Synthesis and biological evaluation of novel 1-substituted 3-(3-phenoxyprop-1-yn-1-yl)-1H-pyrazolo[3, 4-d]pyrimidin-4-amines as potent Bruton's tyrosine kinase (BTK) inhibitors. Issue 2 (15th January 2019)

• Record Type: Journal Article
• Authors: Zheng, Nan; Hao, Qun; Lin, Kuaile; Pan, Jing; Li, Yingxia; Zhou, Weicheng
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 2(2019)
• Page Start: 225
• Page End: 229
• Publication Date: 2019-01-15
• Subjects: BTK inhibitors -- 1-Substituted pyrazolo[3, 4-d]pyrimidine -- Inhibitory activity -- B-cell lymphoblastic leukemia -- Cytotoxicity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.11.051
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: 1-Substituted pyrazolopyrimidine derivatives were designed as BTK inhibitors. Compound9h exhibited high potency against BTK enzyme (IC50 = 4.2 nM). 8 and9f displayed better inhibition against B leukemia cell lines than ibrutinib. Compound8 has low cell cytotoxicity against normal PBMC cells. Abstract: A new series of 1-substituted pyrazolopyrimidine derivatives were synthesized as potent BTK inhibitors and they were evaluated by enzyme-based assay and anti-proliferation against multiple B-cell lymphoma cell lines in vitro . Among these compounds, 9h exhibited the highest potency against BTK enzyme, with IC50 value of 4.2 nM. In particular, 8 and9f performed better inhibition against the proliferation of B lymphoma cell lines DOHH2 and WSU-DLCL2 than the clinical drug ibrutinb. In addition, the test toward the normal PBMC cells showed that8 possessed low cell cytotoxicity. All these explorations indicated that8 could serve as a valuable anti-tumor agent for B-cell lymphoblastic leukemia treatment.