Discovery of New Pyrrolo[2,3-<i>d</i>]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers
In the pursuit of developing more potent and effective targeted kinase inhibitors (TKIs), a series of new compounds, specifically halogenated ‘(<i>E</i>)-4-((7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-4-yl)amino)-<i>N</i>’-benzylidenebenzohydrazides’, we...
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MDPI AG
2023-09-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/9/1324 |
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| author | AbdulAziz A. Alotaibi Mohammed M. Alanazi A. F. M. Motiur Rahman |
| author_facet | AbdulAziz A. Alotaibi Mohammed M. Alanazi A. F. M. Motiur Rahman |
| author_sort | AbdulAziz A. Alotaibi |
| collection | DOAJ |
| description | In the pursuit of developing more potent and effective targeted kinase inhibitors (TKIs), a series of new compounds, specifically halogenated ‘(<i>E</i>)-4-((7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-4-yl)amino)-<i>N</i>’-benzylidenebenzohydrazides’, were successfully synthesized in three steps with high yields. Among these novel compounds, namely <b>5e</b>, <b>5h</b>, <b>5k</b>, and <b>5l</b>, promising cytotoxic effects were observed against four different cancer cell lines, with IC<sub>50</sub> values ranging from 29 to 59 µM. Notably, compound <b>5k</b> emerged as the most potent inhibitor, exhibiting significant activity against EGFR, Her2, VEGFR2, and CDK2 enzymes, with IC<sub>50</sub> values ranging from 40 to 204 nM, comparable to the well-known TKI sunitinib (IC<sub>50</sub> = 261 nM). Mechanistic investigations of compound <b>5k</b> revealed its ability to induce cell cycle arrest and apoptosis in HepG2 cells, accompanied by a notable increase in proapoptotic proteins caspase-3 and Bax, as well as the downregulation of Bcl-2 activity. Furthermore, molecular docking studies indicated similar binding interactions between compound <b>5k</b> and the four enzymes, as observed with sunitinib. These findings highlight the potential of compound <b>5k</b> as a promising candidate for further development as a multi-targeted kinase inhibitor with enhanced potency. |
| first_indexed | 2024-03-10T22:16:41Z |
| format | Article |
| id | doaj.art-b7ae37e240864161a9fd7d617d32c19e |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T22:16:41Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-b7ae37e240864161a9fd7d617d32c19e2023-11-19T12:25:47ZengMDPI AGPharmaceuticals1424-82472023-09-01169132410.3390/ph16091324Discovery of New Pyrrolo[2,3-<i>d</i>]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis InducersAbdulAziz A. Alotaibi0Mohammed M. Alanazi1A. F. M. Motiur Rahman2Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaIn the pursuit of developing more potent and effective targeted kinase inhibitors (TKIs), a series of new compounds, specifically halogenated ‘(<i>E</i>)-4-((7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-4-yl)amino)-<i>N</i>’-benzylidenebenzohydrazides’, were successfully synthesized in three steps with high yields. Among these novel compounds, namely <b>5e</b>, <b>5h</b>, <b>5k</b>, and <b>5l</b>, promising cytotoxic effects were observed against four different cancer cell lines, with IC<sub>50</sub> values ranging from 29 to 59 µM. Notably, compound <b>5k</b> emerged as the most potent inhibitor, exhibiting significant activity against EGFR, Her2, VEGFR2, and CDK2 enzymes, with IC<sub>50</sub> values ranging from 40 to 204 nM, comparable to the well-known TKI sunitinib (IC<sub>50</sub> = 261 nM). Mechanistic investigations of compound <b>5k</b> revealed its ability to induce cell cycle arrest and apoptosis in HepG2 cells, accompanied by a notable increase in proapoptotic proteins caspase-3 and Bax, as well as the downregulation of Bcl-2 activity. Furthermore, molecular docking studies indicated similar binding interactions between compound <b>5k</b> and the four enzymes, as observed with sunitinib. These findings highlight the potential of compound <b>5k</b> as a promising candidate for further development as a multi-targeted kinase inhibitor with enhanced potency.https://www.mdpi.com/1424-8247/16/9/1324Pyrrolo[2,3-<i>d</i>]pyrimidineapoptosis inducertyrosine kinase inhibitormultiple kinase inhibitor |
| spellingShingle | AbdulAziz A. Alotaibi Mohammed M. Alanazi A. F. M. Motiur Rahman Discovery of New Pyrrolo[2,3-<i>d</i>]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers Pharmaceuticals Pyrrolo[2,3-<i>d</i>]pyrimidine apoptosis inducer tyrosine kinase inhibitor multiple kinase inhibitor |
| title | Discovery of New Pyrrolo[2,3-<i>d</i>]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers |
| title_full | Discovery of New Pyrrolo[2,3-<i>d</i>]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers |
| title_fullStr | Discovery of New Pyrrolo[2,3-<i>d</i>]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers |
| title_full_unstemmed | Discovery of New Pyrrolo[2,3-<i>d</i>]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers |
| title_short | Discovery of New Pyrrolo[2,3-<i>d</i>]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers |
| title_sort | discovery of new pyrrolo 2 3 i d i pyrimidine derivatives as potential multi targeted kinase inhibitors and apoptosis inducers |
| topic | Pyrrolo[2,3-<i>d</i>]pyrimidine apoptosis inducer tyrosine kinase inhibitor multiple kinase inhibitor |
| url | https://www.mdpi.com/1424-8247/16/9/1324 |
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