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Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities

Romeo Romagnoli Orcid Logo, Paola Oliva, Filippo Prencipe, Stefano Manfredini Orcid Logo, Federica Budassi, Andrea Brancale Orcid Logo, Salvatore Ferla Orcid Logo, Ernest Hamel, Diana Corallo, Sanja Aveic Orcid Logo, Lorenzo Manfreda, Elena Mariotto Orcid Logo, Roberta Bortolozzi Orcid Logo, Giampietro Viola Orcid Logo

Pharmaceuticals, Volume: 15, Issue: 8, Start page: 1031

Swansea University Author: Salvatore Ferla Orcid Logo

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DOI (Published version): 10.3390/ph15081031

Abstract

A further investigation aiming to generate new potential antitumor agents led us to synthesize a new series of twenty-two compounds characterized by the presence of the 7-(3′,4′,5′-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine pharmacophore modified at its 2-position. Among the synthesized comp...

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Published in: Pharmaceuticals
ISSN: 1424-8247
Published: MDPI AG 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa61417
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spelling 2022-10-27T11:56:10.0928583 v2 61417 2022-10-05 Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities d4c62248f510e3b221916989a7bbe6a6 0000-0002-5918-9237 Salvatore Ferla Salvatore Ferla true false 2022-10-05 PHAR A further investigation aiming to generate new potential antitumor agents led us to synthesize a new series of twenty-two compounds characterized by the presence of the 7-(3′,4′,5′-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine pharmacophore modified at its 2-position. Among the synthesized compounds, three were significantly more active than the others. These bore the substituents p-toluidino (3d), p-ethylanilino (3h) and 3′,4′-dimethylanilino (3f), and these compounds had IC50 values of 30–43, 160–240 and 67–160 nM, respectively, on HeLa, A549 and HT-29 cancer cells. The p-toluidino derivative 3d was the most potent inhibitor of tubulin polymerization (IC50: 0.45 µM) and strongly inhibited the binding of colchicine to tubulin (72% inhibition), with antiproliferative activity superior to CA-4 against A549 and HeLa cancer cell lines. In vitro investigation showed that compound 3d was able to block treated cells in the G2/M phase of the cell cycle and to induce apoptosis following the intrinsic pathway, further confirmed by mitochondrial depolarization and caspase-9 activation. In vivo experiments conducted on the zebrafish model showed good activity of 3d in reducing the mass of a HeLa cell xenograft. These effects occurred at nontoxic concentrations to the animal, indicating that 3d merits further developmental studies. Journal Article Pharmaceuticals 15 8 1031 MDPI AG 1424-8247 colchicine binding site; antitumor activity; [1,2,4]triazolo[1,5-a]pyrimidine; apoptosis; microtubule-targeting agents 21 8 2022 2022-08-21 10.3390/ph15081031 COLLEGE NANME Pharmacy COLLEGE CODE PHAR Swansea University R.R. and S.M. acknowledge the support of the Ministero dell’Istruzione-MIUR, PRIN 2017, by grant 2017E84AA4_002. S.F. is supported by the Sêr Cymru II program, which is partially funded by Swansea University and the European Regional Development Fund through the Welsh Government. This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, which includes federal funds under Contract No. HHSN261200800001E. 2022-10-27T11:56:10.0928583 2022-10-05T06:33:13.2173857 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Romeo Romagnoli 0000-0002-6374-773x 1 Paola Oliva 2 Filippo Prencipe 3 Stefano Manfredini 0000-0003-1348-4422 4 Federica Budassi 5 Andrea Brancale 0000-0002-9728-3419 6 Salvatore Ferla 0000-0002-5918-9237 7 Ernest Hamel 8 Diana Corallo 9 Sanja Aveic 0000-0002-3886-4360 10 Lorenzo Manfreda 11 Elena Mariotto 0000-0002-3960-8561 12 Roberta Bortolozzi 0000-0002-3357-4815 13 Giampietro Viola 0000-0001-9329-165x 14 61417__25595__ae9297ebe2dc410288a689c55731e128.pdf 61417_VoR.pdf 2022-10-27T11:54:12.0837213 Output 4200816 application/pdf Version of Record true © 2022 by the authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license true eng https://creativecommons.org/licenses/by/4.0/
title Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities
spellingShingle Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities
Salvatore Ferla
title_short Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities
title_full Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities
title_fullStr Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities
title_full_unstemmed Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities
title_sort Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities
author_id_str_mv d4c62248f510e3b221916989a7bbe6a6
author_id_fullname_str_mv d4c62248f510e3b221916989a7bbe6a6_***_Salvatore Ferla
author Salvatore Ferla
author2 Romeo Romagnoli
Paola Oliva
Filippo Prencipe
Stefano Manfredini
Federica Budassi
Andrea Brancale
Salvatore Ferla
Ernest Hamel
Diana Corallo
Sanja Aveic
Lorenzo Manfreda
Elena Mariotto
Roberta Bortolozzi
Giampietro Viola
format Journal article
container_title Pharmaceuticals
container_volume 15
container_issue 8
container_start_page 1031
publishDate 2022
institution Swansea University
issn 1424-8247
doi_str_mv 10.3390/ph15081031
publisher MDPI AG
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description A further investigation aiming to generate new potential antitumor agents led us to synthesize a new series of twenty-two compounds characterized by the presence of the 7-(3′,4′,5′-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine pharmacophore modified at its 2-position. Among the synthesized compounds, three were significantly more active than the others. These bore the substituents p-toluidino (3d), p-ethylanilino (3h) and 3′,4′-dimethylanilino (3f), and these compounds had IC50 values of 30–43, 160–240 and 67–160 nM, respectively, on HeLa, A549 and HT-29 cancer cells. The p-toluidino derivative 3d was the most potent inhibitor of tubulin polymerization (IC50: 0.45 µM) and strongly inhibited the binding of colchicine to tubulin (72% inhibition), with antiproliferative activity superior to CA-4 against A549 and HeLa cancer cell lines. In vitro investigation showed that compound 3d was able to block treated cells in the G2/M phase of the cell cycle and to induce apoptosis following the intrinsic pathway, further confirmed by mitochondrial depolarization and caspase-9 activation. In vivo experiments conducted on the zebrafish model showed good activity of 3d in reducing the mass of a HeLa cell xenograft. These effects occurred at nontoxic concentrations to the animal, indicating that 3d merits further developmental studies.
published_date 2022-08-21T04:20:14Z
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