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Chem Biol Drug Des. 2017 Jan;89(1):98-113. doi: 10.1111/cbdd.12836. Epub 2016 Sep 9.

Design and synthesis of new 2-anilinoquinolines bearing N-methylpicolinamide moiety as potential antiproliferative agents.

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Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon, Republic of Korea.
Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt.
Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.


A series of new 2-anilinoquinolines 6a-o possessing the substantial N-methylpicolinamide motif at C5 has been designed and synthesized as sorafenib analogs. The antiproliferative activities of the target compounds were preliminarily appraised against a panel of three human cancer cell lines (MCF-7, SK-BR3, and HCT116), and a selected array was further tested over a panel of approximately 60 cancer cell lines at NCI at 10 μM concentration. Interestingly, compounds 6c, 6d, 6j, 6k, and 6l showed promising selective anticancer activities (growth inhibition >80%) toward certain cancer cells at 10 μM testing dose. Compounds 6d and 6j were advanced to five-dose testing mode to determine their GI50 values and compared with our previously reported ureidoquinoline B and sorafenib as reference compounds. The 4-chloro-3-trifluoromethylaniline derivative 6j manifested superior potency than both compound B and sorafenib over eleven and eight cell lines, respectively. It showed GI50 values of 0.36, 0.66, 0.68, and 0.60 μM against the breast MDA-MB-468, renal A498, and melanoma SK-MEL-5 and UACC-62 cell lines, respectively. Moreover, both 6d and 6j exerted low cytotoxic effects against HFF-1 normal cell line. Furthermore, compounds 6d and 6j were tested against both B-RafV600E and C-Raf kinases and displayed modest inhibitory activities, which were justified by molecular docking study. Compound 6j could serve as a promising candidate for further development of potent anticancer chemotherapeutics.


2-anilinoquinoline; N-methylpicolinamide; RAF kinase; antiproliferative activity

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