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      New benzoxazole derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative evaluation, flowcytometric analysis, and in silico studies

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          Abstract

          A new series of benzoxazole derivatives were designed and synthesised to have the main essential pharmacophoric features of VEGFR-2 inhibitors. Cytotoxic activities were evaluated for all derivatives against two human cancer cell lines, MCF-7 and HepG2. Also, the effect of the most cytotoxic derivatives on VEGFR-2 protein concentration was assessed by ELISA. Compounds 14o, 14l, and 14b showed the highest activities with VEGFR-2 protein concentrations of 586.3, 636.2, and 705.7 pg/ml, respectively. Additionally, the anti-angiogenic property of compound 14b against human umbilical vascular endothelial cell (HUVEC) was performed using a wound healing migration assay. Compound 14b reduced proliferation and migratory potential of HUVEC cells. Furthermore, compound 14b was subjected to further biological investigations including cell cycle and apoptosis analyses. Compound 14b arrested the HepG2 cell growth at the Pre-G1 phase and induced apoptosis by 16.52%, compared to 0.67% in the control (HepG2) cells. The effect of apoptosis was buttressed by a 4.8-fold increase in caspase-3 level compared to the control cells. Besides, different in silico docking studies were also performed to get better insights into the possible binding mode of the target compounds with VEGFR-2 active sites.

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          Most cited references53

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          A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation. The assay detects living, but not dead cells and the signal generated is dependent on the degree of activation of the cells. This method can therefore be used to measure cytotoxicity, proliferation or activation. The results can be read on a multiwell scanning spectrophotometer (ELISA reader) and show a high degree of precision. No washing steps are used in the assay. The main advantages of the colorimetric assay are its rapidity and precision, and the lack of any radioisotope. We have used the assay to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
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            Recent discoveries of endogenous negative regulators of angiogenesis, thrombospondin, angiostatin and glioma-derived angiogenesis inhibitory factor, all associated with neovascularized tumours, suggest a new paradigm of tumorigenesis. It is now helpful to think of the switch to the angiogenic phenotype as a net balance of positive and negative regulators of blood vessel growth. The extent to which the negative regulators are decreased during this switch may dictate whether a primary tumour grows rapidly or slowly and whether metastases grow at all.
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              Molecular targeted therapies are revolutionized therapeutics which interfere with specific molecules to block cancer growth, progression, and metastasis. Many molecular targeted therapies approved by the Food and Drug Administration (FDA), have demonstrated remarkable clinical success in the treatment of a myriad of cancer types including breast, leukemia, colorectal, lung, and ovarian cancers. This review provides an update on the different types of molecular targeted therapies used in the treatment of cancer, focusing on the fundamentals of molecular targeted therapy, its mode of action in cancer treatment, as well as its advantages and limitations.
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                Author and article information

                Journal
                J Enzyme Inhib Med Chem
                J Enzyme Inhib Med Chem
                Journal of Enzyme Inhibition and Medicinal Chemistry
                Taylor & Francis
                1475-6366
                1475-6374
                27 December 2021
                2022
                27 December 2021
                : 37
                : 1
                : 397-410
                Affiliations
                [a ]Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University , Cairo, Egypt
                [b ]Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University , Cairo, Egypt
                [c ]Biochemistry Department, Faculty of Pharmacy, Badr University in Cairo (BUC) , Badr, Egypt
                [d ]Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University , Riyadh, Saudi Arabia
                Author notes

                Supplemental data for this article can be accessed here.

                Mohammed A. Dahab mohammeddahab@ 123456azhar.edu.eg Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University , Nasr City 11884, Cairo, Egypt
                Article
                2015343
                10.1080/14756366.2021.2015343
                8725875
                34961427
                e9d14aee-501e-47cd-9f30-f03259ae4f67
                © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Figures: 13, Tables: 4, Pages: 14, Words: 7444
                Categories
                Research Article
                Research Paper

                Pharmaceutical chemistry
                anti-proliferative,apoptosis,benzoxazole,vegfr-2 inhibitors
                Pharmaceutical chemistry
                anti-proliferative, apoptosis, benzoxazole, vegfr-2 inhibitors

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