Structural and anticancer properties of hydrogen bonded diphenyl phosphate adducts of Pt(IV) complexes: the importance of pK(a) matching

Timothy W Failes, Andrew R Battle, Catherine Chen, Carleen M Cullinane, Ross Woods, Robyn Elliott, Glen Berenger Deacon, Trevor William Hambley

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Abstract

Co-crystallisation of diphenyl phosphate (Hdpp) with anticancer active Pt(IV) complexes of the type cis, trans,cis-[PtCl2(OH)(2)(am(m)ine)(2)] has produced a new type of supramolecular adduct with short hydrogen bonds from the Hdpp molecules to the hydroxide ligands in all cases. X-ray crystallographic analysis showed within the adduct cisoons-[PtCl2(en)(OH2)(2)](dPP)(2) (1) a hydrogen bond length of 2.341(6) angstrom; the shortest O center dot center dot center dot O distance reported in the literature. Similar, though longer hydrogen bonds were observed in three other complexes: [PtCl2(OH)(NH3)(2)(OH2)]dpp center dot 3H(2)O (2), trans-[Pt(mal)(OH)(OH2)(S,S-chxn)]dpp center dot 3H(2)O (3), and trans-[Pt(ox)(OH)(OH2)(S,S-chxn)]dpp center dot 2H(2)O (4). Co-crystallisation with Hdpp leads to higher aqueous solubility than the parent complexes indicating the potential of the adducts for use as active pharmaceutical ingredients. Anticancer testing of [Pt(mal)(OH)(OH2)(S,S-chxn)]dpp center dot 3H(2)O (3) showed in vitro cytotoxicity is low, as expected for Pt(IV) prodrugs, yet substantial tumour growth inhibition was observed in an in vivo ADJ/PC6 tumour model, with activity retained at maximum tolerated dose (MTD)/2 and MTD/4.
Original languageEnglish
Pages (from-to)220 - 225
Number of pages6
JournalJournal of Inorganic Biochemistry
Volume115
DOIs
Publication statusPublished - 2012

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