Design and synthesis of new RAF kinase-inhibiting antiproliferative quinoline derivatives. Part 2: Diarylurea derivatives

Eur J Med Chem. 2017 Feb 15:127:413-423. doi: 10.1016/j.ejmech.2017.01.006.

Mohammed I El-Gamal ¹, Mohammad Ashrafuddin Khan ², Hamadeh Tarazi ³, Mohammed S Abdel-Maksoud ⁴, Mahmoud M Gamal El-Din ⁴, Kyung Ho Yoo ⁵, Chang-Hyun Oh ⁶

Affiliations

1 Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt.
2 Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Department of Biomolecular Science, Korea University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea.
3 Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates.
4 Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Department of Biomolecular Science, Korea University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea; Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki-Giza 12622, Egypt.
5 Chemical Kinomics Research Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
6 Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Department of Biomolecular Science, Korea University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea. Electronic address: choh@kist.re.kr.

PMID: 28088086 DOI: 10.1016/j.ejmech.2017.01.006

Abstract

This article describes the design, synthesis, and biological screening of a new series of diarylurea derivatives possessing quinoline nucleus. Nine target compounds were selected by the National Cancer Institute (NCI, Bethesda, Maryland, USA) for in vitro antiproliferative screening against a panel of 58 Cancer cell lines of nine Cancer types. Following one-dose initial screening, compounds 1d-g and 2b were selected for 5-dose screening in order to calculate their IC₅₀ and total growth inhibition (TGI) values against the cell lines. Compounds 1e and 1g were the most promising analogues. Both compounds showed strong potency and broad-spectrum antiproliferative activity against the different tested Cancer types. Their IC₅₀ and TGI values were less than those of the reference drug, sorafenib, against most of the tested cell lines of the nine different Cancer types. Furthermore, the most potent compounds 1d-g were tested against c-Raf kinase as a potential molecular target of this series of compounds. All of them showed high potency, and the most potent derivative was compound 1e (IC₅₀ = 0.10 μM). It was further tested against a panel of another twelve kinases, and it showed selectivity against c-Raf kinase. This could be, at least in part, the possible mechanism of antiproliferative action of this series of compounds at molecular level. The binding modes of compounds 1e and 1g were studied by docking studies, which highlighted the importance of the urea linker compared with the amide linker.

Keywords

Antiproliferative activity; C-RAF kinase; Diarylurea; Molecular docking; Quinoline.

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