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      Design, eco-friendly synthesis, molecular modeling and anticancer evaluation of thiazol-5(4 H)-ones as potential tubulin polymerization inhibitors targeting the colchicine binding site†

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      RSC Advances
      The Royal Society of Chemistry

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          Abstract

          In recent years, suppressing tubulin polymerization has been developed as a therapeutic approach for cancer treatment. Thus, new derivatives based on thiazol-5(4 H)-ones have been designed and synthesized in an eco-friendly manner. The synthesized derivatives have the same essential pharmacophoric features of colchicine binding site inhibitors. The anti-proliferative activity of the new derivatives was evaluated on three human cancer cell lines (HCT-116, HepG-2, and MCF-7) using MTT assay procedure and colchicine was used as a positive control. Compounds 4f, 5a, 8f, 8g, and 8k showed superior antiproliferative activities against the three tested cell lines with IC 50 values ranging from 2.89 to 9.29 μM. Further investigation for the most active cytotoxic agents as tubulin polymerization inhibitors was also performed in order to explore the mechanism of their anti-proliferative activity. Tubulin polymerization assay results were found to be comperable with the cytotoxicity results. Compounds 4f and 5a were the most potent tubulin polymerization inhibitors with an IC 50 value of 9.33 and 9.52 nM, respectively. Further studies revealed the ability of 5a to induce apoptosis and arrest cell cycle growth at the G2/M phase. Molecular docking studies were also conducted to investigate possible binding interactions between the target compounds and the tubulin heterodimer active site. From these studies, it was concluded that inhibition of tubulin polymerization yields the reported cytotoxic activity.

          Abstract

          In recent years, suppressing tubulin polymerization has been developed as a therapeutic approach for cancer treatment.

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          Most cited references64

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          Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays

          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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            Cancer drug resistance: an evolving paradigm.

            Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to therapies that are designed to be selective for specific molecular targets share many features, such as alterations in the drug target, activation of prosurvival pathways and ineffective induction of cell death. With the increasing arsenal of anticancer agents, improving preclinical models and the advent of powerful high-throughput screening techniques, there are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.
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              Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function

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                Author and article information

                Journal
                RSC Adv
                RSC Adv
                RA
                RSCACL
                RSC Advances
                The Royal Society of Chemistry
                2046-2069
                15 January 2020
                14 January 2020
                15 January 2020
                : 10
                : 5
                : 2791-2811
                Affiliations
                [a] Chemistry Department, Faculty of Science, Ain Shams University Abbassiya Cairo 11566 Egypt elsayedam@ 123456sci.asu.edu.eg
                [b] Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University Beni-Suef 62415 Egypt
                [c] Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University Cairo 11884 Egypt Ibrahimeissa@ 123456azhar.edu.eg
                Author information
                https://orcid.org/0000-0003-4498-1122
                https://orcid.org/0000-0002-6955-2263
                https://orcid.org/0000-0003-1045-0163
                https://orcid.org/0000-0002-0840-4806
                Article
                c9ra10094f
                10.1039/c9ra10094f
                9048505
                b666e7d1-a45e-45a8-bc3f-cbe1dd6c1e24
                This journal is © The Royal Society of Chemistry
                History
                : 2 December 2019
                : 7 January 2020
                Page count
                Pages: 21
                Categories
                Chemistry
                Custom metadata
                Paginated Article

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