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  2. Diarylurea derivatives comprising 2,4-diarylpyrimidines: Discovery of novel potential anticancer agents via combined failed-ligands repurposing and molecular hybridization approaches

Diarylurea derivatives comprising 2,4-diarylpyrimidines: Discovery of novel potential anticancer agents via combined failed-ligands repurposing and molecular hybridization approaches

  • Bioorg Chem. 2020 Oct;103:104121. doi: 10.1016/j.bioorg.2020.104121.
Ahmed Karam Farag 1 Ahmed H E Hassan 2 Kyung-Sook Chung 3 Jeong-Hun Lee 3 Hyo-Sun Gil 3 Kyung-Tae Lee 3 Eun Joo Roh 4
Affiliations

Affiliations

  • 1 RI Translational Research Team, Division of Applied RI, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul 01812, Republic of Korea. Electronic address: ahmed@kirams.re.kr.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 3 Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 4 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science &Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea. Electronic address: r8636@kist.re.kr.
Abstract

A series of diarylurea derivatives comprising 2,4-diarylpyrimidines were synthesized based on a combination of postulated molecular hybridization design and failed-ligands repurposing approaches, which enabled the discovery of novel potential antiproliferative agents. Towards credible biological evaluation, an in vitro Anticancer activity assay was conducted employing a library of 60 Cancer cell lines constituting nine panels representing blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers. The results revealed high effectiveness and broad-spectrum Anticancer activity of compounds 4m and 4g. Five-dose assay of compounds 4m and 4g proved their high potency that surpassed that of four standard kinase inhibitors FDA-approved Anticancer drugs against many Cancer cells. Towards the identification of their molecular target, screening of kinase inhibitory profile employing a panel of 51 kinases involved in Cancer revealed inhibition of several kinases from the platelet-derived growth factor/vascular endothelial growth factor receptor (PVR) kinase family, which might mediate, at least in part, the antiproliferative activity. Molecular docking of 4g into the crystal structure of the Feline McDonough Sarcoma (FMS) kinase predicted that it binds to a pocket formed by the juxtamembrane domain, the catalytic loop, and the αE helix, thus stabilizing the inhibited conformation of the kinase. Flow cytometric study of the cytotoxic effects of compound 4g in A549 cells showed it induces dose- and time-dependent apoptotic events leading to cell death. Collectively, this work presents compound 4g as a potential broad-spectrum Anticancer agent against multiple Cancer types.

Keywords

2,4-Diarylpyrimidnes; Anticancer; Diarylurea derivatives; Molecular hybridization; Repurposing.

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