Design, synthesis and biological evaluation of novel acrylamide analogues as inhibitors of BCR-ABL kinase.
A series of acrylamide analogues were designed and synthesized from Imatinib and Nilotinib as novel BCR-ABL inhibitors by application of the principle of nonclassical electronic isostere. All new compounds were evaluated for their inhibitory effects on the activity of BCR-ABL kinase and the proliferation of K562 leukemia cancer cells in vitro. The acrylamide analogues in which the substituent in C ring was trifluoromethyl group were identified as highly potent BCR-ABL kinase inhibitors. Compound 13f exhibited an IC(50) value as low as 20.6 nM in ABL kinase inhibition and an IC(50) value of 32.3 nM for antiproliferative activity, about 10.5-fold and 12-fold lower than those of Imatinib respectively. These results suggest that compound 13f is a promising candidate as a novel BCR-ABL kinase inhibitor for further development.
College of Life Science, Department of Chemistry, Capital Normal University, Beijing 100084, China.
Shuxin
S
Li
Zhenglin
Z
Yao
Yanjin
Y
Zhao
Wei
W
Chen
Huijia
H
Wang
Xianzhao
X
Kuang
Wenhu
W
Zhan
Shan
S
Yao
Shanyou
S
Yu
Wenxiang
W
Hu
D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000178:Acrylamides; D000970:Antineoplastic Agents; D001549:Benzamides; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl