Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2H-pyrazolo[4,3-c]pyridines

A library of 2,4,6,7-tetrasubstituted-2H-pyrazolo[4,3-c]pyridines was prepared from easily accessible 1-phenyl-3-(2-phenylethynyl)-1H-pyrazole-4-carbaldehyde via an iodine-mediated electrophilic cyclization of intermediate 4-(azidomethyl)-1-ph...

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Autores principales:	Beatričė Razmienė, Eva Řezníčková, Vaida Dambrauskienė, Radek Ostruszka, Martin Kubala, Asta Žukauskaitė, Vladimír Kryštof, Algirdas Šačkus, Eglė Arbačiauskienė
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	antiproliferation cell death cross-coupling cycloiodination pyrazole pyridine Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/c1e5ffbbb6c3420e803de16af82fd513
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spelling	oai:doaj.org-article:c1e5ffbbb6c3420e803de16af82fd5132021-11-11T18:41:01ZSynthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines10.3390/molecules262167471420-3049https://doaj.org/article/c1e5ffbbb6c3420e803de16af82fd5132021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6747https://doaj.org/toc/1420-3049A library of 2,4,6,7-tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines was prepared from easily accessible 1-phenyl-3-(2-phenylethynyl)-1<i>H</i>-pyrazole-4-carbaldehyde via an iodine-mediated electrophilic cyclization of intermediate 4-(azidomethyl)-1-phenyl-3-(phenylethynyl)-1<i>H</i>-pyrazoles to 7-iodo-2,6-diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines followed by Suzuki cross-couplings with various boronic acids and alkylation reactions. The compounds were evaluated for their antiproliferative activity against K562, MV4-11, and MCF-7 cancer cell lines. The most potent compounds displayed low micromolar GI<sub>50</sub> values. 4-(2,6-Diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridin-7-yl)phenol proved to be the most active<b>,</b> induced poly(ADP-ribose) polymerase 1 (PARP-1) cleavage, activated the initiator enzyme of apoptotic cascade caspase 9, induced a fragmentation of microtubule-associated protein 1-light chain 3 (LC3), and reduced the expression levels of proliferating cell nuclear antigen (PCNA). The obtained results suggest a complex action of 4-(2,6-diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridin-7-yl)phenol that combines antiproliferative effects with the induction of cell death. Moreover, investigations of the fluorescence properties of the final compounds revealed 7-(4-methoxyphenyl)-2,6-diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridine as the most potent pH indicator that enables both fluorescence intensity-based and ratiometric pH sensing.Beatričė RazmienėEva ŘezníčkováVaida DambrauskienėRadek OstruszkaMartin KubalaAsta ŽukauskaitėVladimír KryštofAlgirdas ŠačkusEglė ArbačiauskienėMDPI AGarticleantiproliferationcell deathcross-couplingcycloiodinationpyrazolepyridineOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6747, p 6747 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	antiproliferation cell death cross-coupling cycloiodination pyrazole pyridine Organic chemistry QD241-441
spellingShingle	antiproliferation cell death cross-coupling cycloiodination pyrazole pyridine Organic chemistry QD241-441 Beatričė Razmienė Eva Řezníčková Vaida Dambrauskienė Radek Ostruszka Martin Kubala Asta Žukauskaitė Vladimír Kryštof Algirdas Šačkus Eglė Arbačiauskienė Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines
description	A library of 2,4,6,7-tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines was prepared from easily accessible 1-phenyl-3-(2-phenylethynyl)-1<i>H</i>-pyrazole-4-carbaldehyde via an iodine-mediated electrophilic cyclization of intermediate 4-(azidomethyl)-1-phenyl-3-(phenylethynyl)-1<i>H</i>-pyrazoles to 7-iodo-2,6-diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines followed by Suzuki cross-couplings with various boronic acids and alkylation reactions. The compounds were evaluated for their antiproliferative activity against K562, MV4-11, and MCF-7 cancer cell lines. The most potent compounds displayed low micromolar GI<sub>50</sub> values. 4-(2,6-Diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridin-7-yl)phenol proved to be the most active<b>,</b> induced poly(ADP-ribose) polymerase 1 (PARP-1) cleavage, activated the initiator enzyme of apoptotic cascade caspase 9, induced a fragmentation of microtubule-associated protein 1-light chain 3 (LC3), and reduced the expression levels of proliferating cell nuclear antigen (PCNA). The obtained results suggest a complex action of 4-(2,6-diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridin-7-yl)phenol that combines antiproliferative effects with the induction of cell death. Moreover, investigations of the fluorescence properties of the final compounds revealed 7-(4-methoxyphenyl)-2,6-diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridine as the most potent pH indicator that enables both fluorescence intensity-based and ratiometric pH sensing.
format	article
author	Beatričė Razmienė Eva Řezníčková Vaida Dambrauskienė Radek Ostruszka Martin Kubala Asta Žukauskaitė Vladimír Kryštof Algirdas Šačkus Eglė Arbačiauskienė
author_facet	Beatričė Razmienė Eva Řezníčková Vaida Dambrauskienė Radek Ostruszka Martin Kubala Asta Žukauskaitė Vladimír Kryštof Algirdas Šačkus Eglė Arbačiauskienė
author_sort	Beatričė Razmienė
title	Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines
title_short	Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines
title_full	Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines
title_fullStr	Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines
title_full_unstemmed	Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines
title_sort	synthesis and antiproliferative activity of 2,4,6,7-tetrasubstituted-2<i>h</i>-pyrazolo[4,3-<i>c</i>]pyridines
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/c1e5ffbbb6c3420e803de16af82fd513
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Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines

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