Structural and anticancer properties of hydrogen bonded diphenyl phosphate adducts of Pt(IV) complexes: the importance of pKa matching.
Co-crystallisation of diphenyl phosphate (Hdpp) with anticancer active Pt(IV) complexes of the type cis,trans,cis-[PtCl(2)(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-[PtCl(2)(en)(OH(2))(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: [PtCl(2)(OH)(NH(3))(2)(OH(2))]dpp·3H(2)O (2), trans-[Pt(mal)(OH)(OH(2))(S,S-chxn)]dpp·3H(2)O (3), and trans-[Pt(ox)(OH)(OH(2))(S,S-chxn)]dpp·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)(OH(2))(S,S-chxn)]dpp·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.
School of Chemistry, The University of Sydney, NSW, 2006, Australia.
Timothy W
TW
Failes
Andrew R
AR
Battle
Catherine
C
Chen
Carleen
C
Cullinane
Ross
R
Woods
Robyn
R
Elliott
Glen B
GB
Deacon
Trevor W
TW
Hambley
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D063065:Organophosphonates; D010984:Platinum; C507805:diphenyl phosphite