当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Discovery and structure-activity relationship of novel diphenylthiazole derivatives as BTK inhibitor with potent activity against B cell lymphoma cell lines.

Discovery and structure-activity relationship of novel diphenylthiazole derivatives as BTK inhibitor with potent activity against B cell lymphoma cell lines.

Abstract：

:By the analysis of different binding modes with Bruton's tyrosine kinase (BTK), series of novel diphenylthiazole derivatives were rationally designed, synthesized and characterized. Biologically evaluation in biochemistry and cellular assay indicated that, compounds 5m, 5o, 6b, 6c, 6g, 6i, 7h, 7i, 7k, 7m, 7n, 7o and 7s exhibited improved potency against Ramos cell (IC50 = 1.36-8.60 μM) and Raji cell (IC50 = 1.20-14.04 μM) as compared with ibrutinib (IC50 = 14.69 and 15.99 μM, respectively). Especially, compounds 7m and 7n showed 10-time improved potency against Ramos cell viability over ibrutinib. Compound 6b improved 13-fold activity against Raji cell viability than ibrutinib. In addition, active compound 7o potently inhibited C481S mutant BTK with IC50 value of 0.061 μM. Apoptosis analysis of both Ramos and Raji cells indicated that 7o was remarkably more potent than CGI-1746 and ibrutinib. Compound 7o potently inhibited BTK Y223 phosphorylation in Raji cells, and arrested cell cycle progression in the G0/G1 phase in Raji and Ramos cells. This study expanded the structural diversity of BTK inhibitors and compound 7o was discovered as an active lead inhibitor with great potential for further studies.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Guo X,Yang D,Fan Z,Zhang N,Zhao B,Huang C,Wang F,Ma R,Meng M,Deng Y

doi

10.1016/j.ejmech.2019.06.035

subject

Has Abstract

pub_date

2019-09-15 00:00:00

pages

767-781

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(19)30552-5

journal_volume

178

pub_type

杂志文章

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