Dinuclear platinum complexes containing planar aromatic ligands to enhance stacking interactions with proteins.

In an approach to design drugs with higher affinity for π-π stacking and electrostatic interactions with targeted biomolecules, complexes of the type [{cis-Pt(A)2 (L)}2 -µ-{trans-1,4-dach}](NO3 )4 ((A)2 =(NH3 )2 or ethylenediamine (en), L=quinoline (quin) or benzothiazole (bztz), dach=trans-1,4-diaminocyclohexane) were synthesized. The quinoline complex, [{cis-Pt(en)(quin)}2 -µ-(dach)](NO3 )4 (9) was synthesized from the precursor K[PtCl3 (quin)] (1), while the benzothiazole complexes, [{cis-Pt(A)2 (bztz)}2 -µ-(dach)](NO3 )4 ((A)2 =(NH3 )2 (10) and (A)2 =en (11)) were synthesized from the precursors cis-[Pt(A)2 Cl(bztz)] ((A)2 =(NH3 )2 (7) and (A)2 =en (8)). Their interactions with N-acetyltryptophan and a model pentapeptide (N-Ac-WLDSW-OH), modeled on the pentapeptide recognition sequence (FSDLW) of p53-mdm2 interaction, were examined by fluorescence spectroscopy. The dinuclear complexes were found to be significantly stronger at quenching the fluorescence of tryptophan than their mononuclear Pt-based analogues indicating stronger binding. Molecular modeling suggests a "sandwich" mode of binding, and the flexibility of the dinuclear motif can allow the design of more selective and stronger-binding complexes. Based on these results a further prototype, [{Pt(en)(9-EtGua)}2 µ-H2 N(CH2 )6 NH2 ](4+) , incorporating the purine 9-ethylguanine (9-EtG) as a stacking moiety, was prepared which showed good cytotoxicity in A2780 and OsACL tumor cell lines.

Binding of CO and NH3 at a five-coordinate Ru(II) centre in the solid state and in solution.

The known five-coordinate, square-pyramidal, green trans-RuCl2(P-N)(PR3) complexes (P-N = o-diphenylphosphino-N,N'-dimethylaniline; R = Ph (1a), p-tolyl), in the solid state at ambient conditions, or in CDCl3 solution at low temperatures, coordinate CO (at 1 atm) to form beige-coloured trans-monocarbonyl derivatives. In the solution reactions at room temperature, the PR3 ligand dissociates and the yellow dicarbonyl complex RuCl2(CO)2(P-N) is formed as a mixture of trans,cis- and cis,cis-isomers. With use of (13)CO, the carbonyls complexes are characterized by variable temperature NMR and IR data, and (for the monocarbonyls) elemental analyses. Similarly, 1a and the dibromo analogue (1b) in the solid state bind NH3 to form the beige trans-monoammine species RuX2(P-N)(PPh3)(NH3), trans-4a (X = Cl) and trans-4b (X = Br), with cis P-atoms. The solution NH3 reactions, however, generate a species, speculatively thought to be the unusual, tight ion-pair, bisammine species [RuX(P-N)(PPh3)(NH3)2···X], 5a (X = Cl) and 5b (X = Br), in which a halide is considered strongly H-bonded to the cis-ammine ligands, although an alternative RuX(P-N)(PPh3)(NH3)2 formulation with a monodentate P-N ligand cannot be ruled out; dissolution in CDCl3 of isolated 5a and 5b, which are characterized by NMR, elemental analysis, and conductivity data, results in a partial, reversible loss of NH3 to form some cis- and trans-4a or -4b, respectively. Treatment of 5a with one mole equivalent of NH4PF6 in acetone solution removes the H-bonded chloride to give [RuCl(P-N)(PPh3)(NH3)2]PF6 (6), and this is converted by thermal loss of NH3 to generate the extremely air-sensitive, five-coordinate, ionic species [RuCl(P-N)(PPh3)(NH3)]PF6 (7). NMR evidence is presented for formation of the tris(ammine) species [Ru(P-N)(PPh3)(NH3)3](PF6)2 (8) via treatment of trans-RuCl2(P-N)(PPh3) with an atmosphere of NH3 in the presence of 2 mole equivalents of NH4PF6.

Comparative properties of coordinated H2 and H2S at a ruthenium(II) centre.

Thermodynamic data for the reversible formation of cis-RuCl2(P-N)(PPh3)(η(2)-H2) () from trans-RuCl2(P-N)(PPh3) in C6D6 are determined by variable temperature (31)P{(1)H} and (1)H NMR spectroscopy; P-N = o-diphenylphosphino-N,N'-dimethylaniline. Values of ΔH° = -26 ± 4 kJ mol(-1), ΔS° = -40 ± 15 J mol(-1) K(-1), and ΔG° (at 25 °C) = -13.8 ± 0.2 kJ mol(-1) are compared with recently reported data for the corresponding H2S adduct (4a), where the exothermicity is greater by ~20 kJ mol(-1), but this is counteracted by a more unfavourable entropy change, and overall the K and ΔG° values at 25 °C are close. For loss of H2 from 2a in the solid state, whose X-ray structure is presented, ΔH° is 50 ± 3 kJ mol(-1) as measured by Differential Scanning Calorimetry. The pKa values of the coordinated H2 (~11) and H2S (~14) are estimated by reactions of 2a and 4a with proton sponge (1,8-bis(dimethylamino)naphthalene) in CD2Cl2 at 20 °C; the mono-hydrido and -mercapto products are identified in situ. A corresponding H2O adduct is not deprotonated under the same conditions. Related dihydrido, mercapto and hydroxy species are formed by in situ reactions of 1a with NaH, NaSH, and NaOH, respectively.

Reversible binding of water, methanol, and ethanol to a five-coordinate ruthenium(II) complex.

The known green, five-coordinate, square-pyramidal trans-RuCl(2)(P-N)(PPh(3)) complex reversibly binds water, MeOH and EtOH in the vacant coordination site in the solid state and in CH(2)Cl(2) solution to give pink adducts (P-N = o-diphenylphosphino-N,N'-dimethylaniline). The adducts are well characterized, including X-ray analysis of the aqua complex, trans-RuCl(2)(P-N)(PPh(3))(H(2)O), which crystallizes in two different benzene-solvated forms. Comparison of the structural data with those determined previously for the binding of H(2)S, thiols, and H(2), which form cis-RuX(2)(P-N)(PPh(3))L products (X = Cl, Br; L = a S-ligand or H(2)) reveals the trans-influence trend P > H(2)S ~ thiols > H(2) > Cl ~ Br > H(2)O. Thermodynamic data for the binding of water were estimated in solution by UV-Vis spectroscopy, and ΔH(o) data for the aqua and alcohol adducts in the solid state were obtained by differential scanning calorimetry. Inclusion of published data for the S-ligand adducts reveals the thermal stability trend of the solid complexes as MeSH > MeOH > H(2)S > H(2)O > EtSH > EtOH.

Ruthenium(II) thiol and H2S complexes: synthesis, characterization, and thermodynamic properties.

The known, green, five-coordinate species trans-RuCl(2)(P-N)(PPh(3)) react with R'SH thiols to give yellow cis-RuCl(2)(P-N)(PPh(3))(R'SH) products (P-N = o-diphenylphosphino-N,N'-dimethylaniline; R' = alkyl). The MeSH and EtSH compounds are structurally characterized, with the former being the first reported for a transition metal-MeSH complex, while the thiol complexes with R' = (n)Pr, (i)Pr, (n)Pn (pentyl), (n)Hx (hexyl), and Bn (benzyl) are synthesized in situ. Other trans-RuX(2)(P-N)(PR(3)) complexes (X = Br, I; R = Ph, p-tolyl) are synthesized, and their H(2)S adducts, of a type reported earlier by our group, are also prepared. Thermodynamic data are presented for the reversible formation of the MeSH and EtSH complexes and the H(2)S analogues. The Ru(II)Cl(2)(P-N)(PPh(3)) complex in solution decomposes under O(2) to form [Ru(III)Cl(P-N)](2)(µ-O)(µ-Cl)(2).

trans-Platinum planar amine compounds with [N2O2] ligand donor sets: effects of carboxylate leaving groups and steric hindrance on chemical and biological properties.

Replacement of NH3 by a planar amine L to give trans-[PtCl2(L)(L')] (L = NH3, L'= pyridine or substituted pyridine, quinoline, isoquinoline, thiazole; L = L'= pyridine, thiazole), greatly enhances the cytotoxicity of the transplatinum geometry. The "parent" compound trans-[PtCl2(NH3)2] is therapeutically inactive. Modification of the ligands to an [N2O2] donor set, where O represents an acetate leaving group, enhances the aqueous solubility while retaining the cytotoxicity of the parent chloride compounds. The effect of two mutual trans leaving groups with weak trans influence is to impart remarkable chemical stability on the structure. This strategy is analogous to the use of the inert dicarboxylate leaving groups in the clinical compounds carboplatin and oxaliplatin. In this paper, systematic modification of the steric effects of carrier pyridine groups and, especially, carboxylate leaving groups in trans-[Pt(O2CR)2(NH3)(pyr)] is shown to modulate aqueous solubility and hydrolysis to the activated aqua species. The results presented here demonstrate the utility of the "carboxylate strategy" in "fine-tuning" the chemical and pharmacokinetic properties in the design of clinically relevant transplatinum complexes.

Enhancement of aqueous solubility and stability employing a trans acetate axis in trans planar amine platinum compounds while maintaining the biological profile.

A general approach to solubilization and possible in vivo activation of the transplatinum geometry is presented. The synthesis and characterization of new water-soluble cytotoxic transplatinum compounds are described. Use of acetate ligands (and carboxylate ligands in general) in trans-[Pt(OAc)(2)(L)(L')] results in significantly enhanced aqueous solubility and chemical stability in comparison to the parent dichlorides. The new compounds are the first cytotoxic transplatinum compounds containing an N(2)O(2) donor set, similar to carboplatin and oxaliplatin.