Structure–Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell Proliferation
Recently, we have shown that harmine induces β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. We explore structure–activity relationships of the 7-position of harmine for both DYRK1A kinase inhibition and β-cell proliferation based on our related previous structu...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-04-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/25/8/1983 |
| _version_ | 1797569803082268672 |
|---|---|
| author | Kunal Kumar Peng Wang Ethan A. Swartz Susmita Khamrui Cody Secor Michael B. Lazarus Roberto Sanchez Andrew F. Stewart Robert J. DeVita |
| author_facet | Kunal Kumar Peng Wang Ethan A. Swartz Susmita Khamrui Cody Secor Michael B. Lazarus Roberto Sanchez Andrew F. Stewart Robert J. DeVita |
| author_sort | Kunal Kumar |
| collection | DOAJ |
| description | Recently, we have shown that harmine induces β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. We explore structure–activity relationships of the 7-position of harmine for both DYRK1A kinase inhibition and β-cell proliferation based on our related previous structure–activity relationship studies of harmine in the context of diabetes and β-cell specific targeting strategies. 33 harmine analogs of the 7-position substituent were synthesized and evaluated for biological activity. Two novel inhibitors were identified which showed DYRK1A inhibition and human β-cell proliferation capability. The DYRK1A inhibitor, compound <b>1-2b</b>, induced β-cell proliferation half that of harmine at three times higher concentration. From these studies we can draw the inference that 7-position modification is limited for further harmine optimization focused on β-cell proliferation and cell-specific targeting approach for diabetes therapeutics. |
| first_indexed | 2024-03-10T20:16:43Z |
| format | Article |
| id | doaj.art-c564a90b2224461da09b8c606d089956 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T20:16:43Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-c564a90b2224461da09b8c606d0899562023-11-19T22:31:28ZengMDPI AGMolecules1420-30492020-04-01258198310.3390/molecules25081983Structure–Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell ProliferationKunal Kumar0Peng Wang1Ethan A. Swartz2Susmita Khamrui3Cody Secor4Michael B. Lazarus5Roberto Sanchez6Andrew F. Stewart7Robert J. DeVita8Drug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADiabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADiabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADrug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADrug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADiabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADrug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USARecently, we have shown that harmine induces β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. We explore structure–activity relationships of the 7-position of harmine for both DYRK1A kinase inhibition and β-cell proliferation based on our related previous structure–activity relationship studies of harmine in the context of diabetes and β-cell specific targeting strategies. 33 harmine analogs of the 7-position substituent were synthesized and evaluated for biological activity. Two novel inhibitors were identified which showed DYRK1A inhibition and human β-cell proliferation capability. The DYRK1A inhibitor, compound <b>1-2b</b>, induced β-cell proliferation half that of harmine at three times higher concentration. From these studies we can draw the inference that 7-position modification is limited for further harmine optimization focused on β-cell proliferation and cell-specific targeting approach for diabetes therapeutics.https://www.mdpi.com/1420-3049/25/8/1983dual-specificity tyrosine-regulated kinases (DYRKs)harmineDYRK1A inhibitorstructure–activity relationship studyβ-cell proliferationdiabetes |
| spellingShingle | Kunal Kumar Peng Wang Ethan A. Swartz Susmita Khamrui Cody Secor Michael B. Lazarus Roberto Sanchez Andrew F. Stewart Robert J. DeVita Structure–Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell Proliferation Molecules dual-specificity tyrosine-regulated kinases (DYRKs) harmine DYRK1A inhibitor structure–activity relationship study β-cell proliferation diabetes |
| title | Structure–Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell Proliferation |
| title_full | Structure–Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell Proliferation |
| title_fullStr | Structure–Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell Proliferation |
| title_full_unstemmed | Structure–Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell Proliferation |
| title_short | Structure–Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell Proliferation |
| title_sort | structure activity relationships and biological evaluation of 7 substituted harmine analogs for human β cell proliferation |
| topic | dual-specificity tyrosine-regulated kinases (DYRKs) harmine DYRK1A inhibitor structure–activity relationship study β-cell proliferation diabetes |
| url | https://www.mdpi.com/1420-3049/25/8/1983 |
| work_keys_str_mv | AT kunalkumar structureactivityrelationshipsandbiologicalevaluationof7substitutedharmineanalogsforhumanbcellproliferation AT pengwang structureactivityrelationshipsandbiologicalevaluationof7substitutedharmineanalogsforhumanbcellproliferation AT ethanaswartz structureactivityrelationshipsandbiologicalevaluationof7substitutedharmineanalogsforhumanbcellproliferation AT susmitakhamrui structureactivityrelationshipsandbiologicalevaluationof7substitutedharmineanalogsforhumanbcellproliferation AT codysecor structureactivityrelationshipsandbiologicalevaluationof7substitutedharmineanalogsforhumanbcellproliferation AT michaelblazarus structureactivityrelationshipsandbiologicalevaluationof7substitutedharmineanalogsforhumanbcellproliferation AT robertosanchez structureactivityrelationshipsandbiologicalevaluationof7substitutedharmineanalogsforhumanbcellproliferation AT andrewfstewart structureactivityrelationshipsandbiologicalevaluationof7substitutedharmineanalogsforhumanbcellproliferation AT robertjdevita structureactivityrelationshipsandbiologicalevaluationof7substitutedharmineanalogsforhumanbcellproliferation |