Structural and anticancer properties of hydrogen bonded diphenyl phosphate adducts of Pt(IV) complexes: The importance of pKa matching

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 cis,trans-[PtCl2(en)(OH2)2](dpp)2 (1) a hydrogen bond length of 2.341(6) Å; the shortest O ··· O distance reported in the literature. Similar, though longer hydrogen bonds were observed in three other complexes: [PtCl2(OH)(NH3)2(OH2)]dpp·3H2O (2), trans-[Pt(mal)(OH)(OH2)(S,S-chxn)]dpp·3H2O (3), and trans-[Pt(ox)(OH)(OH2)(S,S-chxn)]dpp·2H2O (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·3H2O (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.