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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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/21/6490 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T05:55:37Z |
| format | Article |
| id | doaj.art-2aca02e9304f479aa5431c7f2e0e1f54 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T05:55:37Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-2aca02e9304f479aa5431c7f2e0e1f542023-11-22T21:22:13ZengMDPI AGMolecules1420-30492021-10-012621649010.3390/molecules26216490Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer AgentsKristina Pavić0Maja Beus1Goran Poje2Lidija Uzelac3Marijeta Kralj4Zrinka Rajić5Faculty of Pharmacy and Biochemistry, University of Zagreb, 10 000 Zagreb, CroatiaFaculty of Pharmacy and Biochemistry, University of Zagreb, 10 000 Zagreb, CroatiaFaculty of Pharmacy and Biochemistry, University of Zagreb, 10 000 Zagreb, CroatiaLaboratory of Experimental Therapy, Division of Molecular Medicine, Ruđer Bošković Institute, 10 000 Zagreb, CroatiaLaboratory of Experimental Therapy, Division of Molecular Medicine, Ruđer Bošković Institute, 10 000 Zagreb, CroatiaFaculty of Pharmacy and Biochemistry, University of Zagreb, 10 000 Zagreb, CroatiaAs 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.https://www.mdpi.com/1420-3049/26/21/6490harmineβ-carbolinecoumarintriazoleantiproliferative activitycell cycle analysis |
| spellingShingle | 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 Molecules harmine β-carboline coumarin triazole antiproliferative activity cell cycle analysis |
| title | 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_short | 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 |
| topic | harmine β-carboline coumarin triazole antiproliferative activity cell cycle analysis |
| url | https://www.mdpi.com/1420-3049/26/21/6490 |
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