Abstract
c-Met is involved in cellular processes that lead to the development and progression of cancer. A series of 2, 4-dichlorophenoxyacetamide-chalcones were synthesized and evaluated for their antiproliferative activities against MCF-7, HT-29, and A549 cancer cell lines. Several compounds showed moderate-to-good antiproliferative activity against MCF-7 and A549 cell lines. Many compounds were inactive against the HT-29 cell line. Some selected compounds were tested against c-Met kinase using the ADP GloTM assay and were found to possess IC50 < 10 µM indicating good activity. Compound 6f was identified as a promising compound and evaluated further for its antiproliferative and antimigratory properties on MCF-7 and A549 cell lines using colony formation and wound healing assays, respectively. Compound 6f had long-term antiproliferative effects and exerted antimigratory activity on both cell lines. Compound 6f had better potential at inhibiting growth and migration in MCF-7 cells. Molecular docking studies indicated that these compounds bind to Met1160 from the hinge region. Furthermore, molecular dynamics simulation studies for compound 6f confirmed this finding. Docking-based selectivity studies showed that these compounds were more selective for c-Met kinase.
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Acknowledgements
This study was funded by Indian Council of Medical Research (ICMR) under Senior Research Fellowship (F. No.45/18/201/-BIO/BMS dated 11th April 2018) awarded to Ms. Heena Bhojwani. Dr. Urmila Joshi acknowledges Department of Science and Technology- SERB (SERB/F/7466/2018-2019) and All India Council for Technical Education (F. No. 8-36/RIFD/RPS/Policy-1/2017-18 dated 4th January 2019) for research facilities. Ms. Heena Bhojwani acknowledges the FTIR facility rendered to her under the DST-FIST Grant (Letter SR/FST/College-264 dated 18th November 2015) and Instrumentation Facility at University of Mumbai for NMR. Authors acknowledge Dr. Anindya Goswami, Cancer Pharmacology Division, CSIR-IIIM, Jammu for the assistance in colony formation and wound healing assay. Authors are thankful to Dr. Jyoti Kode, ACTREC, Kharghar for their anticancer drug screening facility. Authors acknowledge Ms. Khushboo Begwani for helping in kinase inhibition assay. Authors are thankful to Cipla Pvt. Ltd. Mumbai for the drug sorafenib provided as gift sample. Authors acknowledge D. E. Shaw Pvt. Ltd. for academic version of Desmond.
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Bhojwani, H., Patil, S., Joshi, U. et al. Design, synthesis, and biological evaluation of 2, 4-dichlorophenoxyacetamide chalcone hybrids as potential c-Met kinase inhibitors. Med Chem Res 32, 109–127 (2023). https://doi.org/10.1007/s00044-022-02986-9
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DOI: https://doi.org/10.1007/s00044-022-02986-9