title: Design and synthesis of new potent anticancer benzothiazole amides and ureas featuring pyridylamide moiety and possessing dual B-Raf(V600E) and C-Raf kinase inhibitory activities.
abstract: A new series of benzothiazole amide and urea derivatives tethered with the privileged pyridylamide moiety by ether linkage at the 6-position of benzothiazole (22 final compounds) has been designed and synthesized as potent anticancer sorafenib analogs. A selected group of twelve derivatives was appraised for its antiproliferative activity over a panel of 60 human cancer cell lines at a single dose concentration of 10 μM at National Cancer Institute (NCI, USA). Compounds 4b, 5a, 5b and 5d exhibited promising growth inhibitions and thus were further tested in advanced 5-dose testing assay to determine their GI50 values. The cellular based assay results revealed that 3,5-bis-trifluoromethylphenyl (5b) urea member is the best derivative with superior potency and efficacy compared to sorafenib as well as notable extended spectrum activity covering 57 human cancer cell lines. Kinase screening of compound 5b showed its kinase inhibitory effect against both B-Raf(V600E) and C-Raf. Moreover, the most potent derivatives in cells were investigated for their RAF inhibitory activities, and the results were rationalized with the molecular docking study. Profiling of CYP450 and hERG channel inhibitory effects for the active compounds revealed their low possibilities to exhibit undesirable drug-drug interactions and cardiac side effects.
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Gajungro 217, Youseong-gu, Daejeon 305-350, Republic of Korea; Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt.
authors.forename: Ashraf Kareem
authors.initials: AK
authors.lastname: El-Damasy
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Ju-Hyeon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Seo
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biotechnology, Yonsei University 220, Seoul 120-749, Republic of Korea.
authors.forename: Nam-Chul
authors.initials: NC
authors.lastname: Cho
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Gajungro 217, Youseong-gu, Daejeon 305-350, Republic of Korea.
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Gajungro 217, Youseong-gu, Daejeon 305-350, Republic of Korea. Electronic address: gkeum@kist.re.kr.
authors.forename: Gyochang
authors.initials: G
authors.lastname: Keum
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D047428:Protein Kinase Inhibitors; D014508:Urea; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; C005465:benzothiazole
keywords: Amide; Anticancer activity; B-Raf(V600E); Benzothiazole; C-Raf; Pyridylamide; Urea