Novel pyrrolo[2,3-d]pyrimidine derivatives as multi-kinase inhibitors with VEGFR-2 selectivity
Since the discovery of imatinib, the first tyrosine kinase inhibitor, in 2001, targeted therapy has become mainstream of cancer therapeutics. Despite the advantages in efficacy and low side effects compared with conventional chemotherapy, the success of the targeted anticancer drugs is still limited...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Journal of Saudi Chemical Society |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1319610323001163 |
| _version_ | 1797676266565926912 |
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| author | AbdulAziz A. Alotaibi Hanadi H. Asiri A.F.M. Motiur Rahman Mohammed M. Alanazi |
| author_facet | AbdulAziz A. Alotaibi Hanadi H. Asiri A.F.M. Motiur Rahman Mohammed M. Alanazi |
| author_sort | AbdulAziz A. Alotaibi |
| collection | DOAJ |
| description | Since the discovery of imatinib, the first tyrosine kinase inhibitor, in 2001, targeted therapy has become mainstream of cancer therapeutics. Despite the advantages in efficacy and low side effects compared with conventional chemotherapy, the success of the targeted anticancer drugs is still limited by the drug resistance which happens due to the fact that the development of cancer is stimulated by several stimuli and therefore, defeating cancer may occur upon the inhibition of several targets. However, coadministration of multiple drugs always lead to many disadvantages including increased toxicity and less patient compliance. Therefore, the aim of research is to develop anticancer agents with multi-target action based on the modification of the chemical structure of sunitinib, a well-known multi-kinase inhibitor. A series of fifteen compounds comprising pyrrolo[2,3-d]pyrimidine and hydrazone have been designed and successfully synthesized. Among the synthesized compounds, compounds 6f, 6l and 6n inhibited the enzymatic activity of EGFR, Her2, VEGFR-2 and CDK2 kinase enzymes similar to sunitinib and the reference protein kinase inhibitors. Interestingly, remarkable results were revealed by compounds 6j and 6c that demonstrated selective VEGFR-2 inhibition activities and compound 6i that exhibited selective dual inhibition of Her2/VEGFR-2 enzymes. Further analysis revealed that compounds 6f and 6n suppressed cell cycle progression of HepG2 cells and induced early and late apoptosis. Moreover, those two compounds triggered a significant elevation in caspase 3 and Bax proapoptotic proteins and a notable reduction in Bcl-2 anti-apoptotic protein. Finally, molecular docking studies were conducted to predict the possible binding interactions of 6f and 6n with CDK2 and 6f, 6n, 6j and 6c with VEGFR-2. |
| first_indexed | 2024-03-11T22:26:30Z |
| format | Article |
| id | doaj.art-13faa1f36d8b46c6b99697862bfafc6b |
| institution | Directory Open Access Journal |
| issn | 1319-6103 |
| language | English |
| last_indexed | 2024-03-11T22:26:30Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Saudi Chemical Society |
| spelling | doaj.art-13faa1f36d8b46c6b99697862bfafc6b2023-09-24T05:14:27ZengElsevierJournal of Saudi Chemical Society1319-61032023-09-01275101712Novel pyrrolo[2,3-d]pyrimidine derivatives as multi-kinase inhibitors with VEGFR-2 selectivityAbdulAziz A. Alotaibi0Hanadi H. Asiri1A.F.M. Motiur Rahman2Mohammed M. Alanazi3Department 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 ArabiaCorresponding authors.; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaCorresponding authors.; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaSince the discovery of imatinib, the first tyrosine kinase inhibitor, in 2001, targeted therapy has become mainstream of cancer therapeutics. Despite the advantages in efficacy and low side effects compared with conventional chemotherapy, the success of the targeted anticancer drugs is still limited by the drug resistance which happens due to the fact that the development of cancer is stimulated by several stimuli and therefore, defeating cancer may occur upon the inhibition of several targets. However, coadministration of multiple drugs always lead to many disadvantages including increased toxicity and less patient compliance. Therefore, the aim of research is to develop anticancer agents with multi-target action based on the modification of the chemical structure of sunitinib, a well-known multi-kinase inhibitor. A series of fifteen compounds comprising pyrrolo[2,3-d]pyrimidine and hydrazone have been designed and successfully synthesized. Among the synthesized compounds, compounds 6f, 6l and 6n inhibited the enzymatic activity of EGFR, Her2, VEGFR-2 and CDK2 kinase enzymes similar to sunitinib and the reference protein kinase inhibitors. Interestingly, remarkable results were revealed by compounds 6j and 6c that demonstrated selective VEGFR-2 inhibition activities and compound 6i that exhibited selective dual inhibition of Her2/VEGFR-2 enzymes. Further analysis revealed that compounds 6f and 6n suppressed cell cycle progression of HepG2 cells and induced early and late apoptosis. Moreover, those two compounds triggered a significant elevation in caspase 3 and Bax proapoptotic proteins and a notable reduction in Bcl-2 anti-apoptotic protein. Finally, molecular docking studies were conducted to predict the possible binding interactions of 6f and 6n with CDK2 and 6f, 6n, 6j and 6c with VEGFR-2.http://www.sciencedirect.com/science/article/pii/S1319610323001163Anticancer drug designPyrrolo[2,3-d]pyrimidineProtein kinase inhibitorsMulti-kinase inhibition |
| spellingShingle | AbdulAziz A. Alotaibi Hanadi H. Asiri A.F.M. Motiur Rahman Mohammed M. Alanazi Novel pyrrolo[2,3-d]pyrimidine derivatives as multi-kinase inhibitors with VEGFR-2 selectivity Journal of Saudi Chemical Society Anticancer drug design Pyrrolo[2,3-d]pyrimidine Protein kinase inhibitors Multi-kinase inhibition |
| title | Novel pyrrolo[2,3-d]pyrimidine derivatives as multi-kinase inhibitors with VEGFR-2 selectivity |
| title_full | Novel pyrrolo[2,3-d]pyrimidine derivatives as multi-kinase inhibitors with VEGFR-2 selectivity |
| title_fullStr | Novel pyrrolo[2,3-d]pyrimidine derivatives as multi-kinase inhibitors with VEGFR-2 selectivity |
| title_full_unstemmed | Novel pyrrolo[2,3-d]pyrimidine derivatives as multi-kinase inhibitors with VEGFR-2 selectivity |
| title_short | Novel pyrrolo[2,3-d]pyrimidine derivatives as multi-kinase inhibitors with VEGFR-2 selectivity |
| title_sort | novel pyrrolo 2 3 d pyrimidine derivatives as multi kinase inhibitors with vegfr 2 selectivity |
| topic | Anticancer drug design Pyrrolo[2,3-d]pyrimidine Protein kinase inhibitors Multi-kinase inhibition |
| url | http://www.sciencedirect.com/science/article/pii/S1319610323001163 |
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