zisterer5Elisangela Flavia Pimentel6Denise Coutinho Endringer7Mary J. Meegan8School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College Dublin, D02 PN40 Dublin, IrelandDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaSchool of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College Dublin, D02 PN40 Dublin, IrelandMolecular Design Group, School of Chemical Sciences, Dublin City University, Glasnevin, D09 V209 Dublin, IrelandSchool of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College Dublin, D02 PN40 Dublin, IrelandSchool of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, D02 R590 Dublin, IrelandDepartment of Pharmaceutical Sciences, University Vila Velha, Av. Comissário José Dantas de Melo, n°21, Boa Vista, Vila Velha CEP 29102-920, BrazilDepartment of Pharmaceutical Sciences, University Vila Velha, Av. Comissário José Dantas de Melo, n°21, Boa Vista, Vila Velha CEP 29102-920, BrazilSchool of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College Dublin, D02 PN40 Dublin, Ireland<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.https://www.mdpi.com/1424-8247/18/1/118breast cancertubulin polymerization inhibitorhybrid moleculedual targeting molecule1,2,4-triazolearomatase inhibitor |
| spellingShingle | 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 (<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 Pharmaceuticals breast cancer tubulin polymerization inhibitor hybrid molecule dual targeting molecule 1,2,4-triazole aromatase inhibitor |
| title | (<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 |
| title_full | (<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 |
| title_fullStr | (<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 |
| title_full_unstemmed | (<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 |
| title_short | (<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 |
| title_sort | 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 |
| topic | breast cancer tubulin polymerization inhibitor hybrid molecule dual targeting molecule 1,2,4-triazole aromatase inhibitor |
| url | https://www.mdpi.com/1424-8247/18/1/118 |
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