El-Damasy, Ashraf Kareem Lee, Ju-Hyeon Seo, Seon Hee Cho, Nam-Chul Pae, Ae Nim Keum, Gyochang 2024-01-20T04:02:20Z 2024-01-20T04:02:20Z 2021-09-05 2016-06-10 0223-5234 https://pubs.kist.re.kr/handle/201004/123969 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 mu M 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 GI(50) 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. (C) 2016 Published by Elsevier Masson SAS. English ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER RENAL-CELL CARCINOMA BIOLOGICAL EVALUATION ANTITUMOR AGENTS B-RAF ANTIPROLIFERATIVE ACTIVITY CONSTITUTIVE ACTIVATION SIGNALING PATHWAY BRAF MUTATIONS OVARIAN-CANCER MELANOMA 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 Article 10.1016/j.ejmech.2016.02.039 1 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v.115, pp.201 - 216 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 115 201 216 scie scopus 000375360800018 2-s2.0-84962306930 Chemistry, Medicinal Pharmacology & Pharmacy Article RENAL-CELL CARCINOMA BIOLOGICAL EVALUATION ANTITUMOR AGENTS B-RAF ANTIPROLIFERATIVE ACTIVITY CONSTITUTIVE ACTIVATION SIGNALING PATHWAY BRAF MUTATIONS OVARIAN-CANCER MELANOMA Anticancer activity Benzothiazole Urea Amide Pyridylamide B-Raf(V600E) C-Raf