Disulfide bond cleavage induced by a platinum(II) methionine complex

The cleavage of a disulfide bond and the redox equilibrium of thiol/disulfide are strongly related to the levels of glutathione (GSH)/oxidized glutathione (GSSG) or mixed disulfides in vivo. In this work, the cleavage of a disulfide bond in GSSG induced by a platinum(II) complex [Pt(Met)Cl2] (where Met = methionine) was studied and the cleavage fragments or their platinated adducts were identified by means of electrospray mass spectrometry, high-performance liquid chromatography, and ultraviolet techniques. The second-order rate constant for the reaction between [Pt(Met)Cl2] and GSSG was determined to be 0.4 M(-1) s(-1) at 310 K and pH 7.4, which is 100- and 12-fold faster than those of cisplatin and its monoaqua species, respectively. Different complexes were formed in the reaction of [Pt(Met)Cl2] with GSSG, mainly mono- and dinuclear platinum complexes with the cleavage fragments of GSSG. This study demonstrated that [Pt(Met)Cl2] can promote the cleavage of disulfide bonds. The mechanistic insight obtained from this study may provide a deeper understanding on the potential involvement of platinum complexes in the intracellular GSH/GSSG systems.     

Alkylthio bridged 44 cve triangular platinum clusters: synthesis, oxidation, degradation, ligand substitution, and quantum chemical calculations

Acetylplatinum(II) complexes trans-[Pt(COMe)Cl(L)2] (L = PPh3, 2a; P(4-FC6H4)3, 2b) were found to react with dialkyldisulfides R2S2 (R = Me, Et, Pr, Bu; Pr = n-propyl, Bu = n-butyl), yielding trinuclear 44 cve (cluster valence electrons) platinum clusters [(PtL)3(mu-SR)3]Cl (4). The analogous reaction of 2a-b with Ph2S2 gave SPh bridged dinuclear complexes trans-[{PtCl(L)}2(mu-SPh)2] (5), whereas the addition of Bn2S2 (Bn = benzyl) to 2a ended up in the formation of [{Pt(PPh3)}3(mu3-S)(mu-SBn)3]Cl (6). Theoretical studies based on the AIM theory revealed that type 4 complexes must be regarded as triangular platinum clusters with Pt-Pt bonds whereas complex 6 must be treated as a sulfur capped 48 ve (valence electrons) trinuclear platinum(II) complex without Pt-Pt bonding interactions. Phosphine ligands with a lower donor capability in clusters 4 proved to be subject to substitution by stronger donating monodentate phosphine ligands (L' = PMePh2, PMe2Ph, PBu3) yielding clusters [(PtL')3(mu-SR)3]Cl (9). In case of the reaction of clusters 4 and 9 with PPh2CH2PPh2 (dppm), a fragmentation reaction occurred, and the complexes [(PtL)2(mu-SMe)(mu-dppm)]Cl (12) and [Pt(mu-SMe)2(dppm)] (13) were isolated. Furthermore, oxidation reactions of cluster [{Pt(PPh3)}3(mu-SMe)3]Cl (4a) using halogens (Br2, I2) gave dimeric platinum(II) complexes cis-[{PtX(PPh3)}2(mu-SMe)2] (14, X = Br, I) whereas oxidation reactions using sulfur and selenium afforded chalcogen capped trinuclear 48 ve complexes [{Pt(PPh3)}3(mu3-E)(mu-SMe)3] (15, E = S, Se). All compounds were fully characterized by means of NMR and IR spectroscopy, microanalyses, and ESI mass spectrometry. Furthermore, X-ray diffraction analyses were performed for the triangular cluster 4a, the trinuclear complex 6, as well as for the dinuclear complexes trans-[{Pt(AsPh3)}2(mu-SPh)2] (5c), [{Pt(PPh3)}2(mu-SMe)(mu-dppm)]Cl (12a), and [{{PtBr(PPh3)}2(mu-SMe)2] (14a).     

The neglected Pt-N(sulfonamido) bond in Pt chemistry. New fluorophore-containing Pt(II) complexes useful for assessing Pt(II) interactions with biomolecules

Treatment of cis-Pt(Me2SO)2Cl2 with DNSH-tren afforded [Pt(DNSH-tren)Cl]Cl and with DNSH-dienH, under increasingly more basic conditions, led to Pt(DNSH-dienH)Cl(2), Pt(DNSH-dien)Cl, and Pt(DNS-dien). (DNSH = 5-(dimethylamino)naphthalene-1-sulfonyl, linked via a sulfonamide group to tris(2-aminoethyl)amine (DNSH-tren) and diethylenetriamine (DNSH-dienH); the H's in DNSH-dienH designate protons sometimes lost upon Pt binding, i.e., sulfonamide NH for the dienH moiety and H8 for the DNSH moiety). Respectively, the three neutral DNSH-dienH-derived complexes are difunctional, monofunctional, and nonfunctional and exhibit decreasing fluorescence in this order as the dansyl group distance to Pt decreases. 2D NMR data establish that Pt(DNS-dien) has a Pt-C8 bond and a Pt-N(sulfonamido) bond. Pt(DNSH-dien)Cl and [Pt(DNSH-tren)Cl]Cl bind to N7 of 6-oxopurines (e.g., 5'-GMP, 3'-IMP, and 9-ethylguanine) and sulfur of methionine (met). Competition and challenge reactions for Pt(II) with met and 5'-GMP typically reveal that met binding is favored kinetically but that 5'-GMP binding is favored thermodynamically. This common type of behavior was found for [Pt(DNSH-tren)Cl]Cl. In contrast, Pt(DNSH-dien)Cl had reduced kinetic selectivity for met. This unusual behavior undoubtedly arises as a consequence of the bound Pt-N(sulfonamido) group, which donates strongly to Pt (as indicated by relatively upfield dien NH signals) and which places the bulky DNSH moiety close to the monofunctional reaction site. The decrease in the relatively upfield shifts of the DNSH group signals indicates that this group stacks with the purine. This stacking could explain the unprecedented, relatively low reactivity of a Pt complex bearing a dien-type ligand toward met vs 5'-GMP.     

Specificity in template syntheses of hexaaza-macrobicyclic cages: [Pt(Me5-tricosatrieneN6)]4+ and [Pt(Me5-tricosaneN6)]4+

The racemic C3 hexadentate cage complex, [Pt(Me5-tricosatrieneN6)]Cl4 (1,5,9,13,20-pentamethyl-3,7,11,15,18,22-hexaazabicyclo[7.7.7]tricosa- 3,14,18-triene)platinum(IV) tetrachloride), was synthesised stereospecifically and regiospecifically from a reaction of the bis-triamine template [Pt(tamc)2]Cl4 (bis[1,1,1-tris(aminomethyl)ethane]- platinum(IV) tetrachloride) with formaldehyde and then propanal, in acetonitrile under basic conditions. Largely, one racemic diastereoisomer was obtained in a surprisingly high yield (approximately 50%), even though the molecule has seven chiral centres. The origins of the stereoselective synthesis are addressed. The crystal structure of [Pt(Me5-tricosatrieneN6)]-(ZnCl4)1.5Cl.2H2O showed that all three imines were attached to one tame fragment with a chiral amine site ([symbol: see text] SSS, delta RRR) and a chiral methine carbon site ([symbol: see text] RRR, delta SSS) on each ligand strand. The PtN6(4+) moiety had a slightly distorted octahedral configuration with the two types of Pt-N bonds related to the imine and the amine donors, 2.050(7) and 2.072(6) A, respectively. Treatment with sodium borohydride (15 s, 20 degrees C) at pH approximately 12.5 reduced the imine groups, but not the Pt(IV) ion, producing a C3 saturated ligand complex [Pt(Me5-tricosaneN6)]Cl4 ((1,5,9,13,20- pentamethyl-3,7,11,15,18,22- hexaazabicyclo[7.7.7]tricosane)platinum(IV)tetrachloride). X-ray crystallographic analysis showed that the average Pt-N bond distance in the cation increased upon imine reduction to 2.10 (av) A. The cyclic voltammograms of the two cage complexes displayed irreversible two-electron reduction waves in aqueous media and a approximately 0.3 V shift to more positive potentials compared to that of the smaller cavity sar (3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane) analogue. After reduction, net dissociation of one strand of the cage was also evident, to give unstable square planar Pt(II) macrocyclic products.     

Thiolate bridging and metal exchange in adducts of a zinc finger model and Pt(II) complexes: biomimetic studies of protein/Pt/DNA interactions

To provide precedents for the possible interactions of platinum DNA adducts with zinc finger proteins, the complexes [Pt(dien)Cl]Cl (dien = diethylenetriamine) and [Pt(terpy)Cl]Cl (terpy = 2,2':6',2'-terpyridine) were exposed to the N,N'-bis(2-mercaptoethyl)-1,4-diazacycloheptanezinc(II) dimer, [Zn(bme-dach)]2, and the products defined by electrospray ionization mass spectrometry (ESI-MS), X-ray crystallography and (195)Pt NMR spectroscopy. The presence of a leaving chloride in both platinum(II) complexes facilitates electrophilic substitution involving sulfur-containing zinc finger synthetic models or, as in previous studies, zinc finger peptidic sequences. Monitored via ESI-MS, both reactants yielded evidence for Zn-(mu-SR)-Pt bridges followed by zinc ejection from the N2S2 coordination sphere and subsequent formation of a trimetallic Zn-(mu-SR)2-Pt-(mu-SR)2-Zn-bridged species. The isolation of Zn-(mu-SR)-Pt-bridged species [(Zn(bme-dach)Cl)(Pt(dien))]Cl is, to our knowledge, the first Zn-Pt bimetallic thiolate-bridged model demonstrating the interaction between Zn-bound thiolates and Pt(2+). In the case of the [Pt(terpy)Cl]Cl reaction with the [Zn(bme-dach)]2, ESI-MS analysis further suggests metal exchange by formation of [Zn(terpy)Cl](+), whereas the [Pt(dien)Cl]Cl reaction does not yield the corresponding [Zn(dien)Cl](+) ion. Direct synthesis of the Zn-Pt thiolate-bridged species and the Pt(N2S2) chelate, where Pt has displaced the Zn from the chelate core, permitted the isolation of X-ray-quality crystals to confirm the bridging and metal-exchanged structures. The ESI-MS, (195)Pt NMR spectroscopy, and molecular structures of the di- and trinuclear complexes will be discussed, as they provide insight into the metal-exchange mechanism.     

Platinum(IV) complexes with dipeptide. X-ray crystal structure, 195Pt NMR spectra, and their inhibitory glucose metabolism activity in Candida albicans

Three dipeptide complexes of the form K[Pt(IV)(dipep)Cl3] and two complexes of the form K[Pt(IV)(Hdipep)Cl4] were newly prepared and isolated. The platinum(IV) complexes containing the dipeptide were obtained directly by adding KI to H2[PtCl6] solution. The reaction using KI was rapidly completed and provided analytically pure yellow products in the form of K[Pt(dipeptide)Cl3] for H2digly, H2gly(alpha)-ala, H2alpha-alagly and H2di(alpha)-ala. The K[Pt(IV)(digly)Cl3] complex crystallizes in the monoclinic space group P2(1)/c with unit cell dimensions a = 10.540(3) A, b = 13.835(3) A, c = 8.123(3) A, beta = 97.01(2) degrees, Z = 4. The crystal data represented the first report of a Pt(IV) complex with a deprotonated peptide, and this complex has the rare iminol type diglycine(2-) coordinating to Pt(IV) with the bond lengths of the C2-N1 (amide) bond (1.285(13) A). The 195Pt NMR peaks of the K[Pt(IV)(dipep)Cl3] and the K[Pt(IV)(Hdipep)Cl4] complexes appeared at about 270 ppm and at about -130 ppm, respectively, and were predicted for a given set of ligand atoms. While the K[Pt(IV)(x-gly)Cl3] complexes, where x denotes the glycine or alpha-alanine moieties, were easily reduced to the corresponding platinum(II) complexes, the K[Pt(IV)(x-alpha-ala)Cl3] complexes were not reduced, but the Cl- ion was substituted for OH- ion in the reaction solution. The K[Pt(digly)Cl3] and K[Pt(gly-L-alpha-ala)Cl3] complexes inhibited the growth of Candida albicans, and the antifungal activities were 3- to 4-fold higher than those of cisplatin. The metabolism of glucose in C. albicans was strongly inhibited by K[Pt(digly)Cl3] and K[Pt(gly-L-alpha-ala)Cl3] but not by the antifungal agent fluconazole.     

Substitution behaviour of amine-bridged dinuclear Pt(II) complexes with bio-relevant nucleophiles

Complexes of the type [Pt2(N,N,N',N'-tetrakis(2-pyridylmethyl)diamine(HO)2]4+ and [Pt2(N,N,N',N'-tetrakis(2-pyridylmethyl)diamine(Cl)2]2+ were used to study their reactions with a series of bio-relevant nucleophiles, viz. thiourea, L-methionine and guanosine-5'-monophosphate (5'-GMP2-) as a function of nucleophile concentration and temperature. The reactions with the sulfur containing nucleophiles (thiourea and L-methionine) were followed under pseudo-first-order conditions by stopped-flow and UV-Vis spectrophotometry. The reaction with 5'-GMP2- was carried out under second order conditions and studied by NMR spectroscopy. The results indicate that the bridged dinuclear complexes remain intact after coordination of the studied nucleophiles for an extended period of time, which differs significantly from that reported for other multinuclear platinum complexes in the literature.     

Reactions of platinum(II) complexes with sulfur- and histidine-containing peptides: a model for selective platination of peptides and proteins

The reactions between two monofunctional platinum complexes [Pt(Me₄dien)Cl]⁺ (Me₄dien = 1,1,7,7-tetramethyl-diethylenetriamine) and [Pt(Et₄dien)Cl]⁺ (Et₄dien = 1,1,7,7-tetraethyldiethylenetriamine) and the peptides, N-acetylated L-methionyl-L-histidine (MeCO–Met–His) and glutathione (GSH), have been investigated by ¹H-n.m.r. spectroscopy and u.v.–vis. spectrophotometry. The reactions of the platinum(II) complexes with MeCO–Met–His were carried out at room temperature and at pH 3.0 and 7.0, whereas with GSH the reactions were studied only at pH 3.0. No binding of these two platinum complexes to the sulfur atom of methionine or to nitrogen atoms of histidine residue of MeCO–Met–His was observed during the first 24 h. When the reaction was followed further, after 24 h very slow binding of [Pt(Me₄dien)Cl]⁺ to the N3 nitrogen atom of imidazole was observed. Both platinum complexes react with the sulfur atom of the cysteine residue in GSH. Kinetic data show that GSH reacts twice as fast with [Pt(Me₄dien)Cl]⁺ than with [Pt(Et₄dien)Cl]⁺. Our findings indicate that sterically crowded platinum(II) complexes are only capable of reacting with the sulfhydryl group of the cysteine residue. This influences the design of new platinum(II) complexes for selective covalent modification of peptides and proteins.     

Conformer distribution in (cis-1,4-DACH)bis(guanosine-5'-phosphate)platinum(II) adducts: a reliable model for DNA adducts of antitumoral cisplatin

In [PtCl2(cis-1,4-DACH)] (DACH = diaminocyclohexane), the N-Pt-N bite angle (> or =97 degrees , as determined by X-ray diffraction analysis) is much larger than those found in other Pt complexes with bidentate diamines or in cisplatin (approximately 91 degrees ). Hence, the possibility exists that in (cis-1,4-DACH)PtG 2 adducts, rotation of the G's around the Pt-N7 bonds is slowed enough to allow observation of different conformers. In accord with this prevision, decreasing the temperature to 238 K enabled us to observe different conformers of (cis-1,4-DACH)Pt(5'-GMP) 2 (GMP = guanosine monophosphate). This observation is the first case in which such conformers for a platinum derivative with primary diamines and untethered guanines have been resolved and represents the closest model to clinically effective cisplatin obtained to date. We also found that the presence of the 1,4-DACH ligand increased the intensity of the circular dichroism signal stemming from the dominance of an HT conformer (DeltaHT in the adduct with 3'-GMPs and LambdaHT in the adduct with 5'-GMPs).     

Triphenyl phosphine adducts of platinum(IV) and palladium(II) dithiocarbamates complexes: a spectral and in vitro study

Triphenyl phosphine adducts of dithiocarbamate complexes of platinum(IV) and palladium(II) of the type [Pt(L)2PPh3Cl2] and [Pd(L)2PPh3] [L: morpholine dithiocarbamate (L1), aniline dithiocarbamate (L2) and N-(methyl, cyclohexyl) dithiocarbamate (L3)] were prepared and characterized by elemental analysis, electronic, IR, 1H NMR and 13C NMR spectral studies. Thermal studies of the complexes were carried out. In vitro antitumor activity has been screened towards human adenocarcinoma cell lines and showed significant inhibition even at very low concentration.     

High resolution mass spectrometry for studying the interactions of cisplatin with oligonucleotides

Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) has been used to probe the interaction of the anticancer drug cisplatin with oligonucleotides. The binding kinetics, the nature of the adducts formed, and the location of the binding site within the specifically designed double-stranded DNA oligonucleotides, ds(GTATTGGCACGTA) and ds(GTACCGGTGTGTA), were determined by recording mass spectra over time and/or employing tandem mass spectrometry (MS/MS). The FT-ICR MS studies show that binding to DNA takes place via a [Pt(NH 3) 2Cl] (+) intermediate prior to formation of bifunctional [Pt(NH 3) 2] (2+) adducts. Tandem MS reveals that the major binding sites correspond to GG and GTG, the known preferred binding sites for cisplatin, and demonstrates the preference for binding to guanosine within the oligonucleotide. The obtained results are discussed and compared to published data obtained by other mass spectrometric techniques, NMR spectroscopy and X-ray crystallography.     

Interactions of platinum(II) complexes with sulfur-containing peptides studied by electrospray ionization mass spectrometry and tandem mass spectrometry

Reactions of two platinum(II) complexes, cis-[Pt(NH3)2(H2O)2]2+ (Pt1) and cis-[Pt(en)(H2O)2]2+ (Pt2), with several sulfur-containing peptides, have been investigated by electrospray ionization mass spectrometry (ESI-MS) and tandem mass spectrometry (MS/MS). The species produced in the reactions were detected with ESI-MS, and MS/MS analysis was performed to probe structural information. Collision-induced dissociation revealed different dissociation pathways for the main reaction products of the two platinum(II) complexes with the same peptides. The major difference is the prominent loss of ammonia ligand for complexes of Pt1 due to the strong trans effect of sulfur, whereas the loss of ethylenediamine (en) ligand from Pt2 complexes is less favored, reflecting the chelating effect of the bidentate ligand. Despite the differences in dissociation patterns, Pt1 and Pt2, in general, form structurally similar complexes with the same peptides. In the reactions with Met-Arg-Phe-Ala they both produce a N,S-chelate ring through the N-terminal NH2 and sulfur of the Met residue, and in the reactions with Ac-Met-Ala-Ser they bind to the sulfur of Met and deprotonate an amide nitrogen upstream from the anchor site. Both of them are able to promote hydrolysis of the peptides. In reactions with glutathione they both form four-membered Pt2S2 rings and Pt-S-Pt bonding through the bridging thiolate ligand, although the reaction rate is much slower for Pt2 due to steric hindrance of the en ligand.     

Preparation and structural characterization of ionic five-coordinate palladium(II) and platinum(II) complexes of the ligand tris[2-(diphenylphosphino)ethyl]phosphine. Insertion of SnCl(2) into M-Cl bonds (M = Pd,Pt) and hydroformylation activity of the Pt-SnCl(3) systems

The five-coordinate palladium(II) and platinum(II) complexes [M(PP(3))Cl]Cl [M = Pd (1), Pt (2)] (PP(3) = tris[2-(diphenylphosphino)ethyl]phosphine) were prepared by interaction of aqueous solutions of MCl(4)(2-) salts with PP(3) in CHCl(3). Complexes 1 and 2 undergo facile chloro substitution reactions with KCN in 1:1 and 1:2 ratios to afford complexes [M(PP(3))(CN)]Cl [M = Pt (3)] and [M(PP(3))(CN)](CN) [M = Pd (4), Pt (5)] possessing M-C bonds, both in solution and in the solid state. The reaction of 1 and 2 with SnCl(2) in CDCl(3) occurs with insertion of SnCl(2) into M-Cl bonds leading to the formation of [M(PP(3))(SnCl(3))](SnCl(3)) [M = Pd (6), M = Pt (7)]. The isolation as solids of complexes 6 and 7 by addition of SnCl(2) to the precursors requires the presence of PPh(3) which activates the cleavage of M-Cl bonds, favors the SnCl(2) insertion, and does not coordinate to M in any observable extent. Solutions of 6 in CDCl(3) undergo tin dichloride elimination in higher proportion than solutions of 7. The reaction of complexes 1 and 2 with SnPh(2)Cl(2) leads to [M(PP(3))Cl](2)[SnPh(2)Cl(4)] [M = Pd (8)]. Complexes 2, 5, 7, and 8 were shown by X-ray diffraction to contain distorted trigonal bipyramidal monocations [M(PP(3))X](+) [M = Pt, X = Cl(-) (2), X = CN(-) (5), X = SnCl(3)(-) (7); M = Pd, X = Cl(-) (8)], the central P atom of PP(3) being trans to X in axial position and the terminal P donors in the equatorial plane of the bipyramids. The "preformed" catalyst 7 showed a relatively high aldehyde selectivity compared to most of the platinum catalysts.     

Cucurbit[n]uril binding of platinum anticancer complexes

The encapsulation of cisplatin by cucurbit[7]uril (Q[7]) and multinuclear platinum complexes linked via a 4,4'-dipyrazolylmethane (dpzm) ligand by Q[7] and cucurbit[8]uril (Q[8]) has been studied by NMR spectroscopy and molecular modelling. The NMR studies suggest that some cisplatin binds in the cucurbituril cavity, while cis-[PtCl(NH3)2(H2O)]+ only binds at the portals. Alternatively, the dpzm-linked multinuclear platinum complexes are quantitatively encapsulated within the cavities of both Q[7] and Q[8]. Upon encapsulation, the non-exchangeable proton resonances of the multinuclear platinum complexes show significant upfield shifts in 1H NMR spectra. The H3/H3* resonances shift upfield by 0.08 to 0.55 ppm, the H5/H5* shift by 0.9 to 1.6 ppm, while the methylene resonances shift by 0.74 to 0.88 ppm. The size of the resonance shift is dependent on the cavity size of the encapsulating cucurbituril, with Q[7] encapsulation producing larger shifts than Q[8]. The upfield shifts of the dpzm resonances observed upon cucurbituril encapsulation indicate that the Q[7] or Q[8] is positioned directly over the dpzm linking ligand. The terminal platinum groups of trans-[{PtCl(NH3)2}2 mu-dpzm]2+ (di-Pt) and trans-[trans-{PtCl(NH3)2}2-trans-{Pt(dpzm)2(NH3)2}]4+ (tri-Pt) provide a barrier to the on and off movement of cucurbituril, resulting in binding kinetics that are slow on the NMR timescale for the metal complex. Although the dpzm ligand has relatively few rotamers, encapsulation by the larger Q[8] resulted in a more compact di-Pt conformation with each platinum centre retracted further into each Q[8] portal. Encapsulation of the hydrolysed forms of di-Pt and tri-Pt is considerably slower than for the corresponding Cl forms, presumably due to the high-energy cost of passing the +2 platinum centres through the cucurbituril portals. The results of this study suggest that cucurbiturils could be suitable hosts for the pharmacological delivery of multinuclear platinum complexes.     

Acetonimine and 4-imino-2-methylpentan-2-amino platinum(II) complexes: synthesis and in vitro antitumor activity

The reaction of [Pt(dmba)(PPh3)Cl] [where dmba = N,C-chelating 2-(dimethylaminomethyl)phenyl] with aqueous ammonia in acetone in the presence of AgClO4 gives the acetonimine complex [Pt(dmba)(PPh3)(NH=CMe2)]ClO4 (1). The reaction of [Pt(dmba)(DMSO)Cl] with aqueous ammonia in acetone in the presence of AgClO4 gives a mixture of [Pt(dmba)(NH=CMe2)2]ClO4 (2) and [Pt(dmba)(imam)]ClO4 (3a) (where imam = 4-imino-2-methylpentan-2-amino). [Pt(dmba)(DMSO)Cl] reacts with [Ag(NH=CMe2)2]ClO4 in a 1:1 molar ratio to give [Pt(dmba)(DMSO)(NH=CMe2)]ClO4 (4). The reaction of [Pt(dmba)(DMSO)Cl] with 20% aqueous ammonia in acetone at 70 degrees C in the presence of KOH gives [Pt(dmba)(CH2COMe)(NH=CMe2)] (5), whereas the reaction of [Pt(dmba)(DMSO)Cl] with 20% aqueous ammonia in acetone in the absence of KOH gives [Pt(dmba)(imam)]Cl (3b). The reaction of [NBu4]2[Pt2(C6F5)4(mu-Cl)2] with [Ag(NH=CMe2)2]ClO4 in a 1:2 molar ratio produces cis-[Pt(C6F5)2(NH=CMe2)2] (6). The crystal structures of 1 x 2 Me2CO, 2, 3a, 5, and 6 have been determined. Values of IC50 were calculated for the new platinum complexes against a panel of human tumor cell lines representative of ovarian (A2780 and A2780 cisR) and breast cancers (T47D). At 48 h incubation time complexes 1, 4, and 5 show very low resistance factors against an A2780 cell line which has acquired resistance to cisplatin. 1, 4, and 5 were more active than cisplatin in T47D (up to 30-fold in some cases). The DNA adduct formation of 1, 4, and 5 was followed by circular dichroism and electrophoretic mobility.     

Palladium(II) and platinum(II) complexes of 6-methyl-2-acetylpyridine 3-hexamethyleneiminylthiosemicarbazones: A structural and spectral study

The reaction of 6-methyl-2-acetylpyridine 3-hexamethyleneiminyl-thiosemicarbazone, H6MAchexim, with potassium tetrachloropalladate(II) and tetrachloroplantinate(II) in methanol afforded the complexes [Pd(6MAchexim)Cl] and [Pt(6MAchexim)Cl], respectively. The X-ray crystal structure determination of both shows that anions of H6MAchexim coordinate in a planar conformation to the central palladium(II) or platinum(II) via the pyridyl nitrogen, azomethine nitrogen and thiolato sulfur atoms. The complexes have also been characterized by spectroscopic techniques (IR, UV–VIS and ¹H NMR).     

Tetranuclear platinum phosphido complexes with different structures

The addition of [NBu4]Br or [NBu4][BH4] to solutions of [Pt4(mu-PPh2)4(C6F5)4(CO)2] yields the complexes [NBu4]2[Pt4(mu-PPh2)4(mu-X)2(C6F5)4] (X=Br, H,) in which the two CO groups have been replaced by two anionic, bridging X ligands. The total valence electron counts are 64 and 60, respectively; thus, complex does not require Pt-Pt bonds, while two metal-metal bonds are present in, as their NMR spectra confirm. Also, the NMR spectra indicate a nonsymmetrical "Pt(mu-PPh2)2Pt(mu-PPh2)(mu-X)Pt(mu-PPh2)(mu-X)Pt" disposition for and. Treatment of with HX (X=Cl, Br) yields the complexes [NBu4]2[Pt4(mu-PPh2)4(mu-H)2(C6F5)3X] (X=Cl, Br,). These complexes react with [Ag(OClO 3)PPh3] with displacement of the halide and formation of [NBu4][Pt4(mu-PPh2)4(mu-H)2(C6F5)3PPh3]. Complexes maintain the same basic skeleton as, with two Pt-Pt bonds. Complex is, however, an isomer of the symmetric [NBu4]2[{(C6F5)2Pt(mu-PPh2)2Pt(mu-Br)}2], which has been prepared by a metathetical process from the well-known [NBu4]2[{(C6F5)2Pt(mu-PPh2)2Pt(mu-Cl)}2]. The comparison of the X-ray structures of and confirms the different disposition of the bridging ligands, and their main structural differences seem to be related to the size of Br- and its position in the skeleton.     

Unprecedented monofunctional metalation of adenine nucleobase in guanine- and thymine-containing dinucleotide sequences by a cytotoxic platinum-acridine hybrid agent

We have investigated the reactions of [PtCl(en)(ACRAMTU-S)](NO(3))(2) (2) (en = ethane-1,2-diamine; ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, acridinium cation, 1), the prototype of a new class of cytotoxic DNA-targeted agents, with 2'-deoxyguanosine (dGuo) and random-sequence native DNA by in-line liquid chromatography/mass spectrometry (LC/MS) and NMR spectroscopy ((1)H, (195)Pt) to identify the covalent adducts formed by platinum. In the mononucleoside model system, two adducts are observed, [Pt(en)(ACRAMTU)(dGuo)](3+) (P1, major) and [Pt(en)(dGuo)(2)](2+) (P2, minor). The reaction, which proceeds significantly slower (half-life 11-12 h at 37 degrees C, pH 6.5) than analogous reactions with cisplatin and reactions of 2 with double-stranded DNA, results in the unexpected displacement of the sulfur-bound acridine ligand in approximately 15% of the adducts. This reactivity is not observed in double-stranded DNA, rendering 1 a typical nonleaving group in reactions with this potential biological target. In enzymatic digests of calf thymus DNA treated with 2, three adducts were identified: [Pt(en)(ACRAMTU)(dGuo)](3+) (A1, approximately 80%), [Pt(en)(ACRAMTU)[d(GpA)]](2+) (A2, approximately 12%), and [Pt(en)(ACRAMTU)[d(TpA)]](2+) (A3, approximately 8%). A1 and P1 proved to be identical species. In the dinucleotide adducts A2 and A3, complex 2 covalently modifies adenine at GA and TA base steps, which are high-affinity intercalation sites of the acridine derivative 1. A2 and A3, which may be formed in the minor groove of DNA, are the first examples of monofunctional adenine adducts of divalent platinum formed in double-stranded DNA. The analysis of the adduct profile indicates that the sequence specificity of 1 plays an important role in the molecular recognition between DNA and the corresponding conjugate, 2. Possible biological consequences of the unusual adduct profile are discussed.