2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2019 Jan 15;29(2):225-229. doi: 10.1016/j.bmcl.2018.11.051.
Nan Zheng 1,  Qun Hao 2,  Kuaile Lin 2,  Jing Pan 1,  Yingxia Li 3,  Weicheng Zhou 4
Affiliations

Affiliations

  • 1 Shanghai Key Lab. of Anti-infectives, State Key Lab. of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China; School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
  • 2 Shanghai Key Lab. of Anti-infectives, State Key Lab. of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China.
  • 3 School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China. Electronic address: liyx417@fudan.edu.cn.
  • 4 Shanghai Key Lab. of Anti-infectives, State Key Lab. of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China. Electronic address: zhouweicheng58@163.com.
PMID: 30522954 DOI: 10.1016/j.bmcl.2018.11.051
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 and 9f 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 that 8 possessed low cell cytotoxicity. All these explorations indicated that 8 could serve as a valuable anti-tumor agent for B-cell lymphoblastic leukemia treatment.

Keywords

1-Substituted pyrazolo[3,4-d]pyrimidine; B-cell lymphoblastic leukemia; BTK inhibitors; Cytotoxicity; Inhibitory activity.

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