Synthesis and Biological Evaluation of Highly Active 7-Anilino Triazolopyrimidines as Potent Antimicrotubule Agents

Oliva, Paola; Romagnoli, Romeo; Cacciari, Barbara; Manfredini, Stefano; Padroni, Chiara; Brancale, Andrea; Ferla, Salvatore; Hamel, Ernest; Corallo, Diana; Aveic, Sanja; Milan, Noemi; Mariotto, Elena; Viola, Giampietro; Bortolozzi, Roberta

doi:10.3390/pharmaceutics14061191

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Synthesis and Biological Evaluation of Highly Active 7-Anilino Triazolopyrimidines as Potent Antimicrotubule Agents

Paola Oliva, Romeo Romagnoli

, Barbara Cacciari, Stefano Manfredini

, Chiara Padroni, Andrea Brancale

, Salvatore Ferla

, Ernest Hamel, Diana Corallo, Sanja Aveic

, Noemi Milan

, Elena Mariotto

, Giampietro Viola

, Roberta Bortolozzi

Pharmaceutics, Volume: 14, Issue: 6, Start page: 1191

Swansea University Author: Salvatore Ferla

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DOI (Published version): 10.3390/pharmaceutics14061191

Abstract

Two different series of fifty-two compounds, based on 3′,4′,5′-trimethoxyaniline (7a–ad) and variably substituted anilines (8a–v) at the 7-position of the 2-substituted-[1,2,4]triazolo [1,5-a]pyrimidine nucleus, had moderate to potent antiproliferative activity against A549, MDA-MB-231, HeLa, HT-29...

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Published in:	Pharmaceutics
ISSN:	1999-4923
Published:	MDPI AG 2022
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URI:	https://cronfa.swan.ac.uk/Record/cronfa60340
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spelling	2022-07-13T16:01:31.0396421 v2 60340 2022-06-30 Synthesis and Biological Evaluation of Highly Active 7-Anilino Triazolopyrimidines as Potent Antimicrotubule Agents d4c62248f510e3b221916989a7bbe6a6 0000-0002-5918-9237 Salvatore Ferla Salvatore Ferla true false 2022-06-30 PHAR Two different series of fifty-two compounds, based on 3′,4′,5′-trimethoxyaniline (7a–ad) and variably substituted anilines (8a–v) at the 7-position of the 2-substituted-[1,2,4]triazolo [1,5-a]pyrimidine nucleus, had moderate to potent antiproliferative activity against A549, MDA-MB-231, HeLa, HT-29 and Jurkat cancer cell lines. All derivatives with a common 3-phenylpropylamino moiety at the 2-position of the triazolopyrimidine scaffold and different halogen-substituted anilines at its 7-position, corresponding to 4′-fluoroaniline (8q), 4′-fluoro-3′-chloroaniline (8r), 4′-chloroaniline (8s) and 4′-bromoaniline (8u), displayed the greatest antiproliferative activity with mean IC50′s of 83, 101, 91 and 83 nM, respectively. These four compounds inhibited tubulin polymerization about 2-fold more potently than combretastatin A-4 (CA-4), and their activities as inhibitors of [3H]colchicine binding to tubulin were similar to that of CA-4. These data underlined that the 3′,4′,5′-trimethoxyanilino moiety at the 7-position of the [1,2,4]triazolo [1,5-a]pyrimidine system, which characterized compounds 7a–ad, was not essential for maintaining potent antiproliferative and antitubulin activities. Compounds 8q and 8r had high selectivity against cancer cells, and their interaction with tubulin led to the accumulation of HeLa cells in the G2/M phase of the cell cycle and to apoptotic cell death through the mitochondrial pathway. Finally, compound 8q significantly inhibited HeLa cell growth in zebrafish embryos. Journal Article Pharmaceutics 14 6 1191 MDPI AG 1999-4923 antimitotic agents; structure–activity relationship; [1,2,4]triazolo [1,5-a]pyrimidine; antiproliferative activity; tubulin polymerization 2 6 2022 2022-06-02 10.3390/pharmaceutics14061191 Data Availability Statement: Data supporting the reported results are available on request from thecorresponding authors. COLLEGE NANME Pharmacy COLLEGE CODE PHAR Swansea University R.R., B.C. 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 partfunded 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. 2022-07-13T16:01:31.0396421 2022-06-30T12:23:23.9781893 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Paola Oliva 1 Romeo Romagnoli 0000-0002-6374-773x 2 Barbara Cacciari 3 Stefano Manfredini 0000-0003-1348-4422 4 Chiara Padroni 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 Noemi Milan 0000-0002-1204-3142 11 Elena Mariotto 0000-0002-3960-8561 12 Giampietro Viola 0000-0001-9329-165x 13 Roberta Bortolozzi 0000-0002-3357-4815 14 60340__24586__4ded47356bd645429fe96067ed8c7fe0.pdf 60340.pdf 2022-07-13T15:59:51.0054231 Output 6087124 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	Synthesis and Biological Evaluation of Highly Active 7-Anilino Triazolopyrimidines as Potent Antimicrotubule Agents
spellingShingle	Synthesis and Biological Evaluation of Highly Active 7-Anilino Triazolopyrimidines as Potent Antimicrotubule Agents Salvatore Ferla
title_short	Synthesis and Biological Evaluation of Highly Active 7-Anilino Triazolopyrimidines as Potent Antimicrotubule Agents
title_full	Synthesis and Biological Evaluation of Highly Active 7-Anilino Triazolopyrimidines as Potent Antimicrotubule Agents
title_fullStr	Synthesis and Biological Evaluation of Highly Active 7-Anilino Triazolopyrimidines as Potent Antimicrotubule Agents
title_full_unstemmed	Synthesis and Biological Evaluation of Highly Active 7-Anilino Triazolopyrimidines as Potent Antimicrotubule Agents
title_sort	Synthesis and Biological Evaluation of Highly Active 7-Anilino Triazolopyrimidines as Potent Antimicrotubule Agents
author_id_str_mv	d4c62248f510e3b221916989a7bbe6a6
author_id_fullname_str_mv	d4c62248f510e3b221916989a7bbe6a6_***_Salvatore Ferla
author	Salvatore Ferla
author2	Paola Oliva Romeo Romagnoli Barbara Cacciari Stefano Manfredini Chiara Padroni Andrea Brancale Salvatore Ferla Ernest Hamel Diana Corallo Sanja Aveic Noemi Milan Elena Mariotto Giampietro Viola Roberta Bortolozzi
format	Journal article
container_title	Pharmaceutics
container_volume	14
container_issue	6
container_start_page	1191
publishDate	2022
institution	Swansea University
issn	1999-4923
doi_str_mv	10.3390/pharmaceutics14061191
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
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description	Two different series of fifty-two compounds, based on 3′,4′,5′-trimethoxyaniline (7a–ad) and variably substituted anilines (8a–v) at the 7-position of the 2-substituted-[1,2,4]triazolo [1,5-a]pyrimidine nucleus, had moderate to potent antiproliferative activity against A549, MDA-MB-231, HeLa, HT-29 and Jurkat cancer cell lines. All derivatives with a common 3-phenylpropylamino moiety at the 2-position of the triazolopyrimidine scaffold and different halogen-substituted anilines at its 7-position, corresponding to 4′-fluoroaniline (8q), 4′-fluoro-3′-chloroaniline (8r), 4′-chloroaniline (8s) and 4′-bromoaniline (8u), displayed the greatest antiproliferative activity with mean IC50′s of 83, 101, 91 and 83 nM, respectively. These four compounds inhibited tubulin polymerization about 2-fold more potently than combretastatin A-4 (CA-4), and their activities as inhibitors of [3H]colchicine binding to tubulin were similar to that of CA-4. These data underlined that the 3′,4′,5′-trimethoxyanilino moiety at the 7-position of the [1,2,4]triazolo [1,5-a]pyrimidine system, which characterized compounds 7a–ad, was not essential for maintaining potent antiproliferative and antitubulin activities. Compounds 8q and 8r had high selectivity against cancer cells, and their interaction with tubulin led to the accumulation of HeLa cells in the G2/M phase of the cell cycle and to apoptotic cell death through the mitochondrial pathway. Finally, compound 8q significantly inhibited HeLa cell growth in zebrafish embryos.
published_date	2022-06-02T04:18:22Z
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score	11.016593

Synthesis and Biological Evaluation of Highly Active 7-Anilino Triazolopyrimidines as Potent Antimicrotubule Agents

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