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      New Isatin–Indole Conjugates: Synthesis, Characterization, and a Plausible Mechanism of Their in vitro Antiproliferative Activity

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          Cancer remains the leading cause of human morbidity universally. Hence, we sought to assess the in vitro antiproliferative activity of new isatin-based conjugates ( 5a–s) against three human cancer cell lines.


          The antiproliferative activities of compounds 5a–s were evaluated in vitro and their ADME (absorption, distribution, metabolism and excretion) was carried out using standard protocols. Subsequently, Western blot analysis was conducted to elucidate the potential antiproliferative mechanism of compounds 5a–s.


          The in vitro antiproliferative activities of compounds 5a–s against the tested cancer cell lines ranged from 20.3 to 95.9%. Compound 5m had an IC 50 value of 1.17 µM; thus, its antiproliferative potency was approximately seven-fold greater than that of sunitinib (IC 50 = 8.11 µM). In-depth pharmacological testing was conducted with compound 5m to gain insight into the potential antiproliferative mechanism of this class of compounds. Compound 5m caused an increase in the number of cells in the G1 phase, with a concomitant reduction of those in the G2/M and S phases. Additionally, compound 5m significantly and dose-dependently reduced the amount of phosphorylated retinoblastoma protein detected. Compound 5m enhanced expression of B cell translocation gene 1, cell cycle-associated proteins (cyclin B1, cyclin D1, and phosphorylated cyclin-dependent kinase 1), and a pro-apoptotic protein (Bcl-2-associated X protein gene), and activated caspase-3. ADME predictions exposed the oral liability of compounds 5a-s.


          Herein, we revealed the antiproliferative activity and ADME predictions of the newly-synthesized compounds 5a–s and provided a detailed insight into the pharmacological profile of compound 5m. Thus, compounds 5a–s can potentially be exploited as new antiproliferative lead compounds for cancer chemotherapeutic.

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          Most cited references 44

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          Global cancer statistics

           A. JEMAL,  F BRAY,  MM Center (2011)
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            Epithelioid cell cultures from rat small intestine. Characterization by morphologic and immunologic criteria

            Rat small intestinal epithelial cell lines have been established in vitro and subcultured serially for periods up to 6 mo. These cells have an epithelioid morphology, grow as monolayers of closely opposed polygonal cells, and during the logarithmic phase of growth have a population doubling time of 19--22 h. Ultrastructural studies revealed the presence of microvilli, tight junctions, an extensive Golgi complex, and the presence of extracellular amorphous material similar in appearance to isolated basement membrane. These cells exhibit a number of features characteristic of normal cells in culture; namely, a normal rat diploid karyotype, strong density inhibition of growth, lack of growth in soft agar, and a low plating efficiency when seeded at low density. They did not produce tumors when injected in syngeneic animals. Immunochemical studies were performed to determine their origin using antisera prepared against rat small intestinal crypt cell plasma membrane, brush border membrane of villus cells and isolated sucrase-isomaltase complex. Antigenic determinants specific for small intestinal epithelial (crypt and villus) cells were demonstrated on the surface of the epithelioid cells, but they lacked immunological determinants specific for differentiated villus cells. An antiserum specifically staining extracellular material surrounding the cells cultured in vitro demonstrated cross-reactivity to basement membrane in rat intestinal frozen sections. It is concluded that the cultured epithelioid cells have features of undifferentiated small intestinal crypt cells.
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              Receptor tyrosine kinase signalling as a target for cancer intervention strategies.

              In multicellular organisms, communication between individual cells is essential for the regulation and coordination of complex cellular processes such as growth, differentiation, migration and apoptosis. The plethora of signal transduction networks mediating these biological processes is regulated in part by polypeptide growth factors that can generate signals by activating cell surface receptors either in paracrine or autocrine manner. The primary mediators of such physiological cell responses are receptor tyrosine kinases (RTKs) that couple ligand binding to downstream signalling cascades and gene transcription. Investigations over the past 18 years have revealed that RTKs are not only key regulators of normal cellular processes but are also critically involved in the development and progression of human cancers. Therefore, signalling pathways controlled by tyrosine kinases offer unique opportunities for pharmaco logical intervention. The aim of this review is to give a broad overview of RTK signalling involved in tumorigenesis and the possibility of target-selective intervention for anti-cancer therapy.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                03 February 2020
                : 14
                : 483-495
                [1 ]Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University , Riyadh 11451, Saudi Arabia
                [2 ]Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama , Mobile, AL 36604-1405, USA
                [3 ]Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618) , Giza 12622, Egypt
                Author notes
                Correspondence: Mohamed I Attia Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University , P.O. Box. 2457, Riyadh11451, Saudi ArabiaTel +966-146-77337Fax +966-146-76220 Email mattia@ksu.edu.sa
                © 2020 Al-Wabli et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, Tables: 5, References: 54, Pages: 13
                Original Research

                Pharmacology & Pharmaceutical medicine

                cancer cell line, synthesis, antiproliferative, indole, isatin


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