title: Design and synthesis of new 2-anilinoquinolines bearing N-methylpicolinamide moiety as potential antiproliferative agents.
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 GI50values 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 GI50values 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-RafV600Eand 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.
authors: 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.
authors: Ashraf Kareem
authors: AK
authors: El-Damasy
authors: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors: Seon Hee
authors: SH
authors: Seo
authors: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors: Nam-Chul
authors: NC
authors: Cho
authors: 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.
authors: Ae Nim
authors: AN
authors: Pae
authors: Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon, Republic of Korea.|Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors: Eunice Eunkyeong
authors: EE
authors: Kim
authors: 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.
authors: Gyochang
authors: G
authors: Keum
mesh_terms: D000577:Amides / Q000737:chemistry*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D062105:Molecular Docking Simulation; D066244:Proton Magnetic Resonance Spectroscopy; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000577:Amides; D011804:Quinolines
keywords: 2-anilinoquinoline; N-methylpicolinamide; RAF kinase; antiproliferative activity