Trevor G. Appleton

DONOR ATOM PREFERENCES IN COMPLEXES OF PLATINUM AND PALLADIUM WITH AMINO ACIDS AND RELATED MOLECULES

Amino acids present metal ions with a choice of potential donor atoms. The preferences for a particular donor atom for palladium(II) depends primarily on relative thermodynamic stabilities of the complexes formed, but for platinum thermodynamically less preferred complexes may be kinetically preferred, leading often to spontaneous conversion of a metastable complex into a thermodynamically preferred linkage isomer. Sizes of potential chelate rings often play a crucial role in determining donor atom preferences. On a more subtle level, when geometric isomers are possible with the same set of donor atoms bound to the metal, there may frequently be thermodynamic or kinetic preferences for a particular isomer depending on trans influences and trans effects of other ligands. These preferences are most marked when the trans influences of some of these ligands are very high, as in methylplatinum(IV) complexes. The review focuses on results obtained in the authors laboratory, and on related work of other groups.

Reactions of cisplatin hydrolytes with methionine, cysteine, and plasma ultrafiltrate studied by a combination of HPLC and NMR techniques.

The reactions of cis-[PtCl(NH3)2(H2O)]+ with L-methionine have been studied by 1D 195Pt and 15N NMR, and by 2D[1H, 15N] NMR. When the platinum complex is in excess, the initial product, cis-[PtCl(NH3)2(Hmet-S)]+ undergoes slow ring closure to [Pt(NH3)2(Hmet-N,S)]2+. Slow ammine loss then occurs to give the isomer of [PtCl(NH3)(Hmet-N,S)]+ with chloride trans to sulfur. When methionine is in excess, a reaction sequence is proposed in which trans-[PtCl(NH3)(Hmet-S)2]+ isomerises to the cis-isomer, with subsequent ring closure reactions leading to cis-[Pt(Hmet-N,S)2]2+. Near pH 7, methionine is unreactive toward cis-[PtCl(OH)(NH3)2]. By contrast, L-cysteine reacts readily with cis-[PtCl(OH)(NH3)2] at pH 7, but there were many reaction products, including bridged species. Cis-[PtCl(OH)(NH3)2] reacts with reduced thiols in ultrafiltered plasma but these are oxidized if the plasma is not fresh or appropriately stored. With very low concentrations of the platinum complexes (35.5 microM), HPLC experiments (UV detection at 305 nm) indicate that the thiolate (probably cysteine) reactions become simpler as bridging becomes less important.

Metal clips that induce unstructured pentapeptides to be α-helical in water

Short peptides corresponding to protein helices do not form thermodynamically stable helical structures in water, a solvent that strongly competes for hydrogen-bonding amides of the peptide backbone. Metalloproteins often feature metal ions coordinated to amino acids within hydrogen-bonded helical regions of protein structure, so there is a prospect of metals stabilizing or inducing helical structures in short peptides. However, this has only previously been observed in nonaqueous solvents or under strongly helix-favoring conditions in water. Here cis-[Ru(NH(3))(4)(solvent)(2)](2+) and [Pd(en)(solvent)(2)](2+) are compared in water for their capacity as metal clips to induce alpha-helicity in completely unstructured peptides as short as five residues, Ac-HARAH-NH(2) and Ac-MARAM-NH(2). More alpha-helicity was observed for the latter pentapeptide and, when chelated to ruthenium, it showed the greatest alpha-helicity yet reported for a short metallopeptide in water (approximately 80%). Helicity was clearly induced rather than stabilized, and the two methionines were 10(13)-fold more effective than two histidines in stabilizing the lower oxidation state Ru(II) over Ru(III). The study identifies key factors that influence stability of an alpha-helical turn in water, suggests metal ions as tools for peptide folding, and raises an intriguing possibility of transiently coordinated metal ions playing important roles in native folding of polypeptides in water.

The Chemistry of Cisplatin in Aqueous Solution

The antitumor properties of platinum-containing drugs are attributable in large measure to the kinetics of their ligand displacement reactions. As is discussed at length in other contributions to this volume, their primary target is believed to be nitrogen donor atoms in the nucleobases of DNA. The bonds formed between the metal ion and these atoms must be sufficiently long-lived to interfere with the process of cell division, or to trigger the intracellular mechanisms that recognize irreparable damage to a cell. Bonds between the nucleobase nitrogen atoms and platinum(II) clearly fulfil this requirement. Metal ions that form labile bonds with the nucleobase nitrogen atoms cannot act in a similar way and do not give active compounds (1).

Displacement of norbornadiene (NBD) from PtMe2(NBD) BY N-donors, dimethylsulfoxide, and cyanide, and reactions of cis-PtMe2L2 iodomethane

Norbornadiene (NBD) was displaced from PtMe2(NBD) by a range of ligands L to form cis-PtMe2L2 (L = pyridine (py), NH3, dimethylsulfoxide (DMSO); L2 = 2,2′-bipyridyl (bipy), ethylenediamine (en), N,N,N′,N′-tetramethylethylenediamine (tmen) - but not L = acetonitrile, benzonitrile, N, N-dimethylformamide, or water). These reactions occur more readily than the corresponding displacements of 1,5-cyclooctadiene (COD) from PtMe2(COD). Cyanide readily displaced the diolefin from either PtMe2(NBD) or PtMe2(COD) to form cis-PtMe2CN)2 2-, but no reaction occurred with bromide, chloride, and acetylacetonate. Thiocyanate and iodide slowly reacted, but no methyl-platinum product was obtained. The reaction of each of the compounds PtMe2L2 with MeI was studied in benzene. PtMe2(NBD) gave [PtMe3I]4. With L = py, 1 2(bipy), or 1 2(tmen), PtMe3IL2 was obtained rapidly at room temperature. For the sparingly soluble compounds with L = NH3 or 1 2(en), heating was necessary for reaction. The product from PtMe2(en) was PtMe3I(en), but cis-PtMe2(NH3)2 gave a mixture of [PtMe3(NH3)(μ-I)]2 and fac-[PtMe3(NH3)3]I. With L = DMSO, heating initially gave PtMe3I(DMSO)2, which slowly lost DMSO to form [PtMe3I]4. For L = py, 1 2(tmen), treatment with acid readily removed L from PtMe3IL2.

Amino acid complexes of platinum(IV). I. Trimethylplatinum(IV) complexes with glycinate, iminodiacetate, n-methyliminodiacetate, nitrilotriacetate, and ethylenediamine-tetraacetate

Reaction between PtMe3(H2O)+ 3 and sodium glycinate gives a series of glycinato complexes, PtMe3(gly)(H2O), [PtMe3(gly)]2, PtMe3(gly)- 2 and PtMe3(gly)2- 3. Variable-temperature PMR has been used to study rapid intramolecular exchange reactions in PtMe3(gly)(D2O) and PtMe3(gly)- 2 in D2O.Iminodiacetate, N-Methyliminodiacetate, and nitrilotriacetate act as tridentate ligands, coordinating through the N- and two O-atoms. The most stable EDTA complex is (Me3Pt)2(EDTA)2-, in which each Pt-atom is coordinated to one N and two O-atoms of bridging EDTA.

Displacement of norbornadiene (NBD) from Pt(CF3)2(NBD) by weak donor ligands L, and reactions of cis-Pt(CF3)2L2 with water and acids

The NBD ligand in Pt(CF3)2(NBD) has been replaced under mild conditions by a number of neutral S-, N-, and O-donor ligands to form cis-Pt(CF3)2L2 complexes (L2 = N,N,N′,N′-tetramethylethylenediamine (tmen), bipyridine (bipy), ethylenediamine (en); L = pyridine (py), NH3, dimethylsulfoxide (DMSO), CH3CN, C6H5CN, N,N-dimethylformamide (DMF)). Reaction with DMSO produces predominantly the isomer cis-Pt(CF3)2(DMSO-S)(DMSO-O), with cis-Pt(CF3)2(DMSO-S)2 a minor component, as a result of steric constraints. Water or methanol attacks the CF3 groups, producing fluoride ion. The fluorine atoms of cis-Pt(CF3)2L2 (L2 = bipy, tmen; L = py) are susceptible to electrophilic attack by H+. Reaction with aqueous HCl or HClO4 converts one CF3 group into a coordinated CO group. With HCl, simultaneous protonation and displacement of the N-donor ligands occurred, yielding cis-Pt(CF3)(CO)Cl2 -. With HClO4, the complexes cis-Pt(CF3)(CO)L2 + are initially generated, with subsequent displacement of the tmen and py (but not bipy) ligands to form cis-Pt(CF3)(CO)(OH2)2 +. The remaining CF3 group is not attacked by H+. Reaction of Pt(CF3)2(NBD) with halide ions in acetone initially produced the binuclear complexes [(CF3)2Pt(μ-X)2Pt(CF3)2]2- (X = I, Cl) containing bridging halide. With larger amounts of halide ion the expected cis-Pt(CF3)2X2 2- complexes were not obtained, and instead cis-Pt(CF3)(CO)X2 - and fluoride ion were formed. When the complexes [(CF3)2Pt(μ-X)2Pt(CF3)2]2- were kept in the presence of NBD, cis-Pt(CF3)(CO)X2 - and Pt(CF3)2(NBD) were formed. When X = I, these two complexes then reacted together to yield cis-Pt(CF3)2I(CO)- and Pt(CF3)I(NBD).

Oxidative addition to bis(trifluoromethyl)platinum(II) complexes with N-donor ligands

Abstract Reaction of cis -Pt(CF 3 ) 2 L 2 (L = pyridine (py); L 2 = 2,2′-bipyridyl (bipy), N , N , N′ , N′ -tetramethylethylenediamine (tmen)) with halogens, X 2 , in dry CH 2 Cl 2 gave initially the isomer of Pt(CF 3 ) 2 X 2 L 2 in which the halogen has added trans across the original square plane. The initial products, Pt(CF 3 ) 2 X 2 (bipy) (X  Cl, Br), slowly isomerize under light to the isomer with the two X-ligands cis , apparently to relieve steric pressure. Cis -Pt(CF 3 ) 2 L 2 with L  py, 1/2(bipy) (but not that with L = 1/2(tmen)) reacted slowly with alkyl halides, RX (MeI, PhCH 2 Br, CF 3 I), in acetone under light to give Pt(CF 3 ) 2 RXL 2 . Only the isomer of Pt(CF 3 ) 2 MeI(bipy) with methyl trans to iodide was observed, but for the pyridine analogue two isomeric products were in equilibrium. Pt(CF 3 ) 2 MeI(py) 2 also slowly lost MeI in acetone; addition of NaI or py to the solution accelerated the reaction. Pt(CF 3 ) 2 (bipy) with PhCH 2 Br gave only the isomer of Pt(CF 3 ) 2 -(CH 2 Ph)Br(bipy) in which benzyl bromide had added trans across the square plane, but with Pt(CF 2 ) 2 py 2 only the isomer of Pt(CF 3 ) 2 -(CH 2 Ph)Brpy 2 with benzyl cis to bromide was observed. Subsequent reaction in the presence of excess PhCH 2 Br gave, among other products, [PhCH 2 NC 5 H 5 ]-[Pt(CF 3 ) 2 Brpy]. Fac -Pt(CH 3 ) 3 IL 2 was the only significant product from the reactions involving CF 3 I. Aspects of 19 F, 13 C and 195 Pt NMR spectra, and IR spectra, are discussed.

NMR spectra of platinum(III) complexes with sulfato- and phosphato-bridges

195Pt NMR data are reported for Pt(III) dimeric anions Pt2(Z)4XYn-, where Z = SO4 or PO4H, and X, Y are anionic or neutral ligands. 13CN-, 15NO2- , and 15NH3 were included among these, and couplings between 195Pt and 13C or 15N allowed unambiguous assignments to be made in the 195Pt spectra of their compounds. Substitution of one water molecule in Pt2(Z)4(H2O)22- frequently causes large shifts of the Pt atom not directly involved in the substitution. Where X and Y are different, 1J(PtPt) has been measured directly from the 195Pt spectrum, and this coupling constant has also been obtained for Pt2(Z)2(13CN)24- by analysis of the spectrum. For corresponding compounds, 1J(PtPt) is always larger in magnitude for Z = PO4H than for Z = SO4, although v(PtPt) from Raman spectra and PtPt bond lengths do not indicate a stronger PtPt bond. In a series Pt2(Z)4XYn- where X is kept constant (e.g., X = H2O, CN-), J(PtPt) decreases with increasing trans influence of Y. For Pt2(SO4)4(13CN)Yn- , 1J(PtC) and 2J(PtPtC), both decrease as the trans influence of Y increases, and δC becomes more positive. These and other observations are interpreted in terms of rehybridization of both Pt-atoms when one of them is substituted.

Displacement of norbornadiene (NBD) from PtR2(NBD) (R = Me, CF3) by weak ligands

Norbornadiene (NBD) is more easily displaced from PtMe2 (NBD) by other ligands than is cyclooctadiene (COD) from PtMe2 (COD). cis-PtMe2L2 (L = py, 1 2tmen, 1 2en, NH3, DMSO) have been prepared in this way. cis-PtMe2py2 is very reactive toward oxidative addition. Pyridine can usually be removed from the platinum(IV) products using acid. NBD is even more readily displaced from Pt(CF3)2 (NBD), giving cis-Pt(CF3)2L2 (L = py, 1 2tmen, 1 2en, NH3, DMSO, NCR, DMF, CN-, I-, acac-). cis-Pt(CF3)2py2 with CF2I gives fac-Pt(CF3)3py2I.