Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2
VEGFR-2, the subtype receptor tyrosine kinase (RTK) responsible for angiogenesis, is expressed in various cancer cells. Thus, VEGFER-2 inhibition is an efficient approach for the discovery of new anticancer agents. Accordingly, a new set of nicotinamide derivatives were designed and synthesized to b...
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MDPI AG
2022-06-01
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| author | Reda G. Yousef Wagdy M. Eldehna Alaa Elwan Abdelaziz S. Abdelaziz Ahmed B. M. Mehany Ibraheem M. M. Gobaara Bshra A. Alsfouk Eslam B. Elkaeed Ahmed M. Metwaly Ibrahim H. Eissa |
| author_facet | Reda G. Yousef Wagdy M. Eldehna Alaa Elwan Abdelaziz S. Abdelaziz Ahmed B. M. Mehany Ibraheem M. M. Gobaara Bshra A. Alsfouk Eslam B. Elkaeed Ahmed M. Metwaly Ibrahim H. Eissa |
| author_sort | Reda G. Yousef |
| collection | DOAJ |
| description | VEGFR-2, the subtype receptor tyrosine kinase (RTK) responsible for angiogenesis, is expressed in various cancer cells. Thus, VEGFER-2 inhibition is an efficient approach for the discovery of new anticancer agents. Accordingly, a new set of nicotinamide derivatives were designed and synthesized to be VEGFR-2 inhibitors. The chemical structures were confirmed using IR, <sup>1</sup>H-NMR, and <sup>13</sup>C-NMR spectroscopy. The obtained compounds were examined for their anti-proliferative activities against the human cancer cell lines (HCT-116 and HepG2). VEGFR-2 inhibitory activities were determined for the titled compounds. Compound <b>8</b> exhibited the strongest anti-proliferative activities with IC<sub>50</sub> values of 5.4 and 7.1 µM against HCT-116 and HepG2, respectively. Interestingly, compound <b>8</b> was the most potent VEGFR-2 inhibitor with an IC<sub>50</sub> value of 77.02 nM (compare to sorafenib: IC<sub>50</sub> = 53.65 nM). Treatment of HCT-116 cells with compound <b>8</b> produced arrest of the cell cycle at the G0–G1 phase and a total apoptosis increase from 3.05 to 19.82%—6.5-fold in comparison to the negative control. In addition, compound <b>8</b> caused significant increases in the expression levels of caspase-8 (9.4-fold) and Bax (9.2-fold), and a significant decrease in the Bcl-2 expression level (3-fold). The effects of compound <b>8</b> on the levels of the immunomodulatory proteins (TNF-α and IL-6) were examined. There was a marked decrease in the level of TNF-α (92.37%) compared to the control (82.47%) and a non-significant reduction in the level of IL-6. In silico docking, molecular dynamics simulations, and MM-PBSA studies revealed the high affinity, the correct binding, and the optimum dynamics of compound 8 inside the active site of VEGFR-2. Finally, in silico ADMET and toxicity studies indicated acceptable values of drug-likeness. In conclusion, compound <b>8</b> has emerged as a promising anti-proliferative agent targeting VEGFR-2 with significant apoptotic and immunomodulatory effects. |
| first_indexed | 2024-03-09T12:44:30Z |
| format | Article |
| id | doaj.art-08d1daded8fe4409a86a1ceeb66c0680 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T12:44:30Z |
| publishDate | 2022-06-01 |
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| spelling | doaj.art-08d1daded8fe4409a86a1ceeb66c06802023-11-30T22:13:51ZengMDPI AGMolecules1420-30492022-06-012713407910.3390/molecules27134079Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2Reda G. Yousef0Wagdy M. Eldehna1Alaa Elwan2Abdelaziz S. Abdelaziz3Ahmed B. M. Mehany4Ibraheem M. M. Gobaara5Bshra A. Alsfouk6Eslam B. Elkaeed7Ahmed M. Metwaly8Ibrahim H. Eissa9Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, EgyptPharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, EgyptPharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, EgyptZoology Department, Faculty of Science (Boys), Al-Azhar University, Cairo 11884, EgyptZoology Department, Faculty of Science (Boys), Al-Azhar University, Cairo 11884, EgyptDepartment of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi ArabiaDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, EgyptPharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, EgyptPharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, EgyptVEGFR-2, the subtype receptor tyrosine kinase (RTK) responsible for angiogenesis, is expressed in various cancer cells. Thus, VEGFER-2 inhibition is an efficient approach for the discovery of new anticancer agents. Accordingly, a new set of nicotinamide derivatives were designed and synthesized to be VEGFR-2 inhibitors. The chemical structures were confirmed using IR, <sup>1</sup>H-NMR, and <sup>13</sup>C-NMR spectroscopy. The obtained compounds were examined for their anti-proliferative activities against the human cancer cell lines (HCT-116 and HepG2). VEGFR-2 inhibitory activities were determined for the titled compounds. Compound <b>8</b> exhibited the strongest anti-proliferative activities with IC<sub>50</sub> values of 5.4 and 7.1 µM against HCT-116 and HepG2, respectively. Interestingly, compound <b>8</b> was the most potent VEGFR-2 inhibitor with an IC<sub>50</sub> value of 77.02 nM (compare to sorafenib: IC<sub>50</sub> = 53.65 nM). Treatment of HCT-116 cells with compound <b>8</b> produced arrest of the cell cycle at the G0–G1 phase and a total apoptosis increase from 3.05 to 19.82%—6.5-fold in comparison to the negative control. In addition, compound <b>8</b> caused significant increases in the expression levels of caspase-8 (9.4-fold) and Bax (9.2-fold), and a significant decrease in the Bcl-2 expression level (3-fold). The effects of compound <b>8</b> on the levels of the immunomodulatory proteins (TNF-α and IL-6) were examined. There was a marked decrease in the level of TNF-α (92.37%) compared to the control (82.47%) and a non-significant reduction in the level of IL-6. In silico docking, molecular dynamics simulations, and MM-PBSA studies revealed the high affinity, the correct binding, and the optimum dynamics of compound 8 inside the active site of VEGFR-2. Finally, in silico ADMET and toxicity studies indicated acceptable values of drug-likeness. In conclusion, compound <b>8</b> has emerged as a promising anti-proliferative agent targeting VEGFR-2 with significant apoptotic and immunomodulatory effects.https://www.mdpi.com/1420-3049/27/13/4079anticancerimmunomodulatoryapoptosisin silico studiesnicotinamideVEGFR-2 |
| spellingShingle | Reda G. Yousef Wagdy M. Eldehna Alaa Elwan Abdelaziz S. Abdelaziz Ahmed B. M. Mehany Ibraheem M. M. Gobaara Bshra A. Alsfouk Eslam B. Elkaeed Ahmed M. Metwaly Ibrahim H. Eissa Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2 Molecules anticancer immunomodulatory apoptosis in silico studies nicotinamide VEGFR-2 |
| title | Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2 |
| title_full | Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2 |
| title_fullStr | Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2 |
| title_full_unstemmed | Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2 |
| title_short | Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2 |
| title_sort | design synthesis in silico and in vitro studies of new immunomodulatory anticancer nicotinamide derivatives targeting vegfr 2 |
| topic | anticancer immunomodulatory apoptosis in silico studies nicotinamide VEGFR-2 |
| url | https://www.mdpi.com/1420-3049/27/13/4079 |
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