Targeting the interplay between MMP-2, CA II and VEGFR-2 via new sulfonamide-tethered isomeric triazole hybrids; Microwave-assisted synthesis, computational studies and evaluation.
Autor: | Reda Aouad M; Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia. Electronic address: aouadmohamedreda@yahoo.fr., Almehmadi MA; Deanship of Preparatory Year, Prince Sattam Bin Abdulaziz University, Al-Kharj 16273 16278, Saudi Arabia., Faleh Albelwi F; Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia., Teleb M; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address: mohamed.t.ismail@alexu.edu.eg., Tageldin GN; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt., Abu-Serie MM; Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Egypt., Hagar M; Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt., Rezki N; Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia. |
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Jazyk: | angličtina |
Zdroj: | Bioorganic chemistry [Bioorg Chem] 2022 Jul; Vol. 124, pp. 105816. Date of Electronic Publication: 2022 Apr 16. |
DOI: | 10.1016/j.bioorg.2022.105816 |
Abstrakt: | Recently, the interest in targeting metalloenzymes is obviously growing for halting various tumor progression events and surmounting the resistance due to routine chemotherapy regimen. In this regard, attention to MMP-2 and CA II has been drawn as validated druggable anticancer targets that share vital signaling pathways. The vast majority of MMP and CA inhibitors are designed to function as directed single-target agents. In spite of their transient efficacy, they are often susceptible to tumor resistance. Hence, several dual inhibitors of correlated MMPs and CAs were introduced. This set the stage to simultaneously target the common vital signaling nodes as well. VEGFR-2 is considered central to various tumorigenesis processes involving both MMP-2 and CA II. Herein, we report concomitant inhibition of MMP-2, CA II, and VEGFR-2 via rationally designed 1,2,3- and 1,2,4-triazole hybrids bearing various sulfonamide appendages following pharmacophore hybridization strategy. The designed adducts were efficiently elaborated in an almost quantitative yield utilizing microwave-assisted click 1,3-dipolar cycloaddition reaction between various alkynes-based 1,2,4-triazole and 4-azido benzensulfonamides. All derivatives were evaluated for their anticancer potential against three human cancer cell lines (Caco-2, MDA-MB-231, and HepG-2) after safety assessment on normal human cells (Wi-38). Amongst those click adducts, 8d and 8e were the most potent and safest anticancer agents exhibiting low range nanomolar IC (Copyright © 2022 Elsevier Inc. All rights reserved.) |
Databáze: | MEDLINE |
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