title: New diarylamides and diarylureas possessing 8-amino(acetamido)quinoline scaffold: synthesis, antiproliferative activities against melanoma cell lines, kinase inhibition, and in silico studies.
abstract: Synthesis of a new series of diarylureas and diarylamides possessing 4-aryl-8-amino(acetamido)quinoline scaffold is described. Their in vitro antiproliferative activities against ten melanoma cell lines were tested. Compounds 1l, 2l, 3c, and 4c showed the highest potency against A375P cell line with IC50 values in sub-micromolar scale. Compound 4c was equipotent to Vemurafenib against A375P. In addition, compounds 1l, 2a, and 2l showed high potency over the NCI-9 tested melanoma cell line panel. The IC50 values of compounds 1l and 2l were in 2-digit nanomolar scale over four and five cell lines, respectively. Compound 2l showed high, dose-dependent inhibition of ERK kinase. ADME profiling showed that compounds 1l, 2l, 3c, 4c, and 5b are estimated to be orally bioavailable.
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea; Department of Chemistry and Nano Science (BK21), Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Koh
authors.forename: Mohammed I
authors.initials: MI
authors.lastname: El-Gamal
authors.forename: Chang-Hyun
authors.initials: CH
authors.lastname: Oh
authors.forename: So Ha
authors.initials: SH
authors.lastname: Lee
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.forename: Garam
authors.initials: G
authors.lastname: Kim
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Choi
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Hong
authors.forename: Sang-gi
authors.initials: SG
authors.lastname: Lee
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Yoo
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000577:Amides / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry*
chemical_list: C000591457:8-amino(acetamido)quinoline; D000081:Acetamides; D000577:Amides; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D014508:Urea; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Antiproliferative activity; Diarylamide; Diarylurea; ERK kinase; Melanoma; Quinoline