title: A novel platinum complex of the histone deacetylase inhibitor belinostat: rational design, development and in vitro cytotoxicity.
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.
authors.affiliation: Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland.
authors.forename: James P
authors.initials: JP
authors.lastname: Parker
authors.forename: Hassan
authors.initials: H
authors.lastname: Nimir
authors.forename: Darren M
authors.initials: DM
authors.lastname: Griffith
authors.forename: Brian
authors.initials: B
authors.lastname: Duff
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Chubb
authors.forename: Marian P
authors.initials: MP
authors.lastname: Brennan
authors.forename: Maria P
authors.initials: MP
authors.lastname: Morgan
authors.forename: Denise A
authors.initials: DA
authors.lastname: Egan
authors.forename: Celine J
authors.initials: CJ
authors.lastname: Marmion
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017671:Platinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D003603:Cytotoxins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D017671:Platinum Compounds; D013449:Sulfonamides; C487081:belinostat