New diarylureas and diarylamides containing 1,3,4-triarylpyrazole scaffold: Synthesis, antiproliferative evaluation against melanoma cell lines, ERK kinase inhibition, and molecular docking studies.
Synthesis of a new series of diarylureas and diarylamides possessing 1,3,4-triarylpyrazole scaffold is described. Their in vitro antiproliferative activities against 9 human melanoma cell lines were tested. Compounds 12, 13, 15, and 21-23 showed the highest potency against A375P melanoma cell line. In addition, compounds 10-15 and 19-24 showed high potency over the NCI 8 tested melanoma cell-lines panel. The IC(50) values for compound 23 were 0.36 μM and 0.84 μM over LOX IMVI and M14 cell lines, respectively. Compounds 21 and 23 showed high, dose-dependent inhibition of ERK kinase. Virtual screening was carried out through docking of compound 21 into the domain of V600E-B-RAF and the binding mode was studied.
Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131,Cheongryang, Seoul 130-650, Republic of Korea.
Won-Kyoung
WK
Choi
Mohammed I
MI
El-Gamal
Hong Seok
HS
Choi
Daejin
D
Baek
Chang-Hyun
CH
Oh
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy*; D008958:Models, Molecular; 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
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D048493:Proto-Oncogene Proteins B-raf