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      Amino Acid Conjugates of Aminothiazole and Aminopyridine as Potential Anticancer Agents: Synthesis, Molecular Docking and in vitro Evaluation

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          The development of resistance to available anticancer drugs is increasingly becoming a major challenge and new chemical entities could be unveiled to compensate this therapeutic failure. The current study demonstrated the synthesis of 2-aminothiazole [ S3( a-d) and S5( a-d)] and 2-aminopyridine [ S4( a-d) and S6( a-d)] derivatives that can target multiple cellular networks implicated in cancer development.


          Biological assays were performed to investigate the antioxidant and anticancer potential of synthesized compounds. Redox imbalance and oxidative stress are hallmarks of cancer, therefore, synthesized compounds were preliminarily screened for their antioxidant activity using DPPH assay, and further five derivatives S3b, S3c, S4c, S5b, and S6c, with significant antioxidant potential, were selected for investigation of in vitro anticancer potential. The cytotoxic activities were evaluated against the parent (A2780) and cisplatin-resistant (A2780CISR) ovarian cancer cell lines. Further, Molecular docking studies of active compounds were performed to determine binding affinities.


          Results revealed that S3c, S5b, and S6c displayed promising inhibition in cisplatin-resistant cell lines in comparison to parent cells in terms of both resistance factor (RF) and IC 50 values. Moreover, S3c proved to be most active compound in both parent and resistant cell lines with IC 50 values 15.57 µM and 11.52 µM respectively. Our docking studies demonstrated that compounds S3c, S5b, and S6c exhibited significant binding affinity with multiple protein targets of the signaling cascade.


          Anticancer activities of compounds S3c, S5b, and S6c in cisplatin-resistant cell lines suggested that these ligands may contribute as lead compounds for the development of new anticancer drugs.

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          Most cited references 56

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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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            Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks.

            Crosstalk and complexity within signaling pathways and their perturbation by oncogenes limit component-by-component approaches to understanding human disease. Network analysis of how normal and oncogenic signaling can be rewired by drugs may provide opportunities to target tumors with high specificity and efficacy. Using targeted inhibition of oncogenic signaling pathways, combined with DNA-damaging chemotherapy, we report that time-staggered EGFR inhibition, but not simultaneous coadministration, dramatically sensitizes a subset of triple-negative breast cancer cells to genotoxic drugs. Systems-level analysis-using high-density time-dependent measurements of signaling networks, gene expression profiles, and cell phenotypic responses in combination with mathematical modeling-revealed an approach for altering the intrinsic state of the cell through dynamic rewiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death by reactivation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Network medicine: a network-based approach to human disease.

              Given the functional interdependencies between the molecular components in a human cell, a disease is rarely a consequence of an abnormality in a single gene, but reflects the perturbations of the complex intracellular and intercellular network that links tissue and organ systems. The emerging tools of network medicine offer a platform to explore systematically not only the molecular complexity of a particular disease, leading to the identification of disease modules and pathways, but also the molecular relationships among apparently distinct (patho)phenotypes. Advances in this direction are essential for identifying new disease genes, for uncovering the biological significance of disease-associated mutations identified by genome-wide association studies and full-genome sequencing, and for identifying drug targets and biomarkers for complex diseases.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                01 April 2021
                : 15
                : 1459-1476
                [1 ]Riphah Institute of Pharmaceutical Sciences, Riphah International University , Islamabad, 44000, Pakistan
                [2 ]Shenzhen University Clinical Research Center for Neurological Diseases, Health Management Center, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University , Shenzhen, People's Republic of China
                [3 ]Hospital of Chengdu University of Traditional Chinese Medicine , Chengdu, People’s Republic of China
                [4 ]State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University , Shenzhen, People’s Republic of China
                Author notes
                Correspondence: Humaira Nadeem Riphah Institute of Pharmaceutical Sciences, Riphah International University , G-7/4, 7th Avenue, Islamabad, 44000, PakistanTel +92 51-2891835Fax +92 51-8350180 Email humaira.nadeem@riphah.edu.pk
                Shupeng Li State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University , Shenzhen, People’s Republic of China Email lisp@pku.edu.cn
                © 2021 Naz 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: 9, Tables: 5, References: 56, Pages: 18
                This work was supported by Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions No: 2019SHIBS0004, Shenzhen, 518055, China.
                Original Research


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