title: Systematic differences in electrochemical reduction of the structurally characterized anti-cancer platinum(IV) complexes [Pt{((p-HC6F4)NCH2)2}-(pyridine)2Cl2], [Pt{((p-HC6F4)NCH2)2}(pyridine)2(OH)2], and [Pt{((p-HC6F4)NCH2)2}(pyridine)2(OH)Cl].
abstract: The putative platinum(IV) anticancer drugs, [Pt{((R)NCH(2))(2)}(py)(2)XY] (X,Y=Cl, R=p-HC(6)F(4) (1a), C(6)F(5) (1b); X,Y=OH, R=p-HC(6)F(4) (2); X=Cl, Y=OH, R=p-HC(6)F(4) (3), py = pyridine) have been prepared by oxidation of the Pt(II) anticancer drugs [Pt{((R)NCH(2))(2)}(py)(2)] (R=p-HC(6)F(4) (4a) or C(6)F(5) (4b)) with PhICl(2) (1a,b), H(2)O(2) (2) and PhICl(2)/Bu(4)NOH (3). NMR spectroscopy and the X-ray crystal structures of 1b, 2 and 3 show that they have octahedral stereochemistry with the X,Y ligands in the trans-position. The net two electron electrochemical reduction of 1a, 2 and 3 has been studied by voltammetric, spectroelectrochemical and bulk electrolysis techniques in acetonitrile. NMR and other data reveal that reduction of 1a gives pure 4a via the elimination of both axial chloride ligands. In the case of 2, one end of the diamide ligand is protonated and the resulting -NH(p-HC(6)F(4)) group dissociated giving a [Pt{N(p-HC(6)F(4))CH(2)CH(2)NH(p-HC(6)F(4))}] arrangement, one pyridine ligand is lost and a hydroxide ion retained in the coordination sphere. Intriguingly, in the case of reduction of 3, a 50% mixture of the reduction products of pure 1a and 2 is formed. The relative ease of reduction is 1>3>2. Testing of 1a, 2 and 3 against L1210 and L1210(DDP) (DDP = cis-diamine-dichloroplatinum(II)) mouse leukaemia cells shows all to be cytotoxic with IC(50) values of 1.0-3.5 μM. 2 and 3 are active in vivo against AHDJ/PC6 tumor line when delivered in peanut oil despite being hard to reduce electrochemically, and notably are more active than 4a delivered in this medium whilst comparable with 4a delivered in saline/Tween.
authors.affiliation: School of Chemistry, Monash University, Clayton, Vic. 3800, Australia.
authors.forename: Si-Xuan
authors.initials: SX
authors.lastname: Guo
authors.forename: Dayna N
authors.initials: DN
authors.lastname: Mason
authors.forename: Susan A
authors.initials: SA
authors.lastname: Turland
authors.forename: Eric T
authors.initials: ET
authors.lastname: Lawrenz
authors.forename: Lance C
authors.initials: LC
authors.lastname: Kelly
authors.forename: Gary D
authors.initials: GD
authors.lastname: Fallon
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Gatehouse
authors.forename: Alan M
authors.initials: AM
authors.lastname: Bond
authors.forename: Glen B
authors.initials: GB
authors.lastname: Deacon
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Battle
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Hambley
authors.forename: Silvina
authors.initials: S
authors.lastname: Rainone
authors.forename: Lorraine K
authors.initials: LK
authors.lastname: Webster
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D007938:Leukemia / Q000188:drug therapy*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D011725:Pyridines; D010984:Platinum