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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.

Author information

1
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
2
Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon, Republic of Korea.
3
Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt.
4
Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.

Abstract

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.

KEYWORDS:

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

PMID:
27496071
DOI:
10.1111/cbdd.12836
[Indexed for MEDLINE]

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