A novel platinum complex of the histone deacetylase inhibitor belinostat: rational design, development and in vitro cytotoxicity

J Inorg Biochem. 2013 Jul:124:70-7. doi: 10.1016/j.jinorgbio.2013.03.011. Epub 2013 Mar 29.

Abstract

The successful design and synthesis of a novel Pt complex of the histone deacteylase inhibitor belinostat are reported. Molecular modelling assisted in the identification of a suitable malonate derivative of belinostat (mal-p-Bel) for complexation to platinum. Reaction of [Pt(NH3)2(H2O)2](NO3)2 with the disodium salt of mal-p-Bel gave cis-[Pt(NH3)2(mal-p-Bel-2H)] (where -2H indicates that mal-p-Bel is doubly deprotonated) in excellent yield. An in vitro cytotoxicity study revealed that cis-[Pt(NH3)2(mal-p-Bel-2H)] possesses (i) considerable cytotoxicity against reported ovarian cancer cell lines, (ii) enhanced cytotoxicity relative to the previously reported Pt histone deacetylase inhibitor conjugate, cis-[Pt(II)(NH3)2(malSAHA-2H)] and (iii) favourable cyto-selective properties as compared to cisplatin and belinostat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cytotoxins* / chemical synthesis
  • Cytotoxins* / chemistry
  • Cytotoxins* / pharmacology
  • Female
  • Histone Deacetylase Inhibitors* / chemical synthesis
  • Histone Deacetylase Inhibitors* / chemistry
  • Histone Deacetylase Inhibitors* / pharmacology
  • Humans
  • Hydroxamic Acids* / chemical synthesis
  • Hydroxamic Acids* / chemistry
  • Hydroxamic Acids* / pharmacology
  • Platinum Compounds* / chemical synthesis
  • Platinum Compounds* / chemistry
  • Platinum Compounds* / pharmacology
  • Sulfonamides* / chemical synthesis
  • Sulfonamides* / chemistry
  • Sulfonamides* / pharmacology

Substances

  • Cytotoxins
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Platinum Compounds
  • Sulfonamides
  • belinostat