title: Design and synthesis of a new series of highly potent RAF kinase-inhibiting triarylpyrazole derivatives possessing antiproliferative activity against melanoma cells.
abstract: Inhibition of V600E-B-RAF kinase represents a potential avenue for melanoma treatment. Herein, a series of 1,3,4-triarylpyrazoles possessing amide linker were designed, synthesized and evaluated for RAF kinase inhibition.
  
  
  
  Compounds 1d and 1f were more potent than sorafenib against A375 cell line, and their selectivity indexes toward A375 than HS27 fibroblasts were 25.43 and 45.83, respectively. Compound 1f was more potent against the melanoma cell lines with B-RAF V600E mutation than melanoma cells with NRAS mutation and normal skin epithelial cells. Compounds 1d and 1f showed strong potency and selectivity against V600E-B-RAF kinase with IC50values of 3.80 and 2.98 nM, respectively. Molecular docking studies revealed their binding mode.
  
  
  
  Potent and selective V600E-B-RAF antimelanoma agents were discovered. [Formula: see text].
authors.affiliation: Center for Biomaterials, Korea Institute of Science & Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.|Department of Biomolecular Science, University of Science & Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea.
authors.forename: Mohammad Ashrafuddin
authors.initials: MA
authors.lastname: Khan
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates.|Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates.|Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt.
authors.forename: Mohammed I
authors.initials: MI
authors.lastname: El-Gamal
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates.|Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates.
authors.forename: Hamadeh
authors.initials: H
authors.lastname: Tarazi
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Chosun University, Gwangju, Republic of Korea.
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Center for Biomaterials, Korea Institute of Science & Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.|Department of Biomolecular Science, University of Science & Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea.
authors.forename: Chang-Hyun
authors.initials: CH
authors.lastname: Oh
mesh_terms: 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; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology*; D008958:Models, Molecular; 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; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D048493:Proto-Oncogene Proteins B-raf
keywords: A375; RAF kinase; docking; melanoma; pyrazole