Novel 4-alkoxy Meriolin Congeners Potently Induce Apoptosis in Leukemia and Lymphoma Cells
<i>Meriolins</i> (3-(pyrimidin-4-yl)-7-azaindoles) are synthetic hybrids of the naturally occurring alkaloids <i>variolin</i> and <i>meridianin</i> and display a strong cytotoxic potential. We have recently shown that the novel derivative <i>meriolin</i&g...
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2024-12-01
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| author | Karina S. Krings Tobias R. Wassenberg Pablo Cea-Medina Laura Schmitt Ilka Lechtenberg Tanya R. Llewellyn Nan Qin Holger Gohlke Sebastian Wesselborg Thomas J. J. Müller |
| author_facet | Karina S. Krings Tobias R. Wassenberg Pablo Cea-Medina Laura Schmitt Ilka Lechtenberg Tanya R. Llewellyn Nan Qin Holger Gohlke Sebastian Wesselborg Thomas J. J. Müller |
| author_sort | Karina S. Krings |
| collection | DOAJ |
| description | <i>Meriolins</i> (3-(pyrimidin-4-yl)-7-azaindoles) are synthetic hybrids of the naturally occurring alkaloids <i>variolin</i> and <i>meridianin</i> and display a strong cytotoxic potential. We have recently shown that the novel derivative <i>meriolin</i> <b>16</b> is highly cytotoxic in several lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells and predominantly targets cyclin-dependent kinases (CDKs). Here, we efficiently synthesized nine novel 2-aminopyridyl <i>meriolin</i> congeners (<b>3a</b>–<b>3i</b>), i.e., <i>pyrimeriolins</i>, using a one-pot <i>Masuda</i> borylation-<i>Suzuki</i> coupling (MBSC) sequence, with eight of them bearing lipophilic alkoxy substituents of varying length, to systematically determine the influence of the alkoxy sidechain length on the biological activity. All the synthesized derivatives displayed a pronounced cytotoxic potential, with six compounds showing IC<sub>50</sub> values in the nanomolar range. Derivatives <b>3b</b>–<b>3f</b> strongly induced apoptosis and activated caspases with rapid kinetics within 3–4 h in Jurkat leukemia and Ramos lymphoma cells. The induction of apoptosis by the most potent derivative <b>3e</b> was mediated by the intrinsic mitochondrial death pathway, as it was blocked in caspase-9 deficient and Apaf-1 knockdown Jurkat cells. However, as recently shown for <i>meriolin</i> <b>16,</b> derivative <b>3e</b> was able to induce apoptosis in the Jurkat cells overexpressing the antiapoptotic protein Bcl-2. Since tumor cells often inactivate the intrinsic mitochondrial apoptosis pathway (e.g., by overexpression of Bcl-2), these <i>meriolin</i> congeners represent promising therapeutic agents for overcoming therapeutic resistance. |
| format | Article |
| id | doaj-art-d014057e7a994d85b9f9582dfd2010b1 |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2024-12-01 |
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| spelling | doaj-art-d014057e7a994d85b9f9582dfd2010b12025-08-20T02:57:20ZengMDPI AGMolecules1420-30492024-12-012924605010.3390/molecules29246050Novel 4-alkoxy Meriolin Congeners Potently Induce Apoptosis in Leukemia and Lymphoma CellsKarina S. Krings0Tobias R. Wassenberg1Pablo Cea-Medina2Laura Schmitt3Ilka Lechtenberg4Tanya R. Llewellyn5Nan Qin6Holger Gohlke7Sebastian Wesselborg8Thomas J. J. Müller9Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, GermanyInstitute of Organic Chemistry and Macromolecular Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, GermanyInstitute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, GermanyInstitute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, GermanyInstitute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, GermanyDepartment of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, GermanyDepartment of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, GermanyInstitute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, GermanyInstitute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, GermanyInstitute of Organic Chemistry and Macromolecular Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, Germany<i>Meriolins</i> (3-(pyrimidin-4-yl)-7-azaindoles) are synthetic hybrids of the naturally occurring alkaloids <i>variolin</i> and <i>meridianin</i> and display a strong cytotoxic potential. We have recently shown that the novel derivative <i>meriolin</i> <b>16</b> is highly cytotoxic in several lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells and predominantly targets cyclin-dependent kinases (CDKs). Here, we efficiently synthesized nine novel 2-aminopyridyl <i>meriolin</i> congeners (<b>3a</b>–<b>3i</b>), i.e., <i>pyrimeriolins</i>, using a one-pot <i>Masuda</i> borylation-<i>Suzuki</i> coupling (MBSC) sequence, with eight of them bearing lipophilic alkoxy substituents of varying length, to systematically determine the influence of the alkoxy sidechain length on the biological activity. All the synthesized derivatives displayed a pronounced cytotoxic potential, with six compounds showing IC<sub>50</sub> values in the nanomolar range. Derivatives <b>3b</b>–<b>3f</b> strongly induced apoptosis and activated caspases with rapid kinetics within 3–4 h in Jurkat leukemia and Ramos lymphoma cells. The induction of apoptosis by the most potent derivative <b>3e</b> was mediated by the intrinsic mitochondrial death pathway, as it was blocked in caspase-9 deficient and Apaf-1 knockdown Jurkat cells. However, as recently shown for <i>meriolin</i> <b>16,</b> derivative <b>3e</b> was able to induce apoptosis in the Jurkat cells overexpressing the antiapoptotic protein Bcl-2. Since tumor cells often inactivate the intrinsic mitochondrial apoptosis pathway (e.g., by overexpression of Bcl-2), these <i>meriolin</i> congeners represent promising therapeutic agents for overcoming therapeutic resistance.https://www.mdpi.com/1420-3049/29/24/6050apoptosis inducers7-azaindolesbiheteroarylscyclin dependent kinases (CDK)leukemia cell lineslymphoma cell lines |
| spellingShingle | Karina S. Krings Tobias R. Wassenberg Pablo Cea-Medina Laura Schmitt Ilka Lechtenberg Tanya R. Llewellyn Nan Qin Holger Gohlke Sebastian Wesselborg Thomas J. J. Müller Novel 4-alkoxy Meriolin Congeners Potently Induce Apoptosis in Leukemia and Lymphoma Cells Molecules apoptosis inducers 7-azaindoles biheteroaryls cyclin dependent kinases (CDK) leukemia cell lines lymphoma cell lines |
| title | Novel 4-alkoxy Meriolin Congeners Potently Induce Apoptosis in Leukemia and Lymphoma Cells |
| title_full | Novel 4-alkoxy Meriolin Congeners Potently Induce Apoptosis in Leukemia and Lymphoma Cells |
| title_fullStr | Novel 4-alkoxy Meriolin Congeners Potently Induce Apoptosis in Leukemia and Lymphoma Cells |
| title_full_unstemmed | Novel 4-alkoxy Meriolin Congeners Potently Induce Apoptosis in Leukemia and Lymphoma Cells |
| title_short | Novel 4-alkoxy Meriolin Congeners Potently Induce Apoptosis in Leukemia and Lymphoma Cells |
| title_sort | novel 4 alkoxy meriolin congeners potently induce apoptosis in leukemia and lymphoma cells |
| topic | apoptosis inducers 7-azaindoles biheteroaryls cyclin dependent kinases (CDK) leukemia cell lines lymphoma cell lines |
| url | https://www.mdpi.com/1420-3049/29/24/6050 |
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