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  3. Design and synthesis of new quinoline derivatives as selective C-RAF kinase inhibitors with potent anticancer activity

Design and synthesis of new quinoline derivatives as selective C-RAF kinase inhibitors with potent anticancer activity

  • Eur J Med Chem. 2022 Aug 5;238:114434. doi: 10.1016/j.ejmech.2022.114434.
Seyed-Omar Zaraei 1,  Nour N Al-Ach 1,  Hanan S Anbar 2,  Randa El-Gamal 3,  Hamadeh Tarazi 4,  Rimas T Tokatly 1,  Rawan R Kalla 1,  Mouna A Munther 1,  Marwa M Wahba 1,  Aya M Alshihabi 1,  Mahmoud K Shehata 1,  Rawan M Sbenati 1,  Afnan I Shahin 1,  Raafat El-Awady 5,  Taleb H Al-Tel 4,  Mohammed I El-Gamal 6
Affiliations

Affiliations

  • 1 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 2 Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, 19099, United Arab Emirates.
  • 3 Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt.
  • 4 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 5 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 6 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. Electronic address: malgamal@sharjah.ac.ae.
PMID: 35551038 DOI: 10.1016/j.ejmech.2022.114434
Abstract

This article describes the design, synthesis, and biological screening of a new series of diarylurea and diarylamide derivatives including quinoline core armed with dimethylamino or morpholino side chain. Fifteen target compounds were selected by the National Cancer Institute (NCI, USA) for in vitro antiproliferative screening against a panel of 60 Cancer cell lines of nine Cancer types. Compounds 1j-l showed the highest mean inhibition percentage values over the 60-cell line panel at 10 μM with broad-spectrum antiproliferative activity. Subsequently, compounds 1j-l were subjected to a dose-response study to measure their GI50 and total growth inhibition (TGI) values against the cell lines. Three of the tested molecules exerted higher potency against most of the cell lines than the reference drug, sorafenib. Compound 1l indicated a higher potency than sorafenib against 53 of tested Cancer cell lines. Compounds 1j-l demonstrated promising selectivity against Cancer cells than normal cells. Moreover, compound 1l induced Apoptosis and necrosis in RPMI-8226 cell line in a dose-dependent manner. In addition, compounds 1j-l were tested against c-Raf kinase as a potential molecular target. The three compounds showed high potency, and the most potent c-Raf kinase inhibitor was compound 1j with an IC50 value of 0.067 μM. In addition, Compounds 1j-l were further tested at 1 μM concentration against a panel of another twelve kinases and they showed a high selectivity for c-Raf kinase. Molecular modeling studies were performed to illuminate on the putative binding interactions of these motifs in the active site of c-Raf kinase. Additional studies were conducted to measure aqueous solubility, partition coefficient, and Caco-2 permeability of the most promising derivatives.

Keywords

C-RAF kinase; Cancer; Kinase inhibitor; Quinoline; Urea.

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