2. Academic Validation
  3. Design, synthesis and pharmacological evaluation of 4,5-diarylisoxazols bearing amino acid residues within the 3-amido motif as potent heat shock protein 90 (Hsp90) inhibitors

Design, synthesis and pharmacological evaluation of 4,5-diarylisoxazols bearing amino acid residues within the 3-amido motif as potent heat shock protein 90 (Hsp90) inhibitors

  • Eur J Med Chem. 2017 Jan 5:125:315-326. doi: 10.1016/j.ejmech.2016.09.043.
Chi Zhang 1,  Xin Wang 2,  Hongchun Liu 3,  Minmin Zhang 3,  Meiyu Geng 3,  Liping Sun 4,  Aijun Shen 5,  Ao Zhang 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China; CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: chslp@cpu.edu.cn.
  • 5 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: shenaj@simm.ac.cn.
  • 6 CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: aozhang@simm.ac.cn.
PMID: 27688186 DOI: 10.1016/j.ejmech.2016.09.043
Abstract

A structure-based medicinal chemistry optimization was conducted on the clinical HSP90 Inhibitor diarylisoxazole 3. Several series of new compounds were designed and synthesized by incorporating diversified Amino Acid Derivatives with various lengths to the 3-amido motif of the isoxazole scaffold. Compound 14j was identified to have high HSP90 binding potency (14 nM) and antiproliferative activity against H3122 human lung Cancer and BT-474 breast Cancer cells. Treatment of 14j with H3122 cell led to degradation of client protein ALK, reduction of downstream phosphorylation of Akt and ERK, and up-regulation of HSP70. Molecular docking suggested that the terminal valine moiety and the ethyleneglycol linker in compound 14j formed additional apolar and polar interaction network with a number of amino acid residues.

Keywords

Amino acid; Antiproliferative effect; Diarylisoxazole; Hsp90 inhibitor; Resorcinol.

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