Model of the Second Most Abundant Cisplatin-DNA Cross-Link: X-ray Crystal Structure and Conformational Analysis of cis-[(NH(3))(2)Pt(9-MeA-N7)(9-EtGH-N7)](NO(3)).2H(2)O (9-MeA = 9-Methyladenine; 9-EtGH = 9-Ethylguanine)

A model compound of the second most abundant DNA adduct of the antitumor agent cisplatin has been synthesized and structurally and spectroscopically characterized and its conformational behavior examined: cis-[(NH(3))(2)Pt(9-MeA-N7)(9-EtGH-N7)](NO(3))(2).2H(2)O (9-MeA = 9-methyladenine; 9-EtGH = 9-ethylguanine) crystallizes in the monoclinic system, space group P2(1)/n (No. 14) with a = 7.931(2), b = 11.035(3), c = 26.757(6) ?, beta = 94.94(2) degrees, and Z = 4. The two purine bases adopt a head-to-head orientation, with NH(2) of 9-MeA and CO of 9-EtGH being at the same side of the Pt coordination plane. A theoretical conformational analysis of the complex cis-[(NH(3))(2)Pt(Ade)(Gua)](2+) (Ade = adenine; Gua = guanine) based on molecular mechanics calculations of the nonbonded energy has revealed four minimum-energy zones similar to those derived previously for cis-[(NH(3))(2)Pt(Gua)(2)](2+) (Kozelka; et al. Eur. J. Biochem. 1992, 205, 895). This conformational analysis has allowed, together with the calculation of chemical shifts due to ring effects, the attribution of the two conformers observed for cis-[(NH(3))(2)Pt{d(ApG)}](+) by Dijt et al. (Eur. J. Biochem. 1989, 179, 344) to the two head-to-head conformational zones. The orientation of the two nucleobases in the crystal structure of cis-[(NH(3))(2)Pt(9-MeA)(9-EtGH)](2+) corresponds, according to our analysis, roughly to that preferentially assumed by the minor rotamer of cis-[(NH(3))(2)Pt{d(ApG)}](+).     

Synthesis characterization and X-ray crystal structures of cis-1,4-diaminocyclohexane-platinum(II) nucleobase adducts

Platinum complexes of the type [Pt(cis-1,4-DACH)(L)₂]X, where cis-1,4-DACH = cis-1,4-diaminocyclohexane; L = adenine (ade) (1), hypoxanthine (hyp) (2), 9-methylguanine (9-megua) (3), cytosine (cyt) (4), or 1-methylcytosine (1-mecyt) (5); and X = SO₄ or Cl₂ groups, were synthesized and characterized by elemental analysis and by ¹H, ¹³C, and ¹⁹⁵Pt nuclear magnetic resonance spectroscopy. The crystals of [Pt(cis-1,4-DACH)(9-megua)₂]SO₄[9-megua-H]₂SO₄ (3) and [Pt(cis-1,4-DACH)(1-mecyt)₂]Cl₂ · 6H₂O (5) were also subjected to single-crystal X-ray diffraction. The base/PtN4 coordination plane dihedral angles were 74.55° and 85.61° in complex 3 and 78.12° and 81.80° in complex 5. The platinum had distorted square planar geometry in both complexes; the two adjacent corners were occupied by the two nitrogen atoms of cis-1,4-DACH, and the other two corners were occupied by the two N7 atoms of 9-megua in complex 3 and the two N3 atoms of 1-mecyt in complex 5. The cis-1,4-DACH, which has a unique twist-boat configuration, formed a seven-member chelating ring with platinum, which led to considerable strain during bidentate cis-1,4-DACH binding. Cations of both complexes 3 and 5 adopted C₂ molecular symmetry. These adducts were the models for the intrastand cross-links that were relevant to the binding of the Pt(II) antitumor drugs to DNA.     

Palladium(II) and platinum(II) organometallic complexes with 4,7-dihydro-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine. Antitumor activity of the platinum compounds

Palladium and platinum complexes with HmtpO (where HmtpO=4,7-dihydro-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine, an analogue of the natural occurring nucleobase hypoxanthine) of the types [M(dmba)(PPh3)(HmtpO)]ClO4[dmba=N,C-chelating 2-(dimethylaminomethyl)phenyl; M=Pd or Pt], [Pd(N-N)(C6F5)(HmtpO)]ClO4[N-N=2,2'-bipyridine (bpy), 4,4'-dimethyl-2,2'-bipyridine (Me2bpy), or N, N, N', N'-tetramethylethylenediamine (tmeda)] and cis-[M(C6F5)2(HmtpO)2] (M=Pd or Pt) (head-to-head atropisomer in the solid state) have been obtained. Pd(II) and Pt(II) complexes with the anion of HmtpO of the types [Pd(tmeda)(C6F5)(mtpO)], [Pd(dmba)(micro-mtpO)] 2, and [NBu4]2[M(C6F5)2(micro-mtpO)]2(M=Pd or Pt) have been prepared starting from the corresponding hydroxometal complexes. Complexes containing simultaneously both the neutral HmtpO ligand and the anionic mtpO of the type [NBu4][M(C6F5)2(HmtpO)(mtpO)] (M=Pd or Pt) have been also obtained. In these mtpO-HmtpO metal complexes, for the first time, prototropic exchange is observed between the two heterocyclic ligands. The crystal structures of [Pd(dmba)(PPh 3)(HmtpO)]+, cis-[Pt(C6F5)2(HmtpO)2].acetone, [Pd(C6F5)(tmeda)(mtpO)].2H2O, [Pd(dmba)(micro-mtpO)]2, [NBu4]2[Pd(C6F5)2(micro-mtpO)]2.CH2Cl2.toluene, [NBu4]2[Pt(C6F5)2(micro-mtpO)](2).0.5(toluene), and [NBu4][Pt(C6F5)2(mtpO)(HmtpO)] have been established by X-ray diffraction. Values of IC50 were calculated for the new platinum complexes cis-[Pt(C6F5)2(HmtpO)2] and [Pt(dmba)(PPh3)(HmtpO)]ClO4 against a panel of human tumor cell lines representative of ovarian (A2780 and A2780 cisR), lung (NCI-H460), and breast cancers (T47D). At 48 h incubation time, both complexes were about 8-fold more active than cisplatin in T47D and show very low resistance factors against an A2780 cell line, which has acquired resistance to cisplatin. The DNA adduct formation of cis-[Pt(C6F5)2(HmtpO)2] and [Pt(dmba)(PPh3)(HmtpO)]ClO4 was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the modifications caused by these platinum complexes on plasmid DNA pB R322 were also obtained.     

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.     

fac-[Re(CO)3(H2O)3]+ nucleoside monophosphate adducts investigated in aqueous solution by multinuclear NMR spectroscopy

The fac-[Re(CO)3(H2O)3]+ cation, the putative DNA-binding species accounting for the biological activity of related Re(I) complexes, binds reversibly to N7 of 6-oxopurine nucleotide monophosphates (NMPs), in contrast to Pt(II) anticancer drugs. A relatively high amount of NMP is needed to convert all of the fac-[Re(CO)3(H2O)3]+ to adducts. The Re/nucleotide 1:1 adduct forms more rapidly and builds up to a higher concentration for guanosine 5'-monophosphate (5'-GMP) and inosine 5'-monophosphate (5'-IMP) than for the respective 3'-monophosphates (3'-GMP and 3'-IMP). These results are attributable to the 5'-positioning of the 5'-NMP phosphate group that allows it to approach the metal inner sphere for more favorable cation electrostatic and aqua ligand H-bonding interactions, both in the initial productive ion pair encounter complexes and in the N7-bound 1:1 adducts. A higher reactivity of 5'-GMP over 3'-GMP is known for cisplatin. In contrast, more Re/nucleotide 1:2 adduct was formed by 3'-GMP (and 3'-IMP) than by 5'-GMP (and 5'-IMP). Because the 3'-phosphate group cannot closely approach the metal inner coordination sphere, the greater stability for the 3'-GMP 1:2 adduct reflects the more favorable G N1H-phosphate interligand GMP-GMP interactions for 3'-GMP vs 5'-GMP (G=guanine base derivative). This type of interaction is known for platinum adducts. In 1:2 adducts the bound nucleotides are inequivalent, prompting us to perform mixed 5'-GMP/3'-GMP experiments, leading to the observation of major (M) and minor (m) mixed Re/5'-GMP/3'-GMP 1:1:1 adducts. The order of abundance at equilibrium in a typical experiment was M>bis 3'-GMP>m>or=bis 5'-GMP. This stability order was rationalized by invoking the phosphate interactions described above. When methionine and 5'-GMP were allowed to compete for fac-[Re(CO)3(H2O)3]+, the Re/5'-GMP 1:1 adduct was the kinetic product and the S-bound Re/methionine adduct was the thermodynamic product, a result opposite to that typically found for cisplatin.     

A 1,2-d(GpG) cisplatin intrastrand cross-link influences the rotational and translational setting of DNA in nucleosomes

The mechanism of action of platinum-based anticancer drugs such as cis-diamminedichloroplatinum(II), or cisplatin, involves three early steps: cell entry, drug activation, and target binding. A major target in the cell, responsible for the anticancer activity, is nuclear DNA, which is packaged in nucleosomes that comprise chromatin. It is important to understand the nature of platinum-DNA interactions at the level of the nucleosome. The cis-{Pt(NH3)2}2+ 1,2-d(GpG) intrastrand cross-link is the DNA lesion most commonly encountered following cisplatin treatment. We therefore assembled two site-specifically platinated nucleosomes using synthetic DNA containing defined cis-{Pt(NH3)2}2+ 1,2-d(GpG) cross-links and core histones from HeLa-S3 cancer cells. The structures of these complexes were investigated by hydroxyl radical footprinting and exonuclease III mapping. Our experiments demonstrate that the 1,2-d(GpG) cross-link alters the rotational setting of the DNA on the histone octamer core such that the lesion faces inward, with disposition angles of the major groove relative to the core of xi approximately -20 degrees and xi approximately 40 degrees . We observe increased solvent accessibility of the platinated DNA strand, which may be caused by a structural perturbation in proximity of the 1,2-d(GpG) cisplatin lesion. The effect of the 1,2-d(GpG) cisplatin adduct on the translational setting of the nucleosomal DNA depends strongly on the position of the adduct within the sequence. If the cross-link is located at a site that is in phase with the preferred rotational setting of the unplatinated nucleosomal DNA, the effect on the translational position is negligible. Minor exonuclease III digestion products in this substrate indicate that the cisplatin adduct permits only those translational settings that differ from one another by integral numbers of DNA helical turns. If the lesion is located out of phase with the preferred rotational setting, the translational position of the main conformation was shifted by 5 bp. Additionally, a fraction of platinated nucleosomes with widely distributed translational positions was observed, suggesting increased nucleosome sliding relative to platinated nucleosomes containing the 1,3-intrastrand d(GpTpG) cross-link investigated previously (Ober, M.; Lippard, S. J. J. Am. Chem. Soc. 2007, 129, 6278-6286).     

HPIC-UV-ICP-SFMS study of the interaction of cisplatin with guanosine monophosphate

Interaction of cis-[Pt(NH3)2Cl2] (cisplatin) with 5'-guanosine monophosphate (5'-GMP) has been investigated for the first time by on-line coupling of high performance ion chromatography (HPIC) to inductively coupled plasma sector field mass spectrometry (ICP-SFMS). The time-dependent reaction course of the cisplatin-5'-GMP system was followed after incubation under simulated physiological conditions by monitoring the decrease in the concentration of 5'-GMP and the increase in the concentration of formed adducts, on the basis of speciation analysis. Because of the two-step mechanism an intermediate mono adduct was observed together with the major product, the bis adduct cis-[Pt(NH3)2(GMP)2]2-. The data obtained correlated well with those from earlier studies employing orthogonal techniques such as capillary electrophoresis (CE). Furthermore, HPIC-ICP-SFMS provided unambiguous stoichiometric information about the major GMP-adduct. For this purpose the platinum-to-phosphorus ratio was determined by simultaneously measuring 31P and 195Pt. To separate significant interferences from 15N16O+, 14N16O1H+, 12C18O1H+, and 13C17O1H+ on 31P, high-mass resolution (m/deltam = 4,500) proved to be mandatory. The P/Pt signal ratio of 2/1 obtained corresponds to the molar ratio in the bis adduct cis-[Pt(NH3)2(GMP)2]2-.     

Synthesis and Characterization of New CIS-1,4-Diaminocyclohexane and Piperidine Platinum(II) Complexes Containing Disubstituted Sulfide Groups

Abstract

A series of cationic platinum(II) complexes of the type [Pt(cis-1,4-DACH)(R′R″S)Cl]NO₃ and [Pt(PIP)₂(R′R″S)Cl]NO₃ (where cis-1,4-DACH = cis-1,4-diaminocyclohexane; PIP = piperidine; and R′R″S = dimethylsulfide, diethylsulfide, dipropylsulfide, diisopropylsulfide, dibutylsulfide, diphenylsulfide, dibenzylsulfide, methylphenylsulfide, or methyl-p-tolylsulfide) have been synthesized and characterized by elemental analysis and infrared, ¹H, and ¹⁹⁵Pt nuclear magnetic resonance spectroscopy.     

New palladium(II) and platinum(II) complexes with the model nucleobase 1-methylcytosine: antitumor activity and interactions with DNA

Palladium and platinum complexes with the model nucleobase 1-methylcytosine (1-Mecyt) of the types [Pd(N-N)(C6F5)(1-Mecyt)]ClO4 [N-N = bis(3,5-dimethylpyrazol-1-yl)methane (bpzm), bis(pyrazol-1-yl)methane (bpzm), N,N,N',N'-tetramethylethylenediamine (tmeda), or 2,2'-bipyridine (bpy)] and [M(dmba)(L')(1-Mecyt)]ClO4 [dmba = N,C-chelating 2-(dimethylaminomethyl)phenyl; L' = PPh(3) (M = Pd or Pt), DMSO (M = Pt)] have been obtained. Palladium and platinum complexes of the types cis-[M(C6F5)2(1-Mecyt)2] (M = Pd or Pt) and cis-[Pd(L')(C6F5)(1-Mecyt)2]ClO4 (L' = PPh(3) or t-BuNC) have also been prepared. The crystal structures of [Pd(bpzm)(C6F5)(1-Mecyt)]ClO4, [Pt(dmba)(DMSO)(1-Mecyt)]ClO4, cis-[Pd(C6F5)2(1-Mecyt)2], and cis-[Pd(t-BuNC)(C6F5)(1-Mecyt)2]ClO4 have been established by X-ray diffraction. There is extensive hydrogen bonding (N-H...O, C-H...F or C-H...O) in all the compounds. There are also intermolecular pi-pi interactions between pyrimidine rings of adjacent chains in [Pd(C6F5)2(1-Mecyt)2]. DNA adduct formation of the new complexes synthesized was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the modifications caused by the complexes on plasmid DNA pBR322 were also obtained. Values of IC(50) were also calculated for the new complexes against the tumor cell line HL-60. At a short incubation time (24 h) almost all new complexes were more active than cisplatin.     

Chemistry of phosphine-borane adducts at platinum centers: dehydrocoupling reactivity of Pt(II) dihydrides with P-H bonds

The reaction of the Pt(II) dihydride complex cis-[PtH2(dcype)](dcype = 1,2-bis(dicyclohexylphosphino)ethane) with the primary or secondary phosphine-borane adducts PhRPH x BH3(R = H, Ph) was found to exclusively afford the mono-substituted complexes cis-[PtH(PPhR x BH3)(dcype)](1: R = H; 2: R = Ph)via a dehydrocoupling reaction between Pt-H and P-H bonds. Similar reactivity was observed between the uncoordinated phosphines PhRPH (R = H, Ph) and cis-[PtH2(dcype)], which gave cis-[PtH(PPhR)(dcype)](4: R = H; 5: R = Ph). The complexes were characterized by 1H, 11B, 13C and 31P NMR spectroscopy, IR, MS and, in the case of 2, X-ray crystallography that confirmed the cis geometries. The di-substituted complex cis-[Pt(PhPH x BH3)2(dcype)](3) was prepared from the reaction of cis-[PtCl2(dcype)] with two equivalents of Li[PPhH x BH3]. This suggested that steric reasons alone cannot be used to explain the lack of reactivity with respect to a second dehydrocoupling reaction involving the remaining Pt-H bond in complexes 1, 2, 4 and 5.     

A pyrazolato-bridged dinuclear platinum(II) complex induces only minor distortions upon DNA-binding

The cytotoxic, pyrazolato-bridged dinuclear platinum(II) complex [(cis-{Pt(NH3)2})2(mu-OH)(mu-pz)]2+ (pz=pyrazolate) has been found to cross-link two adjacent guanines of a double-stranded DNA decamer without destabilizing the duplex and without changing the directionality of the helix axis. A 1H NMR study of the oligonucleotide d(CTCTG*G*TCTC)-d(GAGACCAGAG), cross-linked at the two G* guanines by [(cis-{Pt(NH3)2})2(mu-pz)]3+, and molecular dynamics simulations of the explicitly solvated duplex were performed to characterize the structural details of the adduct. The dinuclear platinum cross-link unwinds the helix by approximately 15 degrees , that is, to a similar extent as the widely used antitumor drug cisplatin, but, in contrast to the latter, induces no significant bend in the helix axis. The Watson-Crick base-pairing remains intact, and the melting temperature of the duplex is unaffected by the cross-link. The helical twist is considerably reduced between the two platinated bases, as becomes manifest in an unusually short sequential H1'-H1' distance. This unwinding also affects the sugar ring of the guanosine in the 3'-position to the cross-link, which presents an N<-->S equilibrium. This is the first cytotoxic platinum complex that has been successfully designed by envisioning the structural consequences of its binding to DNA.     

Chelating or bridging Pd(II) and Pt(II) metalloligands from the functional phosphine ligand N-(diphenylphosphino)-1,3,4-thiadiazol-2-amine. New heterometallic Pd(II)/Pt(II) and Pt(II)/Au(I) complexes

The reaction of two equivalents of the functional phosphine ligand N-(diphenylphosphino)-1,3,4-thiadiazol-2-amine Ph2PNHC=NNCHS (2) with [PdCl2(NCPh)2] in the presence of NEt3 gives the neutral, P,N-chelated complex cis-[Pd(Ph2PN=CNN=CHS)2] ([Pd(2-H)2], 3b), which is analogous to the Pt(II) analogue cis-[Pt (Ph2PN=CNN=CHS)2] ([Pt(2-H)2], 3a) reported previously. These complexes function as chelating metalloligands when further coordinated to a metal through each of the CH-N atoms. In the resulting complexes, each endo-cyclic N donor of the thiadiazole rings is bonded to a different metal centre. Thus, the heterodinuclear palladium/platinum complexes cis-[Pt(Ph2PN=CNN=CHS)2PdCl2]([Pt(2-H)2·PdCl2], 4a) and cis-[Pd(Ph2PN=CNN=CHS)2PtCl2]([Pd(2-H)2·PtCl2], 4b) were obtained by reaction with [PdCl2(NCPh)2] and [PtCl2(NCPh)2], respectively. In contrast, reaction of 3a with [AuCl(tht)] occurred instead at the P-bound N atom, and afforded the platinum/digold complex cis-[Pt{Ph2PN(AuCl)=CNN=CHS}2] ([Pt(2-H)2(AuCl)2], 5). For comparison, reaction of 4a with HBF4 yielded cis-[Pt(Ph2PNH=CNN=CHS)2PdCl2](BF4)2([H24a](BF4)2, 6), in which the chelated PdCl2 moiety is retained. Complexes 3b, 4a·CH2Cl2, 4b·0.5C7H8, 5·4CHCl3 and 6 have been structurally characterized by X-ray diffraction.     

Isomeric equilibria in aqueous solution involving aromatic ring stacking in the sexternary complexes formed by the quaternary cis-(NH3)2Pt(2'-deoxyguanosine-N7)(dGMP-N7) complex and the binary Cu(2,2'-bipyridine)2+ or Cu(1,10-phenanthroline)2+ complexes (dGMP2- = 2'-deoxyguanosine 5'-monophosphate)

To the best of our knowledge, for the first time the stabilities of sexternary complexes are determined by potentiometric pH titrations in aqueous solution at 25 degrees C and I = 0.1 M (NaNO3). The sexternary complexes form by binding of the binary Cu(Arm)2+ complexes, where Arm = 2,2'-bipyridine (Bpy) or 1,10-phenanthroline (Phen), to the -PO3(2-) group present in the quaternary cis-(NH3)2Pt(dGuo)(dGMP) complex. It is shown by stability constant comparisons and spectrophotometric measurements (observation of charge-transfer bands for the Phen system) that the [cis-(NH3)2Pt(dGuo)(dGMP).Cu(Arm)]2+ complexes can fold in such a way that aromatic ring stacking between the aromatic rings of Bpy or Phen and a guanine residue (most probably the one of dGMP2-) becomes possible. The formation degree of the stacks reaches approximately 25 and 50% for the [cis-(NH3)2Pt-(dGuo)(dGMP).Cu(Bpy)]2+ and [cis-(NH3)2Pt(dGuo)(dGMP).Cu(Phen)]2+ species, respectively. By comparisons with Cu(Arm)(dGMP) complexes, it is shown that the cis-(NH3)2Pt2+ unit coordinated to N7 of the guanine residues in the sexternary complexes inhibits stacking but does not prevent it. This result is of general importance because it demonstrates that in aqueous solution purine residues of nucleotides or nucleic acids that carry a metal ion at N7 can still undergo stacking interactions with other suitable aromatic ring systems.     

Syntheses and Structures of the Complexes cis-[M(C(6)F(5))(2)(N&arcraise;X)] (M = Pd, Pt; N&arcraise;X = 2-Iodoaniline, 2-Benzoylpyridine) Containing N&arcraise;X Acting as a Didentate Chelating Ligand and Displaying I-->M or O-->M Interactions

Complexes cis-[M(C(6)F(5))(2)(THF)(2)] (M = Pd, Pt) are weak Lewis acids and react with the halocarbon ligand 2-iodoaniline (R-I) yielding the corresponding cis-[M(C(6)F(5))(2)(R-I)] [M = Pd (1), Pt (2)]. In these complexes a (C-)I-M bond is present. The use of other 2-haloanilines (halogen = F, Cl, Br) does not yield the analogous complexes because of the lesser nucleophilic character of the halogen involved. The presence of the (C-)I-Pt bond in 2 has been confirmed by an X-ray structure determination, which also reveals an N-H.M hydrogen bond between two neutral molecules. Complex 2 crystallizes in the space group P&onemacr;: Z = 4; a = 11.797(4) ?; b = 13.735(4) ?; c = 14.107(4) ?; alpha = 97.24(2) degrees; beta = 90.91(2) degrees; gamma = 99.44(2) degrees; V = 2235(2) ?(3). Similarly, complexes cis-[M(C(6)X(5))(2)(THF)(2)] (M = Pd, Pt; X = F, Cl) react with the ligand 2-benzoylpyridine {R-C(O)Ph}, in which the oxygen atom of the ketonic group can behave as a nucleophilic center, yielding the complexes cis-[M(C(6)X(5))(2){R-C(O)Ph}] [M = Pd, X = F (3); M = Pt, X = F (4), Cl (5)]. Complex 3 crystallizes in the space group C2/c: Z = 16; a = 26.284(3) ?; b = 10.623(1) ?; c = 31.423(4) ?; beta = 93.15(1) degrees; V = 8760(2) ?(3). The I-M or O-M bonds in complexes 1-5 are weak and can be easily broken by the addition of neutral (CO, PPh(3), and CH(3)CN) or anionic (Br(-)) ligands.     

2.4 A crystal structure of an oxaliplatin 1,2-d(GpG) intrastrand cross-link in a DNA dodecamer duplex

(1R,2R-Diaminocyclohexane)oxalatoplatinum(II) (oxaliplatin) is a third-generation platinum anticancer compound that produces the same type of inter- and intrastrand DNA cross-links as cisplatin. In combination with 5-fluorouracil, oxaliplatin has been recently approved in Europe, Asia, and Latin America for the treatment of metastatic colorectal cancer. We present here the crystal structure of an oxaliplatin adduct of a DNA dodecanucleotide duplex having the same sequence as that previously reported for cisplatin (Takahara, P. M.; Rosenzweig, A. C.; Frederick, C. A.; Lippard, S. J. Nature 1995, 377, 649-652). Pt-MAD data were used to solve this first X-ray structure of a platinated DNA duplex derived from an active platinum anticancer drug other than cisplatin. The overall geometry and crystal packing of the complex, refined to 2.4 A resolution, are similar to those of the cisplatin structure, despite the fact that the two molecules crystallize in different space groups. The platinum atom of the [Pt(R,R-DACH)](2+) moiety forms a 1,2-intrastrand cross-link between two adjacent guanosine residues in the sequence 5'-d(CCTCTGGTCTCC), bending the double helix by approximately 30 degrees toward the major groove. Both end-to-end and end-to-groove packing interactions occur in the crystal lattice. The latter is positioned in the minor groove opposite the platinum cross-link. A novel feature of the present structure is the presence of a hydrogen bond between the pseudoequatorial NH hydrogen atom of the (R,R)-DACH ligand and the O6 atom of the 3'-G of the platinated d(GpG) lesion. This finding provides structural evidence for the importance of chirality in mediating the interaction between oxaliplatin and duplex DNA, calibrating previously published models used to explain the reactivity of enantiomerically pure vicinal diamine platinum complexes with DNA in solution. It also provides a new kind of chiral recognition between an enantiomerically pure metal complex and the DNA double helix.     

Biologically active platinum complexes containing 8-thiotheophylline and 8-(methylthio)theophylline

Complexes [Pt(mu-N,S-8-TT)(PPh(3))(2)](2) (1), [Pt(mu-S,N-8-TT)(PTA)(2)](2) (2), [Pt(8-TTH)(terpy)]BF(4) (3), cis-[PtCl(8-MTT)(PPh(3))(2)] (4), cis-[Pt(8-MTT)(2)(PPh(3))(2)] (5), cis-[Pt(8-MTT)(8-TTH)(PPh(3))(2)] (6), cis-[PtCl(8-MTT)(PTA)(2)] (7), cis-[Pt(8-MTT)(2)(PTA)(2)] (8), and trans-[Pt(8-MTT)(2)(py)(2)] (9) (8-TTH(2) = 8-thiotheophylline; 8-MTTH = 8-(methylthio)theophylline; PTA = 1,3,5-triaza-7-phosphaadamantane) are presented and studied by IR and multinuclear ((1)H, (31)P[(1)H]) NMR spectroscopy. The solid-state structure of 4 and 9 has been authenticated by X-ray crystallography. Growth inhibition of the cancer cells T2 and SKOV3 induced by the above new thiopurine platinum complexes has been investigated. The activity shown by complexes 4 and 9 was comparable with cisplatin on T2. Remarkably, 4 and 9 displayed also a valuable activity on cisplatin-resistant SKOV3 cancer cells.     

ortho-Metallated complexes of platinum(II) and diplatinum(I) containing the carbanions (2-diphenylphosphino)phenyl and (2-diphenylphosphino)-n-tolyl (n = 5, 6)

When the ortho-metallated complexes cis-[Pt(kappa(2)-C6H3-5-R-2-PPh2)2] (R = H 1, Me 2) are either heated in toluene or treated with CO at room temperature, one of the four-membered chelate rings is opened irreversibly to give dinuclear isomers [Pt2(kappa(2)-C6H3-5-R-2-PPh2)2(mu-C6H3-5-R-2-PPh2)2] (R = H 10, Me 11). A single-crystal X-ray diffraction study shows the Pt...Pt separation in 10 to be 3.3875(4) A. By-products of the reactions of 1 and 2 with CO are polymeric isomers (R = H 13, Me 14) in which one of the P-C ligands is believed to bridge adjacent platinum atoms intermolecularly. In contrast to the behaviour of 1 and 2, when cis-[Pt(kappa(2)-C6H3-6-Me-2-PPh2)2] (cis-3) is heated in toluene, the main product is trans-3, and reaction of cis-3 with CO gives a carbonyl complex [Pt(CO)(kappa(1)-C-C6H3-6-Me-2-PPh2)(2-C6H3-6-Me-2-PPh2)] 15, in which one of the carbanions is coordinated only through the carbon. Formation of a dimer analogous to 10 or 11 is sterically hindered by the 6-methyl substituent. Comproportionation of 1 or 2 with [Pt(PPh3)2L] (L = PPh3, C2H4) gives diplatinum(I) complexes [Pt2(mu-C6H3-5-R-2-PPh2)2(PPh3)2] (R = H 16, Me 17). An X-ray diffraction study shows that 17 contains a pair of planar-coordinated metal atoms separated by 2.61762(16) A. There is no evidence for the formation of an analogue containing mu-C6H3-6-Me-2-PPh2. The axial PPh3 ligands of 16 are readily replaced by ButNC giving [Pt2(mu-2-C6H4PPh2)2(CNBut)2] 18, which is protonated by HBF4 to form a mu-hydridodiplatinum(II) salt [Pt2(mu-H)(mu-2-C6H4PPh2)2(CNBut)2]BF4 [21]BF4. The J(PtPt) values in [21]BF4 and 18, 2700 Hz and 4421 Hz, respectively, reflect the weakening of the Pt-Pt interaction caused by protonation. Similarly, 16 and 17 react with the electrophiles iodine and strong acids to give salts of general formula [Pt2(mu-Z)(mu-C6H3-5-R-2-PPh2)2(PPh3)2]Y (Y = Z = I, R = H 19+, Me 20+; Z = H, Y = BF4, PF6, OTf, R = H 22+; Z = H, Y = PF6, R = Me 23+). A single-crystal X-ray diffraction study of [23]PF6 shows that the cation has an approximately A-frame geometry, with a Pt-Pt separation of 2.7888(3) A and a Pt-H bond length of 1.62(1) A, and that the 5-methyl substituents have undergone partial exchange with the 4-hydrogen atoms of the PPh2 groups of the bridging carbanion. The latter observation indicates that the added proton of [23]+ undergoes a reversible reductive elimination-oxidative addition sequence with the Pt-C(aryl) bonds.     

SYNTHESIS AND CHARACTERIZATION OF A SERIES OF LIPOPHILIC CISPLATIN ANALOGS WITH CIS-1,4-DIAMINOCYCLOHEXANE AS NONLEAVING AMINE LIGAND

Abstract

A series of lipophilic platinum(II) complexes of the type [Pt(cis-1,4-DACH)L₂] (where cis-1,4-DACH = cis-1,4-diaminocyclohexane and L = acetate, propionate, butyrate, valerate, hexanoate, heptanoate, octanoate, 2,2′-dimethyloctanoate, nonanoate, decanoate, undecanoate, laureate, tridecanoate, myristate, pentadecanoate, palmitate, heptadecanoate, stearate, nonadecanoate, or eicosanoate) has been synthesized and characterized by elemental analysis and by infrared, ¹³C, and ¹⁹⁵Pt nuclear magnetic resonance spectroscopic techniques.     

Insertion of alkynes into the Pt-Si bond of silylplatinum complexes leading to the formation of 4-sila-3-platinacyclobutenes and 5-sila-2-platina-1,4-cyclohexadienes

The reaction of dimethyl acetylenedicarboxylate (DMAD) with [Pt(SiHPh(2))(2)(PMe(3))(2)] produces cis-[Pt(CZ=CZ-SiHPh(2))(SiHPh(2))(PMe(3))(2)] (cis-1, Z = COOMe) and [Pt(CZ=CZ-SiPh(2))(PMe(3))(2)] (2) depending on the reaction conditions. cis-1 and 2 are equilibrated in solution at room temperature, and they are isolated by recrystallization of the mixtures. cis-1 is converted slowly in solution into trans-[Pt(CZ=CZ-SiHPh(2))(SiHPh(2))(PMe(3))(2)] (trans-1) via intermediate 2 followed by reaction with H(2)SiPh(2). DMAD also reacts with [Pt(SiHPh(2))(2)(dmpe)] (dmpe = 1,2-bis(dimethylphosphino)ethane) to afford [Pt(CZ=CZ-SiHPh(2))(SiHPh(2))(dmpe)] (3). Conversion of 3 into 4-sila-3-platinacyclobutene [Pt(CZ=CZ-SiPh(2))(dmpe)] (4) takes place, accompanied by formation of H(2)SiPh(2), to give an equilibrated mixture of the two complexes. Crystallographic and spectroscopic data of cis-1, trans-1, and 3 suggest the presence of an intramolecular interaction between the Si-H group of the 3-sila-1-propenyl ligand and Pt via an Si-H-Pt three-center-four-electron bond in the solid state and in solution. DMAD reacts with 2 to give 5-sila-2-platina-1,4-cyclohexadiene with pi-coordinated DMAD, [Pt(CZ=CZ-SiPh(2)-CZ=CZ)(DMAD)(PMe(3))(2)] (5), which is also obtained from the reaction of excess DMAD with [Pt(SiHPh(2))(2)(PMe(3))(2)]. Unsymmetrical six-membered silaplatinacycles without pi-coordinated alkyne, [Pt(CZ=CZ-SiPh(2)-CH=CX)(PMe(3))(2)] (6: X = COOMe; 7: X = Ph), are prepared analogously from the respective reactions of phenyl acetylene and of methyl acetylene carboxylate with 2. Methyl 2-butynolate reacts with 2 at 50 degrees C to form a mixture of the regioisomers [Pt(CZ=CZ-SiPh(2)-CMe=CZ)(PMe(3))(2)] (8) and [Pt(CZ=CZ-SiPh(2)-CZ=CMe)(PMe(3))(2)] (9).     

Addition of the phenoxathiin cation radical to alkenes and nonconjugated dienes. Formation of (E)- and (Z)-(10-phenoxathiiniumyl)alkenes and (E)- and (Z)-(10-phenoxathiiniumyl)dienes on basic alumina

Addition of phenoxathiin cation radical (PO*+) to acyclic alkenes in acetonitrile (MeCN) solution occurred stereospecifically to form bis(10-phenoxathiiniumyl)alkane adducts. Stereospecific trans addition is ascribed to the intermediacy of an episulfonium cation radical. The alkenes used were cis- and trans-2-butene, cis- and trans-2-pentene, cis- and trans-4-methyl-2-pentene, cis- and trans-4-octene, trans-3-hexene, trans-3-octene, trans-5-decene, cis-2-hexene, and cis-2-heptene. The erythro bisadducts (compounds 6) were obtained with trans-alkenes, while threo bisadducts (compounds 7) were obtained with cis-alkenes. The assigned structures of 6 and 7 were consistent with their NMR spectra and, in one case, 6c (the adduct of trans-4-methyl-2-pentene) was confirmed with X-ray crystallography. Additions of PO*+ to 1,4-hexa-, 1,5-hexa-, 1,6-hepta-, and 1,7-octadiene gave bis(10-phenoxathiiniumyl)alkenes (compounds 8), the assigned structures of which were consistent with their NMR spectra. Each of these adducts lost a proton and phenoxathiin (PO) when treated with basic alumina in MeCN solution. Compounds 6 (from trans-alkenes) gave mixtures of (Z)- (9) and (E)-(10-phenoxathiiniumyl)alkenes (10) in which the (Z)-isomers (9) were dominant. On the other hand, compounds 7 (from cis-alkenes) gave mixtures of 9 and 10 in which, with one exception (the adduct 7c of cis-4-methyl-2-pentene), compounds 10 were dominant. The path to elimination is discussed. The alkenes 9 and 10 were characterized with NMR spectroscopy and, in one case (9a), with X-ray crystallography. Reactions of 8b-d with basic alumina gave mixtures of (E)- (13) and (Z)-(10-phenoxathiiniumyl)dienes (14), in which compounds 13 were dominant. The configuration of the product from 8a (the adduct of 1,4-hexadiene) could not be settled. Noteworthy features in the coupling patterns and chemical shifts in the NMR spectra of some of the adducts and their products are discussed and related to adduct conformations.