Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents

As cancer remains one of the major health burdens worldwide, novel agents, due to the development of resistance, are needed. In this work, we designed and synthesized harmirins, which are hybrid compounds comprising harmine and coumarin scaffolds, evaluated their antiproliferative activity, and cond...

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Autores principales:	Kristina Pavić, Maja Beus, Goran Poje, Lidija Uzelac, Marijeta Kralj, Zrinka Rajić
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	harmine β-carboline coumarin triazole antiproliferative activity cell cycle analysis Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/2aca02e9304f479aa5431c7f2e0e1f54
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spelling	oai:doaj.org-article:2aca02e9304f479aa5431c7f2e0e1f542021-11-11T18:29:54ZSynthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents10.3390/molecules262164901420-3049https://doaj.org/article/2aca02e9304f479aa5431c7f2e0e1f542021-10-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6490https://doaj.org/toc/1420-3049As cancer remains one of the major health burdens worldwide, novel agents, due to the development of resistance, are needed. In this work, we designed and synthesized harmirins, which are hybrid compounds comprising harmine and coumarin scaffolds, evaluated their antiproliferative activity, and conducted cell localization and cell cycle analysis experiments. Harmirins were prepared from the corresponding alkynes and azides under mild reaction conditions using Cu(I) catalyzed azide–alkyne cycloaddition, leading to the formation of the 1<i>H</i>-1,2,3-triazole ring. Antiproliferative activity of harmirins was evaluated in vitro against four human cancer cell lines (MCF-7, HCT116, SW620, and HepG2) and one human non-cancer cell line (HEK293T). The most pronounced activities were exerted against MCF-7 and HCT116 cell lines (IC<sub>50</sub> in the single-digit micromolar range), while the most selective harmirins were <b>5b</b> and <b>12b</b>, substituted at C-3 and O-7 of the β-carboline core and bearing methyl substituent at position 6 of the coumarin ring (SIs > 7.2). Further experiments demonstrated that harmirin <b>12b</b> is localized exclusively in the cytoplasm. In addition, it induced a strong G1 arrest and reduced the percentage of cells in the S phase, suggesting that it might exert its antiproliferative activity through inhibition of DNA synthesis, rather than DNA damage. In conclusion, harmirin <b>12b</b> is a novel harmine and coumarin hybrid with significant antiproliferative activity and warrants further evaluation as a potential anticancer agent.Kristina PavićMaja BeusGoran PojeLidija UzelacMarijeta KraljZrinka RajićMDPI AGarticleharmineβ-carbolinecoumarintriazoleantiproliferative activitycell cycle analysisOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6490, p 6490 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	harmine β-carboline coumarin triazole antiproliferative activity cell cycle analysis Organic chemistry QD241-441
spellingShingle	harmine β-carboline coumarin triazole antiproliferative activity cell cycle analysis Organic chemistry QD241-441 Kristina Pavić Maja Beus Goran Poje Lidija Uzelac Marijeta Kralj Zrinka Rajić Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents
description	As cancer remains one of the major health burdens worldwide, novel agents, due to the development of resistance, are needed. In this work, we designed and synthesized harmirins, which are hybrid compounds comprising harmine and coumarin scaffolds, evaluated their antiproliferative activity, and conducted cell localization and cell cycle analysis experiments. Harmirins were prepared from the corresponding alkynes and azides under mild reaction conditions using Cu(I) catalyzed azide–alkyne cycloaddition, leading to the formation of the 1<i>H</i>-1,2,3-triazole ring. Antiproliferative activity of harmirins was evaluated in vitro against four human cancer cell lines (MCF-7, HCT116, SW620, and HepG2) and one human non-cancer cell line (HEK293T). The most pronounced activities were exerted against MCF-7 and HCT116 cell lines (IC<sub>50</sub> in the single-digit micromolar range), while the most selective harmirins were <b>5b</b> and <b>12b</b>, substituted at C-3 and O-7 of the β-carboline core and bearing methyl substituent at position 6 of the coumarin ring (SIs > 7.2). Further experiments demonstrated that harmirin <b>12b</b> is localized exclusively in the cytoplasm. In addition, it induced a strong G1 arrest and reduced the percentage of cells in the S phase, suggesting that it might exert its antiproliferative activity through inhibition of DNA synthesis, rather than DNA damage. In conclusion, harmirin <b>12b</b> is a novel harmine and coumarin hybrid with significant antiproliferative activity and warrants further evaluation as a potential anticancer agent.
format	article
author	Kristina Pavić Maja Beus Goran Poje Lidija Uzelac Marijeta Kralj Zrinka Rajić
author_facet	Kristina Pavić Maja Beus Goran Poje Lidija Uzelac Marijeta Kralj Zrinka Rajić
author_sort	Kristina Pavić
title	Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents
title_short	Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents
title_full	Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents
title_fullStr	Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents
title_full_unstemmed	Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents
title_sort	synthesis and biological evaluation of harmirins, novel harmine–coumarin hybrids as potential anticancer agents
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2aca02e9304f479aa5431c7f2e0e1f54
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Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents

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