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

• Belinostat was selected as a potent histone deacetylase inhibitor.
• Molecular modelling identified a suitable belinostat derivative to complex to Pt.
• A novel Pt complex of a belinostat derivative was synthesised.
• This novel complex possesses considerable cytotoxicity against ovarian cancer cells.
• It also exhibits favourable cyto-selectivity relative to cisplatin and belinostat.

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-[PtII(NH3)2(malSAHA-2H)] and (iii) favourable cyto-selective properties as compared to cisplatin and belinostat.

A novel Pt complex of the histone deacteylase inhibitor belinostat, cis-[Pt(NH3)2(mal-p-Bel-2H)], is reported. An in vitro cytotoxicity study revealed that the reported Pt complex possesses (i) considerable cytotoxicity against reported ovarian cancer cell lines and (ii) favourable cyto-selective properties as compared to cisplatin and belinostat.Figure optionsDownload as PowerPoint slide