Efficient synthesis and biological activity of Psammaplin A and its analogues as antitumor agents

Eur J Med Chem. 2015:96:218-30. doi: 10.1016/j.ejmech.2015.04.001. Epub 2015 Apr 6.

Abstract

We describe a new concise method for the synthesis of psammaplin A and its analogues, and antitumor activity of psammaplin A analogues. Psammaplin A was obtained with 41% yield in 5 steps from 3-bromo-4-hydroxybenzaldahyde and ethyl acetoacetate via Knoevenagel condensation and α-nitrosation as key steps. Twenty eight analogues of psammaplin A were prepared employing the new synthetic approach. Structure-activity relationship study against cytotoxicity reveal that the free oxime group and disulfide functional group were responsible for high cytotoxicity. Also the bromotyrosine component was relatively tolerable and hydrophobic aromatic groups preserved the cytotoxicity. The cytotoxicity of aromatic group is dependent on the size and spatial geometry. Among them, five compounds showed comparable cytotoxicity to psammaplin A. Compound 30 exhibited potential HDAC inhibitory activity and in vivo antitumor activity.

Keywords: HDAC; Histone deacetylase inhibitor; Psammaplin A; Structure–activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Disulfides / chemical synthesis
  • Disulfides / chemistry
  • Disulfides / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Structure
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Tyrosine / analogs & derivatives*
  • Tyrosine / chemical synthesis
  • Tyrosine / chemistry
  • Tyrosine / pharmacology

Substances

  • Antineoplastic Agents
  • Disulfides
  • psammaplin A
  • Tyrosine