Novel NO-TZDs and trimethoxychalcone-based DHPMs: design, synthesis, and biological evaluation as potential VEGFR-2 inhibitors
Novel series of nitric oxide-releasing thiazolidine-2,4-diones (NO-TZD-3a-d,5,6) and 3,4,5-trimethoxychalcone-based multifunctional 1,4-dihydropyrimidines (CDHPM-10a-g) have been designed and synthesised as potent broad-spectrum anticancer agents with potential VEGFR-2 inhibition. The designed analo...
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Taylor & Francis Group
2024-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2024.2358934 |
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| author | Mater H. Mahnashi Mohammed Nahari Hassan Almasoudi Abdulaziz Alhasaniah Sara Elgazwi Mahrous A. Abou-Salim |
| author_facet | Mater H. Mahnashi Mohammed Nahari Hassan Almasoudi Abdulaziz Alhasaniah Sara Elgazwi Mahrous A. Abou-Salim |
| author_sort | Mater H. Mahnashi |
| collection | DOAJ |
| description | Novel series of nitric oxide-releasing thiazolidine-2,4-diones (NO-TZD-3a-d,5,6) and 3,4,5-trimethoxychalcone-based multifunctional 1,4-dihydropyrimidines (CDHPM-10a-g) have been designed and synthesised as potent broad-spectrum anticancer agents with potential VEGFR-2 inhibition. The designed analogs were evaluated for their anticancer activities towards a full panel of NCI-60 tumour cell lines and CDHPM-10a-g emerged mean %inhibitions ranging from 76.40 to 147.69%. Among them, CDHPM-10e and CDHPM-10f demonstrated the highest MGI% of 147.69 and 140.24%, respectively. Compounds CDHPM-10a,b,d-f showed higher mean %inhibitory activity than the reference drug sorafenib (MGI% = 105.46%). Superiorly, the hybrid CDHPM-10e displayed the highest potencies towards all the herein tested subpanels of nine types of cancer with MGI50 of 1.83 µM. Also, it revealed potent cytostatic single-digit micromolar activity towards the herein examined cancer cell lines. The designed compounds CDHPM-10a-g were exposed as potent non-selective broad-spectrum anticancer agents over all NCI subpanels with an SI range of 0.66–1.97. In addition, the target analog CDHPM-10e revealed potency towards VEGFR-2 kinase comparable to that of sorafenib with a sub-micromolar IC50 value of 0.11 µM. Also, CDHPM-10e could effectively induce Sub-G1-phase arrest and prompt apoptosis via caspase and p53-dependent mechanisms. Furthermore, CDHPM-10e revealed significant anti-metastatic activity as detected by wound healing assay. The modelling study implies that CDHPM-10e overlaid well with sorafenib and formed a strong H-bond in the DFG binding domain. The ADMET studies hinted out that CDHPM-10e met Pfizer’s drug-likeness criteria. The presented novel potent anticancer agent merits further devotion as a new lead product in developing more chalcone-based VEGFR-2 inhibitors. |
| format | Article |
| id | doaj-art-dc720d31e73c4bbc888d61047edd25b4 |
| institution | Kabale University |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
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| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-dc720d31e73c4bbc888d61047edd25b42024-12-26T09:30:43ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742024-12-0139110.1080/14756366.2024.2358934Novel NO-TZDs and trimethoxychalcone-based DHPMs: design, synthesis, and biological evaluation as potential VEGFR-2 inhibitorsMater H. Mahnashi0Mohammed Nahari1Hassan Almasoudi2Abdulaziz Alhasaniah3Sara Elgazwi4Mahrous A. Abou-Salim5Department of Pharmaceutical Chemistry, College of Pharmacy, Najran University, Najran, Saudi ArabiaDepartment of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran, Saudi ArabiaDepartment of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran, Saudi ArabiaDepartment of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran, Saudi ArabiaDepartment of Chemistry, University of Derna, Derna, LibyaPharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, EgyptNovel series of nitric oxide-releasing thiazolidine-2,4-diones (NO-TZD-3a-d,5,6) and 3,4,5-trimethoxychalcone-based multifunctional 1,4-dihydropyrimidines (CDHPM-10a-g) have been designed and synthesised as potent broad-spectrum anticancer agents with potential VEGFR-2 inhibition. The designed analogs were evaluated for their anticancer activities towards a full panel of NCI-60 tumour cell lines and CDHPM-10a-g emerged mean %inhibitions ranging from 76.40 to 147.69%. Among them, CDHPM-10e and CDHPM-10f demonstrated the highest MGI% of 147.69 and 140.24%, respectively. Compounds CDHPM-10a,b,d-f showed higher mean %inhibitory activity than the reference drug sorafenib (MGI% = 105.46%). Superiorly, the hybrid CDHPM-10e displayed the highest potencies towards all the herein tested subpanels of nine types of cancer with MGI50 of 1.83 µM. Also, it revealed potent cytostatic single-digit micromolar activity towards the herein examined cancer cell lines. The designed compounds CDHPM-10a-g were exposed as potent non-selective broad-spectrum anticancer agents over all NCI subpanels with an SI range of 0.66–1.97. In addition, the target analog CDHPM-10e revealed potency towards VEGFR-2 kinase comparable to that of sorafenib with a sub-micromolar IC50 value of 0.11 µM. Also, CDHPM-10e could effectively induce Sub-G1-phase arrest and prompt apoptosis via caspase and p53-dependent mechanisms. Furthermore, CDHPM-10e revealed significant anti-metastatic activity as detected by wound healing assay. The modelling study implies that CDHPM-10e overlaid well with sorafenib and formed a strong H-bond in the DFG binding domain. The ADMET studies hinted out that CDHPM-10e met Pfizer’s drug-likeness criteria. The presented novel potent anticancer agent merits further devotion as a new lead product in developing more chalcone-based VEGFR-2 inhibitors.https://www.tandfonline.com/doi/10.1080/14756366.2024.2358934NO-TZD3,4,5-trimethoxychalcone1,4-dihydropyrimidineOpenEyefive-dose |
| spellingShingle | Mater H. Mahnashi Mohammed Nahari Hassan Almasoudi Abdulaziz Alhasaniah Sara Elgazwi Mahrous A. Abou-Salim Novel NO-TZDs and trimethoxychalcone-based DHPMs: design, synthesis, and biological evaluation as potential VEGFR-2 inhibitors Journal of Enzyme Inhibition and Medicinal Chemistry NO-TZD 3,4,5-trimethoxychalcone 1,4-dihydropyrimidine OpenEye five-dose |
| title | Novel NO-TZDs and trimethoxychalcone-based DHPMs: design, synthesis, and biological evaluation as potential VEGFR-2 inhibitors |
| title_full | Novel NO-TZDs and trimethoxychalcone-based DHPMs: design, synthesis, and biological evaluation as potential VEGFR-2 inhibitors |
| title_fullStr | Novel NO-TZDs and trimethoxychalcone-based DHPMs: design, synthesis, and biological evaluation as potential VEGFR-2 inhibitors |
| title_full_unstemmed | Novel NO-TZDs and trimethoxychalcone-based DHPMs: design, synthesis, and biological evaluation as potential VEGFR-2 inhibitors |
| title_short | Novel NO-TZDs and trimethoxychalcone-based DHPMs: design, synthesis, and biological evaluation as potential VEGFR-2 inhibitors |
| title_sort | novel no tzds and trimethoxychalcone based dhpms design synthesis and biological evaluation as potential vegfr 2 inhibitors |
| topic | NO-TZD 3,4,5-trimethoxychalcone 1,4-dihydropyrimidine OpenEye five-dose |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2024.2358934 |
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