2. Academic Validation
  3. Design, synthesis and biological activity of novel 2,3,4,5-tetra-substituted thiophene derivatives as PI3Kα inhibitors with potent antitumor activity

Design, synthesis and biological activity of novel 2,3,4,5-tetra-substituted thiophene derivatives as PI3Kα inhibitors with potent antitumor activity

  • Eur J Med Chem. 2020 Jul 1:197:112309. doi: 10.1016/j.ejmech.2020.112309.
Weike Liao 1,  Zhongyuan Wang 2,  Yufei Han 3,  Yinliang Qi 3,  Jiaan Liu 4,  Juan Xie 2,  Ye Tian 3,  Qiancheng Lei 1,  Rui Chen 1,  Ming Sun 3,  Lei Tang 5,  Guowei Gong 6,  Yanfang Zhao 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, PR China.
  • 2 Department of Pharmacy, Guizhou Provincial People's Hospital, Guiyang, 550002, PR China.
  • 3 Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
  • 4 Department of Chemistry, University of Massachusetts-Amherst, Massachusetts, 01003, United States.
  • 5 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, PR China. Electronic address: tlei1974@hotmail.com.
  • 6 Department of Bioengineering, Zunyi Medical University, Zhuhai Campus, Zhuhai, 519041, Guangdong, PR China. Electronic address: sammyld@163.com.
  • 7 Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: yanfangzhao@126.com.
PMID: 32375077 DOI: 10.1016/j.ejmech.2020.112309
Abstract

Using a rational design strategy for isoform-selective inhibition of PI3Kα, two series of novel 2,3,4,5-tetra-substituted thiophene derivatives containing either diaryl urea or N-Acylarylhydrazone scaffold were designed and synthesized. The most promising compound 12k was demonstrated to bear nanomolar PI3Kα inhibitory potency with 12, 28, 30, 196-fold selectivity against isoforms β, γ, δ and mTOR. Besides, it also showed good developability profiles in cell-based proliferation against a panel of human tumor cells as well as ADME assays. We herein report on their design, synthesis, SAR and potential developability properties.

Keywords

2,3,4,5-Tetra-substituted thiophene derivatives; Antiproliferative activities; PI3Kα; Synthesis.

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