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
  • 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: [email protected].
  • 6. Department of Bioengineering, Zunyi Medical University, Zhuhai Campus, Zhuhai, 519041, Guangdong, PR China. Electronic address: [email protected].
  • 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: [email protected].
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.