Reactivity of ammonia ligands of the antitumor agent cisplatin: a unique dodecanuclear Pt4,Pd4,Ag4 platform for four cytosine model nucleobases

The reaction of a potential mono(nucleobase) model adduct of cisplatin, cis-[Pt(NH(3))(2)(1-MeC-N3)(H(2)O)](2+) (6; 1-MeC: 1-methylcytosine), with the electrophile [Pd(en)(H(2)O)(2)](2+) (en: ethylenediamine) at pH approximately 6 yields a kinetic product X which is likely to be a dinuclear Pt,Pd complex containing 1-MeC(-)-N3,N4 and OH bridges, namely cis-[Pt(NH(3))(2)(1-MeC(-)-N3,N4)(OH)Pd(en)](2+). Upon addition of excess Ag(+) ions, conversion takes place to form a thermodynamic product, which, according to (1)H NMR spectroscopy and X-ray crystallography, is dominated by a mu-NH(2) bridge between the Pt(II) and Pd(II) centers. X-ray crystallography reveals that the compound crystallizes out of solution as a dodecanuclear complex containing four Pt(II), four Pd(II), and four Ag(+) entities: [{Pt(2)(1-MeC(-)-N3,N4)(2)(NH(3))(2)(NH(2))(2)(OH)Pd(2)(en)(2)Ag}(2){Ag(H(2)O)}(2)](NO(3))(10) 6 H(2)O (10) is composed of a roughly planar array of the 12 metal ions, in which the metal ions are interconnected by mu-NH(2) groups (between Pt and Pd centers), mu-OH groups (between pairs of Pt atoms), and metal-metal donor bonds (Pt-->Ag, Pd-->Ag). The four 1-methylcytosinato ligands, which are stacked pairwise, as well as the four NH(3) ligands and parts of the en rings, are approximately perpendicular to the metal plane. Two of the four Ag ions (Ag2, Ag2') of 10 are labile in solution and show the expected behavior of Ag(+) ions in water, that is, they are readily precipitated as AgCl by Cl(-) ions. The resulting pentanuclear complex [Pt(2)Pd(2)Ag(1-MeC(-))(2)(NH(2))(2)(OH)(NH(3))(2)(en)(2)](NO(3))(4)7 H(2)O (11) largely maintains the structural features of one half of 10. The other two Ag(+) ions (Ag1, Ag1') of 10 are remarkably unreactive toward excess NaCl. In fact, the pentanuclear complex [Pt(2)Pd(2)AgCl(1-MeC(-))(2)(NH(2))(2)(OH)(NH(3))(2)(en)(2)](NO(3))(3)4.5 H(2)O (12), obtained from 10 with excess NaCl, displays a Cl(-) anion bound to the Ag center (2.459(3) A) and is thus a rare case of a crystallized "AgCl molecule".     

The chemistry of dinuclear analogues of the anticancer drug cisplatin. A DFT/CDM study

The mechanism of the formation of dinuclear platinum(II) mu-hydroxo complexes from cisplatin hydrolysis products, their interconversion, decomposition, and reactions with biomolecules has been explored using a combined DFT/CDM approach. All activation barriers for the formation of [cis-{Pt(NH(3))(2)(X)}-(mu-OH)-cis-{Pt(NH(3))(2)(Y)}](n)()(+) (X, Y = Cl, OH(2), OH) via nucleophilic attack of a hydroxo complex on an aqua complex are lower than the activation barriers for cisplatin hydrolysis. Considering therapeutic Pt(II) concentrations in tumors, however, only the reaction between two molecules of cis-[Pt(NH(3))(2)(OH(2))(OH)](+) (E) yielding [cis-{Pt(NH(3))(2)(OH(2))}-(mu-OH)-cis-{Pt(NH(3))(2)(OH)}](2+) (5) remains kinetically superior to cisplatin hydrolysis. 5 is strongly stabilized by intramolecular hydrogen bonding between the terminal aqua and hydroxo ligands, resulting in an unusually high pK(a) of 5 and a low pK(a) of its conjugate acid. Unimolecular cyclization of 5 yields the dimers [cis-{Pt(NH(3))(2)}(mu-OH)](2)(2+) (7a with antiperiplanar OH groups and 7b with synperiplanar OH groups). The electronic structure of several diplatinum(II) complexes has been analyzed to clarify whether there are metal-metal interactions. The overall reactivity to guanine (Gua) and dimethyl sulfide (Met, representing the thioether functional group of methionine) increases in the order 5 < 7a approximately 7b < mononuclear complexes, whereas the kinetic selectivity to Gua relative to Met increases in the order 7a approximately 5 < 7b approximately monocationic mononuclear complexes < dicationic mononuclear complex. The results of this work (i) help assess whether dinuclear metabolites play a role in cisplatin chemotherapy, (ii) elucidate the toxicity and pharmacological inactivity of [cis-{Pt(NH(3))(2)}(mu-OH)](2)(2+), and (iii) suggest future investigations of dinuclear anticancer complexes that contain one mu-hydroxo ligand.     

Strategy for the rational design of asymmetric triply bridged dinuclear 3d-4f single-molecule magnets

Three triply bridged M(II)-Dy(III) dinuclear complexes, [Ni(μ-L)(μ-OAc)Dy(NO(3))(2)] 1, [Zn(μ-L)(μ-OAc)Dy(NO(3))(2)] 2, and [Ni(μ-L)(μ-NO(3))Dy(NO(3))(2)]·2CH(3)OH 3 were prepared with a new and flexible compartmental ligand, N,N',N″-trimethyl-N,N″-bis(2-hydroxy-3-methoxy-5-methylbenzyl)diethylene triamine (H(2)L), containing N(3)O(2)-inner and O(4)-outer coordination sites. These complexes have diphenoxo/acetate (1 and 2) or diphenoxo/nitrate (3) asymmetric bridging fragments. Compounds 1 and 3 exhibit ferromagnetic interaction between Ni(2+) and Dy(3+) ions and frequency dependence of the out-of-phase (χ″(M)) alternating current (ac) susceptibility signal characteristic of single-molecule-magnet behavior. The energy barriers Δ/k(B) for compound 3 under zero and 1000 Oe applied direct current (dc) magnetic fields were estimated from the Arrhenius plots to be 7.6 and 19.1 K, respectively.     

Reactions of acetonitrile coordinated to a nitrosylruthenium complex with H2O or CH(3)OH under mild conditions: structural characterization of imido-type complexes

The reaction of cis-[Ru(NO)(CH(3)CN)(bpy)(2)](3+) (bpy = 2,2'-bipyridine) in H(2)O at room temperature proceeded to afford two new nitrosylruthenium complexes. These complexes have been identified as nitrosylruthenium complexes containing the N-bound methylcarboxyimidato ligand, cis-[Ru(NO)(NH=C(O)CH(3))(bpy)(2)](2+), and methylcarboxyimido acid ligand, cis-[Ru(NO)(NH=C(OH)CH(3))(bpy)(2)](3+), formed by an electrophilic reaction at the nitrile carbon of the acetonitrile coordinated to the ruthenium ion. The X-ray structure analysis on a single crystal obtained from CH(3)CN-H(2)O solution of cis-[Ru(NO)(NH=C(O)CH(3))(bpy)(2)](PF(6))(3) has been performed: C(22)H(20.5)N(6)O(2)P(2.5)F(15)Ru, orthorhombic, Pccn, a = 15.966(1) A, b = 31.839(1) A, c = 11.707(1) A, V = 5950.8(4) A(3), and Z = 8. The structural results revealed that the single crystal consisted of 1:1 mixture of cis-[Ru(NO)(NH=C(O)CH(3))(bpy)(2)](2+) and cis-[Ru(NO)(NH=C(OH)CH(3))(bpy)(2)](3+) and the structural formula of this single crystal was thus [Ru(NO)(NH=C(OH(0.5))CH(3))(bpy)(2)](PF(6))(2.5). The reaction of cis-[Ru(NO)(CH(3)CN)(bpy)(2)](3+) in dry CH(3)OH-CH(3)CN at room temperature afforded a nitrosylruthenium complex containing the methyl methylcarboxyimidate ligand, cis-[Ru(NO)(NH=C(OCH(3))CH(3))(bpy)(2)](3+). The structure has been determined by X-ray structure analysis: C(25)H(29)N(8)O(18)Cl(3)Ru, monoclinic, P2(1)/c, a = 13.129(1) A, b = 17.053(1) A, c = 15.711(1) A, beta = 90.876(5) degrees, V = 3517.3(4) A(3), and Z = 4.     

G-G base-pairing in nucleobase adducts of the anticancer drug cis-[PtCl2(NH3)(2-picoline)] and its trans isomer

cis-[PtCl2(NH3)(2-picoline)] (AMD473) is a sterically-hindered anticancer complex with a profile of chemical and biological activity that differs significantly from that of cisplatin. Adducts of AMD473 with neutral 9-ethylguanine (9-EtGH) and anionic (N1-deprotonated) 9-ethylguanine (9-EtG) as perchlorate and nitrate salts, and also a nitrate salt of the trans isomer (AMD443), were prepared and their structures determined by X-ray crystallography: cis-[Pt(NH3)(2-pic)(9-EtGH)2](ClO4)2 (1).2H(2)OMe(2)CO, cis-[Pt(NH3)(2-pic)(9-EtGH)2](NO3)2 (2).2H2O, cis-[Pt(NH3)(2-pic)(9-EtGH)(9-EtG)]NO3 (3),3.5 H2O, trans-[Pt(NH3)(2-pic)(9-EtGH)(9-EtG)]NO3 (4).8H2O. In all cases, platinum coordination is through N7 of neutral (1, 2) and anionic (3, 4) guanine. In each complex, the guanine bases are arranged in the head-to-tail conformation. In complex 1, there is an infinite array of six-molecule cycles, based on both hydrogen bonding and pi-pi stacking of the 2-picoline and guanine rings. Platinum(II) coordinated at N7 acidifies the N1 proton of neutral 9-ethylguanine (pKa = 9.57) to give pKa1 = 8.40 and pKa2 = 8.75 for complex 2, and pKa1 = 7.77 and pKa2 = 9.00 for complex 4. In complexes 3 and 4, three intermolecular hydrogen bonds are formed between neutral and deprotonated guanine ligands involving O6, N1 and N2 sites. Unusually, both of the platinated guanine bases of complexes 3 and 4 participate in this triple G triple bond G hydrogen bonding. This is the first report of X-ray crystal structures of nucleobase adducts of the promising anticancer drug AMD473.     

Dinuclear platinum complexes with biological relevance based on the 1,2-diaminocyclohexane carrier ligand

The synthesis of bifunctional dinuclear platinum complexes, [{PtCl(dach)}(2)-mu-Y](n+)Cl(n) (1-3; Y = H(2)N(CH(2))(3)NH(2)(CH(2))(4)NH(2), H(2)N(CH(2))(6)NH(2)(CH(2))(6)NH(2), and H(2)N(CH(2))(6)NH(2)(CH(2))(2)NH(2)(CH(2))(6)NH(2), respectively; Figure 1) is reported. There was no labilization of the polyamine linker groups of the cis-1,2-diaminocyclohexane complexes in the presence of sulfur-containing species at physiological pH, in contrast to previous studies preformed on trans complexes. Metabolism reactions are somewhat dependent on the nature of the polyamine: at physiological pH, the spermidine complex 1 forms an inert (tetraamine)platinum species in which one platinum is chelated by a central and terminal amino group. The stability of cis-geometry complexes may make them viable second-generation polynuclear platinum clinical candidates.     

Amidoximes provide facile platinum(II)-mediated oxime-nitrile coupling

The nucleophilic addition of amidoximes R'C(NH(2))═NOH [R' = Me (2.Me), Ph (2.Ph)] to coordinated nitriles in the platinum(II) complexes trans-[PtCl(2)(RCN)(2)] [R = Et (1t.Et), Ph (1t.Ph), NMe(2) (1t.NMe(2))] and cis-[PtCl(2)(RCN)(2)] [R = Et (1c.Et), Ph (1c.Ph), NMe(2) (1c.NMe(2))] proceeds in a 1:1 molar ratio and leads to the monoaddition products trans-[PtCl(RCN){HN═C(R)ONC(R')NH(2)}]Cl [R = NMe(2); R' = Me ([3a]Cl), Ph ([3b]Cl)], cis-[PtCl(2){HN═C(R)ONC(R')NH(2)}] [R = NMe(2); R' = Me (4a), Ph (4b)], and trans/cis-[PtCl(2)(RCN){HN═C(R)ONC(R')NH(2)}] [R = Et; R' = Me (5a, 6a), Ph (5b, 6b); R = Ph; R' = Me (5c, 6c), Ph (5d, 6d), correspondingly]. If the nucleophilic addition proceeds in a 2:1 molar ratio, the reaction gives the bisaddition species trans/cis-[Pt{HN═C(R)ONC(R')NH(2)}(2)]Cl(2) [R = NMe(2); R' = Me ([7a]Cl(2), [8a]Cl(2)), Ph ([7b]Cl(2), [8b]Cl(2))] and trans/cis-[PtCl(2){HN═C(R)ONC(R')NH(2)}(2)] [R = Et; R' = Me (10a), Ph (9b, 10b); R = Ph; R' = Me (9c, 10c), Ph (9d, 10d), respectively]. The reaction of 1 equiv of the corresponding amidoxime and each of [3a]Cl, [3b]Cl, 5b-5d, and 6a-6d leads to [7a]Cl(2), [7b]Cl(2), 9b-9d, and 10a-10d. Open-chain bisaddition species 9b-9d and 10a-10d were transformed to corresponding chelated bisaddition complexes [7d](2+)-[7f](2+) and [8c](2+)-[8f](2+) by the addition of 2 equiv AgNO(3). All of the complexes synthesized bear nitrogen-bound O-iminoacylated amidoxime groups. The obtained complexes were characterized by elemental analyses, high-resolution ESI-MS, IR, and (1)H NMR techniques, while 4a, 4b, 5b, 6d, [7b](Cl)(2), [7d](SO(3)CF(3))(2), [8b](Cl)(2), [8f](NO(3))(2), 9b, and 10b were also characterized by single-crystal X-ray diffraction.     

Reactions of a platinum(III) dimeric complex with alkynes in water: novel approach to alpha-aminoketone, alpha-iminoketone, and alpha,beta-diimine via ketonyl-Pt(III) dinuclear complexes

Reaction of the platinum(III) dimeric complex [Pt(2)(NH(3))(4)((CH(3))(3)CCONH)(2)(NO(3))(2)](NO(3))(2) (1), prepared in situ by the oxidation of the platinum blue complex [Pt(4)(NH(3))(8)((CH(3))(3)CCONH)(4)](NO(3))(5) (2) with Na(2)S(2)O(8), with terminal alkynes CH[triple bond]CR (R = (CH(2))(n)CH(3) (n = 2-5), (CH(2))(n)CH(2)OH (n = 0-2), CH(2)OCH(3), and Ph), in water gave a series of ketonyl-Pt(III) dinuclear complexes [Pt(2)(NH(3))(4)((CH(3))(3)CCONH)(2)(CH(2)COR)](NO(3))(3) (3, R = (CH(2))(2)CH(3); 4, R = (CH(2))(3)CH(3); 5, R = (CH(2))(4)CH(3); 6, R = (CH(2))(5)CH(3); 7, R = CH(2)OH; 8, R = CH(2)CH(2)OH; 9, R = (CH(2))(2)CH(2)OH; 10, R = CH(2)OCH(3); 11, R = Ph). Internal alkyne 2-butyne reacted with 1 to form the complex [Pt(2)(NH(3))(4)((CH(3))(3)CCONH)(2)(CH(CH(3))COCH(3))](NO(3))(3) (12). These reactions show that Pt(III) reacts with alkynes to give various ketonyl complexes. Coordination of the triple bond to the Pt(III) atom at the axial position, followed by nucleophilic attack of water and hydrogen shift from the enol to keto form, would be the mechanism. The structures of complexes 3.H(2)O, 7.0.5C(3)H(4)O, 9, 10, and 12 have been confirmed by X-ray diffraction analysis. A competitive reaction between equimolar 1-pentyne and 1-pentene toward 1 produced complex 3 and [Pt(2)(NH(3))(4)((CH(3))(3)CCONH)(2)(CH(2)CH(OH)CH(2)CH(2)CH(3))](NO(3))(3) (14) at a molar ratio of 9:1, suggesting that alkyne is more reactive than alkene. The ketonyl-Pt(III) dinuclear complexes are susceptible to nucleophiles, such as amines, and the reactions with secondary and tertiary amines give the corresponding alpha-amino-substituted ketones and the reduced Pt(II) complex quantitatively. In the reactions with primary amines, the once formed alpha-amino-substituted ketones were further converted to the iminoketones and diimines. The nucleophilic attack at the ketonyl group of the Pt(III) complexes provides a convenient means for the preparation of alpha-aminoketones, alpha-iminoketones, and diimines from the corresponding alkynes and amines.     

Dinitrogen formation by oxidative intramolecular N---N coupling in cis,cis-[(bpy)2(NH3)RuORu(NH3)(bpy)2]4+

The (15)N-labeled diammine(mu-oxo)ruthenium complex cis,cis-[(bpy)(2)(H(3)(15)N)Ru(III)ORu(III)((15)NH(3))(bpy)(2)](4+) ((2-(15)N)(4+)) was synthesized from cis,cis-[(bpy)(2)(H(2)O)Ru(III)ORu(III)(H(2)O)(bpy)(2)](4+) by using ((15)NH(4))(2)SO(4) and isolated as its perchlorate salt in 17% yield. A 1:1 mixture of (2-(15)N)(4+) and nonlabeled cis,cis-[(bpy)(2)(H(3)(14)N)Ru(III)ORu(III)((14)NH(3))(bpy)(2)](4+) were electrochemically oxidized in aqueous solution. The gaseous products (14)N(2) and (15)N(2) were formed in equimolar amounts with only a small amount of (14)N(15)N detected. This demonstrates that dinitrogen formation by oxidation of the diammine complex proceeds by intramolecular N---N coupling.     

Synthesis of ketonylplatinum(III) dinuclear complexes: observation of the competitive radical vs electrophilic displacement in Pt(III)-promoted C-H bond activation of ketones.

New ketonylplatinum(III) dinuclear complexes [Pt(2)((CH(3))(3)CCONH)(2)(NH(3))(4)(CH(2)COPh)](NO(3))(3) (4), [Pt(2)((CH(3))(3)CCONH)(2)(NH(3))(4)(CH(CH(3))COC(2)H(5))](NO(3))(3) (5), and [Pt(2)((CH(3))(3)CCONH)(2)(NH(3))(4)(CH(2)COCH(2)COCH(3))](NO(3))(3) (6) were prepared by treatment of platinum blue complex [Pt(4)(NH(3))(8)((CH(3))(3)CCONH)(4)](NO(3))(5) (2) with acetophenone, 3-pentanone, and acetylacetone, respectively, in the presence of concentrated HNO(3). The structures of complexes 4 and 6 have been confirmed by X-ray diffraction analysis, which revealed that the C-H bonds of the methyl groups in acetophenone and acetylacetone have been cleaved and Pt(III)-C bonds are formed. Formation of diketonylplatinum(III) complex 6 provides a novel example of the C-H bond activation not at the central alpha-C-H but at the terminal methyl of acetylacetone. Reaction with butanone having unsymmetrical alpha-H atoms led to two types of ketonylplatinum(III) complexes [Pt(2)((CH(3))(3)CCONH)(2)(NH(3))(4)(CH(CH(3))COCH(3))](NO(3))(3) (7a) and [Pt(2)((CH(3))(3)CCONH)(2)(NH(3))(4)(CH(2)COCH(2)CH(3))](NO(3))(3) (7b) at a molar ratio of 1.7 to 1 corresponding to the C-H bond activation of methylene and methyl groups, respectively. Use of 3-methyl-2-butanone instead of butanone gave complex [Pt(2)((CH(3))(3)CCONH)(2)(NH(3))(4)(CH(2)COCH(CH(3))(2))](NO(3))(3) (8) as a sole product via C-H bond activation in the alpha-methyl group. The reactivity of the ketonylplatinum(III) dinuclear complexes toward nucleophiles, such as H(2)O and HNEt(2), was examined. The alpha-hydroxyl- and alpha-amino-substituted ketones were generated in the reactions of [Pt(2)((CH(3))(3)CCONH)(2)(NH(3))(4)(CH(2)COCH(3))](NO(3))(3) (1), 5, and a mixture of 7a and 7b with water and amine, which indicates that the carbon atom in the ketonyl group bound to the Pt(III) atom can receive a nucleophilic attack. The high electrophilicity of the ketonylplatinum(III) complexes can be accounted for by the high electron-withdrawing ability of the platinum(III) atom. A competition between the radical and electrophilic displacement pathways was observed directly in the C-H bond activation reaction with butanone giving complexes 7a and 7b. Addition of a radical trapping agent suppressed the radical pathway and gave complex 7b as the predominant product. On the contrary, 7a was formed as the main product when the reaction solution was irradiated by mercury lamp light. These results together with other mechanistic studies demonstrate that complex 7a was produced via a radical process, whereas complex 7b is produced via electrophilic displacement of a proton by the Pt(III) atom. The competitive processes were further observed in the reactions of platinum blue complex 2 with a mixture of acetone and 3-pentanone in the presence of HNO(3). The relative molar ratio of acetonyl complex 1 to pentanoyl complex 5 was 3 to 1 under room light, whereas formation of complex 5 was almost suppressed when the reaction was carried out in the dark with the addition of a radical trapping agent.     

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)}](+).     

Highly efficient DNA compaction mediated by an in vivo antitumor-active tetrazolato-bridged dinuclear platinum(II) complex

We investigated the effects of antitumor-active tetrazolato-bridged dinuclear platinum(II) complexes [{cis-Pt(NH(3))(2)}(2)(μ-OH)(μ-tetrazolato-N(1),N(2))](2+) (1) and [{cis-Pt(NH(3))(2)}(2)(μ-OH)(μ-tetrazolato-N(2),N(3))](2+) (2) on the higher-order structure of a large DNA molecule (T4 phage DNA, 166 kbp) in aqueous solution through single-molecule observation by fluorescence microscopy. Complexes 1 and 2 cause irreversible compaction of DNA through an intermediate state in which coil and compact parts coexist in a single DNA molecule. The potency of compaction is in the order 2 > 1 ? cisplatin. Transmission electron microscopic observation showed that both complexes collapsed DNA into an irregularly packed structure. Circular dichroism measurements revealed that the dinuclear platinum(II) complexes change the secondary structure of DNA from the B to C form. These characteristics of platinum(II) complexes are markedly different from those of the usual condensing agents such as spermidine(3+) and [Co(III)(NH(3))(6)](3+). The ability to cause DNA compaction by the platinum(II) complexes is discussed in relation to their potent antitumor activity.     

Multinuclear platinum(II)-amine complexes containing bis(aminopropyl)dicarba-closo-dodecaborane(12) ligands

Treatment of the bridging bidentate 1,Z-bis(aminopropyl)-1,Z-dicarba-closo-dodecaborane(12)(1,Z-bis(aminopropyl)-1,Z-carborane) ligands of the type 1,Z-[H(2)N(CH(2))(3)](2)-1,Z-C(2)B(10)H(10)(L(1), Z= 7, 5) or (L(2), Z= 12, 6) with two equivalents of trans-[PtClI(2)(NH(3))](-), followed by halogen ligand metathesis with AgOTf and HCl((aq)) afforded the novel diplatinum(II)-amine species cis-[[PtCl(2)(NH(3))](2)L(n)](7(n= 1) or 8(n= 2), respectively). Similarly, the reaction of L(1) or L(2) with the labile trans-[PtCl(dmf)(NH(3))(2)](+) afforded trans-[[PtCl(NH(3))(2)](2)L(n)](OTf)(2)(9(n= 1) or 10(n= 2), respectively) in good yield and purity. However, isolation of the analogous 1,2-carborane complexes was not possible owing to decomposition reactions that led to extensive degradation of the carborane cage and reduction of the metal centre. The mixed dinuclear complex [cis-[PtCl(2)(NH(3))]-L(1)-trans-[PtCl(NH(3))(2)]]OTf (19) was prepared by treatment of the Boc-protected amine ligand 1-[(Boc)(2)N(CH(2))(3)]-7-[H(2)N(CH(2))(3)]-1,7-C(2)B(10)H(10)(L(3), 15) with trans-[PtCl(dmf)(NH(3))(2)](+) to yield trans-[PtCl(NH(3))(2)L(3)]OTf (16), followed by acid deprotection of the pendant amine group, complexation with trans-[PtClI(2)(NH(3))](-), and halogen ligand metathesis using AgOTf and HCl((aq)). A novel trinuclear species containing 5 was prepared by the addition of two equivalents of 15 to the labile precursor cis-[Pt(dmf)(2)(NH(3))(2)](2+) followed by acid deprotection of the pendant amine groups. Further complexation with two equivalents of trans-[PtClI(2)(NH(3))](-) followed by halogen ligand metathesis using AgOTf and HCl((aq)) afforded the triplatinum(II)-amine species [cis-[Pt(NH(3))(2)(L(1))(2)]-cis-[PtCl(2)(NH(3))](2)](OTf)(2)(23). Complexes 7-10, 19 and 23 represent the first examples of multinuclear platinum(ii)-amine derivatives containing carborane cages. Preliminary in vitro cytotoxicity studies for selected complexes are also reported.     

Supramolecular isomerism of 2,2'-bipyrazine complexes with cis-(NH(3))(2)Pt(II): ligand rotational state and sequential orientation determine the 3D shape of metallacycles

2,2'-Bipyrazine (2,2'-bpz) reacts with cis-(NH(3))(2)Pt(II) in water to give a variety of products, several of which were isolated and characterized by X-ray analysis: cis-[Pt(NH(3))(2)(2,2'-bpz-N4)(2)](NO(3))(2)·3H(2)O (1), [{cis-Pt(NH(3))(2)(2,2'-bpz-N4,N4')}(3)]-(PF(6))(5)NO(3)·7H(2)O (2a), [{cis-Pt(NH(3))(2)(2,2'-bpz-N4,N4')}(3)](BF(4))(2)-(SiF(6))(2)·15H(2)O (2b), and [{cis-Pt(NH(3))(2)(2,2'-bpz-N4,N4')}(4)]-(SO(4))(4)·22H(2)O (3). In 1, 2b, and 3 the 2,2'-bpz ligands adopt approximately C(2h) symmetries, hence the two pyrazine halves are in trans orientation, whereas in 2a all three 2,2'-bpz bridges are approximately C(2v) symmetric, with the pyrazine halves cis to each other. The topologies of the two triangular complexes 2a and 2b are consequently distinctly different, but nevertheless both cations act as hosts for anions. In 2a a PF(6)(-) and a NO(3)(-) anion are associated simultaneously with the +6 cation, whereas in 2b it is a BF(4)(-) anion and a water molecule, which are trapped in its cavity. There is no anion inclusion in case of the metallasquare 3. In principle, 3 can exist in a large number of stereoisomers, depending on the rotational states of the bridging 2,2'-bpz ligands. Isolation of a single rotamer form of 3 with C(2h) symmetric 2,2'-bpz ligands and an overall meso form is proposed to be a consequence of a highly efficient self-assembly process that starts from the precursor 1 and reaction with two cis-(NH(3))(2)Pt(II) units. This process leads to the isolated rotamer of 3 regardless of whether two cations 1 in head-head form react with two cis-(NH(3))(2)Pt(II), or whether the Δ enantiomer of the chiral head-tail form of 1 combines with its Λ enantiomer through two cis-(NH(3))(2)Pt(II) entities.     

Complexes of platinum(II) containing neutral and deprotonated 9-methyladenine. Synthesis, x-ray structures, and NMR studies on the cyclic trimer cis-[L2Pt[9-MeAd([bond]H)]]3(NO3)3 and the Dinuclear cis-[L2Pt(ONO2)[9-MeAd([bond]H)]PtL2](NO3)2 (L = PMePh2)

The dinuclear hydroxo complex cis-[L(2)Pt(mu-OH)](2)(NO(3))(2) (L = PMePh(2), 1), in CH(2)Cl(2), CH(3)CN, or DMF solution, deprotonates the NH(2) group of 9-methyladenine (9-MeAd) to give the complex cis-[L(2)Pt[9-MeAd(-H)]](3)(NO(3))(3), 2, which was isolated in good yield. The X-ray structure shows that the nucleobase binds symmetrically the metal centers through the N(1),N(6) atoms forming a cyclic trimer with Pt...Pt distances in the range 5.202(1)-5.382(1) A. Dissolution of 2 in DMSO or DMF determines the partial (or total) dissociation of the cyclic structure to form several fragments. A multinuclear NMR analysis of the resulting mixture supports the presence of the mononuclear species cis-[L(2)Pt[9-MeAd(-H)]](+), 3, in which the deprotonated nucleobase chelates the metal center with the N(6),N(7) atoms. Addition of a stoichiometric amount of the nitrato complex cis-[L(2)Pt(ONO(2))(2)] (L = PMePh(2), 4) to a DMSO or DMF solution of 2 affords quantitatively the diplatinated compound cis-[L(2)Pt(ONO(2))[9-MeAd(-H)]PtL(2)](NO(3))(2), 5. The single-crystal X-ray analysis shows that the adenine behaves as a tridentate ligand bridging two cis-L(2)Pt units at the N(1) and N(6),N(7) sites, respectively [Pt(1)-N(1) = 2.109(5) A, Pt(2)-N(6) = 2.095(7) A, Pt(2)-N(7) = 2.126(7) A]. The N(1)-bonded metal center completes the coordination sphere through an oxygen atom of a nitrate group, and its coordination plane is arranged orthogonally with respect the second one. The Pt-O distance [2.109(5) A] is similar to those found in the nitrato complex 4 [2.110 A, average]. The related complex cis-[[L(2)Pt(ONO(2))](2)(9-MeAd)](NO(3))(2), 6, containing the neutral adenine platinated at the N(1),N(7) atoms, was isolated and its stability in solution investigated by NMR spectroscopy. In DMSO, 6 undergoes decomposition forming a mixture of the species 4, 5, and the adenine mono- and bis-adducts cis-[L(2)Pt(9-MeAd)(DMSO)](2+), 7, and cis-[L(2)Pt(9-MeAd)(2)](2+), 8, respectively. This last complex, quantitatively formed upon addition of 9-MeAd (Pt/adenine = 1:2) to the mixture, was also isolated and characterized.     

Study of intramolecular competition between carboxylate and phosphonate for Pt(II) with the aid of a novel tridentate carboxylato-thioether-phosphonato ligand

The tridentate dianionic ligand 2-[2'-(hydroxyisopropoxyphosphoryl)phenylsulfanyl]benzoate (L(2-)) reacts with cis-[Pt(NH(3))(2)(H(2)O)(2)](2+) to form an S,O-chelate in which the O-coordinated group is either carboxylate or phosphonate, depending on the degree of protonation of the complex. Carboxylate appears to be the stronger ligand, and the stoichiometric reaction between cis-[Pt(NH(3))(2)(H(2)O)(2)](2+) and L(2-) yields the neutral species [Pt(L)(NH(3))(2)], with L bound by sulfanyl and carboxylate groups, both in solution and in the solid state. Upon protonation of [Pt(L)(NH(3))(2)], the stronger basicity of the carboxylate causes the Pt coordination to switch from carboxylate to phosphonate, and the uncoordinated carboxylate group becomes protonated. In methanolic solution, the first-order kinetics of this rearrangement could be observed by (31)P NMR spectroscopy. Both complexes-the carboxylate-bound neutral complex [Pt(L)(NH(3))(2)].H(2)O (triclinic, P1 (no. 2), a=9.529(6), b=9.766(6), c=12.299(7) angstroms, alpha=106.91(2), beta=101.71(2), gamma=102.05(2) degrees, Z=2) and the perchlorate salt of the phosphonate-bound complex [Pt(LH)(NH(3))(2)]ClO(4).H(2)O (monoclinic, P2(1)/c (no. 14), a=12.095(2), b=14.046(2), c=14.448(2) angstroms, beta=95.55(2) degrees, Z=4)-were characterized by X-ray crystallography.     

Pyrazine as a building block for molecular architectures with PtII

A series of pyrazine (pz) complexes containing cis-(NH(3))(2)Pt(II), (tmeda)Pt(II) (tmeda = N,N,N',N'-tetramethylethylenediamine), and trans-(NH(3))(2)Pt(II) entities have been prepared and characterized by X-ray crystallography and/or 1H NMR spectroscopy. In these compounds, the pz ligands act as monodentate (1-3) or bidentate bridging ligands (4-7). Three variants of the latter case are described: a dinuclear complex [Pt(II)]2 (4b), a cyclic tetranuclear [Pt(II)](4) complex (5), and a trinuclear mixed-metal complex [Pt2Ag] (7). Mono- and bidentate binding modes are readily differentiated by 1H NMR spectroscopy, and the assignment of pz protons in the case of monodentate coordination is aided by the observation of (195)Pt satellites. Formation of the open molecular box cis-[{(NH3)2Pt(pz)}4](NO3)8.3.67H2O (5) from cis-(NH3)2Pt(II) and pz follows expectations of the "molecular library approach" for the generation of a cyclic tetramer.     

Pt(II)-promoted [2 + 3] cycloaddition of azide to cyanopyridines: convenient tool toward heterometallic structures

The [2 + 3] cycloaddition reactions (which are greatly accelerated by microwave irradiation) of the di(azido)platinum(II) compounds cis-[Pt(N(3))(2)(PPh(3))(2)] (1) with cyanopyridines NCR (2) (R = 4-, 3-, and 2-NC(5)H(4)) give the corresponding bis(pyridyltetrazolato) complexes trans-[Pt(N(4)CR)(2)(PPh(3))(2)] (3) [R = 4-NC(5)H(4) (3a), 3-NC(5)H(4) (3b), and 2-NC(5)H(4) (3c)]. Compound 3c has been characterized as the N(1)N(2)-bonded isomer in the solid state by X-ray crystallography and represents the first bis(tetrazolato) complex of this kind. Complexes 3a and 3b have been used as metallaligands to generate heteronuclear coordination polymers in the presence of copper nitrate. A one-dimensional supramolecular architecture was obtained as the exclusive product, {trans-[Pt(2)(N(4)CR)(4)(PPh(3))(4)Cu](n)(NO(3))(2n).nH(2)O (4.nH(2)O) (R = 4-NC(5)H(4)), when 3a was employed, whereas with 3b the heteronuclear square complex trans-[Pt(N(4)CR)(2)(PPh(3))(2)Cu(NO(3))(2)(H(2)O)](2) (5) (R = 3-NC(5)H(4)), composed of Pt/Cu ions, was obtained. All the isolated complexes were characterized by IR, elemental, and (for 3b, 3c, 4, and 5) X-ray structural analyses. Complexes 3 were additionally characterized by (1)H, (13)C, and (31)P {(1)H} NMR spectroscopies.     

ESI-MS and thermal melting studies of nanoscale platinum(II) metallomacrocycles with DNA

The hydrophilic, long-chain diamine PEGda (O,O'-bis(2-aminoethyl)octadeca(ethylene glycol)), when complexed with cis-protected Pt(II) ions afforded water-soluble complexes of the type [Pt(N,N)(PEGda)](NO(3))(2) (N,N = N,N,N',N'-tetramethyl-1,2-diaminoethane (tmeda), 1,2-diaminoethane (en), and 2,2'-bipyridine (2,2'-bipy)) featuring unusual 62-membered chelate rings. Equimolar mixtures containing either the 16-mer duplex DNA D2 or the single-stranded D2a and [Pt(N,N)(PEGda)](2+) were analyzed by negative-ion ESI-MS. Analysis of D2-Pt(II) mixtures showed the formation of 1 : 1 adducts of [Pt(en)(PEGda)](2+), [Pt(tmeda)(PEGda)](2+) and the previously-described metallomacrocycle [Pt(2)(2,2'-bipy)(2){4,4'-bipy(CH(2))(4)4,4'-bipy}(2)](8+) with D2; the dinuclear species bound to D2 most strongly, consistent with its greater charge and aromatic surface area. D2 formed 1 : 2 complexes with the acyclic species [Pt(2,2'-bipy)(Mebipy)(2)](4+) and [Pt(2,2'-bipy)(NH(3))(2)](2+). Analyses of D2a-Pt(II) mixtures gave results similar to those obtained with D2, although fragmentation was more pronounced, indicating that the nucleobases in D2a play more significant roles in mediating the decomposition of complexes than those in D2, in which they are paired in a complementary manner. Investigations were also conducted into the effects of selected platinum(II) complexes on the thermal denaturation of calf thymus DNA (CT-DNA) in buffered solution. Both [Pt(2)(2,2'-bipy)(2){4,4'-bipy(CH(2))(6)4,4'-bipy}(2)](8+) and [Pt(2,2'-bipy)(Mebipy)(2)](4+) stabilized CT-DNA. In contrast, [Pt(tmeda)(PEGda)](2+) and [Pt(en)(PEGda)](2+) (as well as free PEGda) caused negligible changes in melting temperature (ΔT(m)), suggesting that these species interact weakly with CT-DNA.     

How strong can the bend be on a DNA helix from cisplatin? DFT and MP2 quantum chemical calculations of cisplatin-bridged DNA purine bases

The B3LYP/6-31G(d) level of theory was used for the optimization of [Pt(NH(3))(4)](2+), [Pt(NH(3))(3)(H(2)O)](2+), cis-[Pt(NH(3))(2)(H(2)O)(2)](2+), and related platinum complexes. In addition, water or ammonium ligands were replaced by DNA purine bases so that finally cis-diammineplatinum with two bases (Pt-bridged complexes) is obtained. Single point calculations using the MP2/6-31+G(d) method were performed on the obtained reference geometries and were utilized for estimating bond dissociation energies (BDEs) and stabilization energies, and for electron density analyses. After reoptimization, IR spectra were determined from HF second derivatives. It was found that replacement of both water and ammonium by the DNA base is an exothermic process (20-50 kcal/mol depending on the ligands present in the complex). Asymmetric structures with one interbase H-bond were obtained for cis-diammine[bond](N(7),N(7)'-diadenine)[bond]platinum and mixed cis-diammine[bond](N(7)-adenine)[bond](N(7)-guanine)[bond]platinum complexes. In the case of the diguanine Pt-bridge, a symmetrical complex with two ammonium...O(6) H-bonds was found. The higher stabilization energy of the di-guanine complex is linked to a larger component of the Coulombic interaction. However, the BDE of Pt[bond]N(7)(G) is smaller in this complex than the BDE of Pt[bond]N(7)(G) from the mixed Pt[bond]AG complex. Also, steric repulsion of the ligands is about 10 kcal/mol smaller for the asymmetrical Pt[bond]AA and Pt[bond]AG bridges. The influence of the trans effect on DBE can be clearly seen. Adenine exhibits the largest trans effect, followed by guanine, ammonium, and water. The strength of the H-bond can be determined from the IR spectra. The strongest H-bond is the interbase H-bridge between adenine and guanine in the mixed Pt[bond]AG complex; otherwise, the H-bonds of adenine complexes are weaker than in guanine complexes. BDE can be traced in the guanine-containing complexes. The nature of the covalent bonding is analyzed in terms of partial charges and MO. A general explanation of the lower affinity of transition metals to oxygen than nitrogen can be partially seen in the less favorable geometrical orientation of lone electron pairs of oxygen.