Abstract

Abstract

New nicotinamide derivatives 6, 7, 10, and 11 were designed and synthesised based on the essential features of the VEGFR-2 inhibitors. Compound 10 revealed the highest anti-proliferative activities with IC50 values of 15.4 and 9.8 µM against HCT-116 and HepG2, respectively compared to sorafenib (IC50 = 9.30 and 7.40 µM). Compound 7 owned promising cytotoxic activities with IC50 values of 15.7 and 15.5 µM against the same cell lines, respectively. Subsequently, the VEGFR-2 inhibitory activities were assessed for the titled compounds to exhibit VEGFR-2 inhibition with sub-micromolar IC50 values. Moreover, compound 7 induced the cell cycle cessation at the cycle at %G2-M and G0-G1phases, and induced apoptosis in the HCT-116. Compounds 7 and 10 reduced the levels of TNF-α by 81.6 and 84.5% as well as IL-6 by 88.4 and 60.9%, respectively, compared to dexamethasone (82.4 and 93.1%). In silico docking, molecular dynamics simulations, ADMET, and toxicity studies were carried out.

Details

Title
Anti-cancer and immunomodulatory evaluation of new nicotinamide derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: in vitro and in silico studies
Author
Yousef, Reda G 1 ; Elwan, Alaa 1 ; Gobaara, Ibraheem M M 2 ; Mehany, Ahmed B M 2 ; Eldehna, Wagdy M 3 ; El-Metwally, Souad A 4 ; Alsfouk, Bshra A 5 ; Elkaeed, Eslam B 6 ; Metwaly, Ahmed M 7 ; Eissa, Ibrahim H 1 

1  Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University , Cairo , Egypt 
2  Zoology Department, Faculty of Science (Boys), Al-Azhar University , Cairo , Egypt 
3  Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University , Kafrelsheikh , Egypt 
4  Department of Basic Science, Higher Technological institute , 10th of Ramadan City , Egypt 
5  Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University , Riyadh , Saudi Arabia 
6  Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University , Riyadh , Saudi Arabia 
7  Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University , Cairo , Egypt, Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City) , Alexandria , Egypt 
Pages
2206-2222
Publication year
2022
Publication date
Dec 2022
Publisher
Taylor & Francis Ltd.
ISSN
14756366
e-ISSN
14756374
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1080/14756366.2022.2110868
ProQuest document ID
2727915965
Copyright
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.. This work is licensed under the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.