Synthesis, biological evaluation and molecular modeling studies of psammaplin A and its analogs as potent histone deacetylases inhibitors and cytotoxic agents

Bioorg Med Chem Lett. 2016 Sep 1;26(17):4372-6. doi: 10.1016/j.bmcl.2015.12.094. Epub 2015 Dec 29.

Abstract

In this study, a concise synthetic method of psammaplin A was achieved from 3-bromo-4-hydroxybenzaldahyde and hydantoin through a four-step synthesis via Knoevenagel condensation, hydrolysis, oximation and amidation in 37% overall yield. A collection of novel psammaplin A analogs focused on the variations of substituents at the benzene ring and modifications at the oxime moiety were synthesized. Among all the synthesized compounds, 5d and 5e showed better HDAC inhibition than psammaplin A and comparable cytotoxicity against four cancer cell lines (PC-3, MCF-7, A549 and HL-60). Molecular docking and dynamics simulation revealed that (i) hydrogen atom of the oxime group interacts with Asp99 of HDAC1 through a water bridged hydrogen bond and (ii) a hydroxyl group is optimal attached on the para-position of benzene, interacting with Glu203 at the entrance to the active site tunnel.

Keywords: Antiproliferation; Histone deacetylases inhibitors; Molecular modeling; Psammaplin A; Structure activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytotoxins / chemical synthesis
  • Cytotoxins / chemistry
  • Cytotoxins / pharmacology
  • Disulfides / chemical synthesis*
  • Disulfides / chemistry
  • Disulfides / pharmacology*
  • Enzyme Activation / drug effects
  • Histone Deacetylase Inhibitors* / chemical synthesis
  • Histone Deacetylase Inhibitors* / chemistry
  • Histone Deacetylase Inhibitors* / pharmacology
  • Humans
  • Molecular Docking Simulation*
  • Tyrosine / analogs & derivatives*
  • Tyrosine / chemical synthesis
  • Tyrosine / chemistry
  • Tyrosine / pharmacology

Substances

  • Cytotoxins
  • Disulfides
  • Histone Deacetylase Inhibitors
  • psammaplin A
  • Tyrosine