Studies of the reaction products of adenosine with [Pt(NH3)3Cl]Cl and cis-Pt(NH3)2Cl2 by high performance liquid chromatography

The reaction products of adenosine with [Pt(NH₃)₃Cl]Cl or cis-Pt(NH₃)₂Cl₂ have been studied using high performance liquid chromatography and uv spectroscopy. The reaction of [Pt(NH₃)₃Cl]Cl with adenosine (pH = 7.0, Pt/base = 0.5) gives four products. Two of them, mononuclear complexes in which platinum is bound to adenosine through N(7) or N(1), comprise more than 90% of all the products. The N(1) and N(7) sites on adenosine indicate almost equal binding affinity for [Pt(NH₃)₃Cl]Cl. The reaction of cis-Pt(NH₃)₂Cl₂ with adenosine has been studied in the presence of a large excess of adenosine (Pt/base ? 0.05). The reaction gives four products. One is the monomeric 2:1 complex with cis-Pt(NH₃)₂²⁺ bound to two adenosine molecules through the N(7) site and the N(1) site, and another is the monomeric 2:1 complex with cis-Pt(NH₃)₂²⁺ bound to two adenosine molecules through the N(7) sites. cis-Pt(NH₃)₂Cl₂ is stronger affinity to the N(7) site than of adenosine to the N(1) site.     

The reaction of 14C-labelled platinum ethylenediamine dichloride with adenine compounds and DNA

Various derivatives of adenine have been studied with regard to their rate of reaction with ¹⁴C-labelled platinum ethylenediamine dichloride, Pt(¹⁴C-en)Cl₂. The reactivities have been calculated from the “rate of disappearance” of Pt(¹⁴C-en)Cl₂ using chromatographic separation of reactants and products.Adenine and adenosine react very slowly at 37° whereas other adenine derivatives react much more readily in the order: poly A > AMP > ApA > poly d(AT). From the numerical values of the rate constants it is concluded that the presence of a phosphate group increases the reaction rate considerably. This is partly the explanation of the rapid reaction of poly A which possesses terminal phosphate groups. However adjacent adenine moieties such as those in polyadenylic acid (poly A) and adenosyl-3′5′-adenosine (ApA) may also react by another mechanism which involves the 6-NH₂ groups.The energies of activation of the second order reaction with platinum ethylenediamine dichloride (PtenCl₂) are 12.9, 18.8, 19.0 kcal/mole for poly A, AMP and ApA respectively.In DNA, no free phosphate groups are present, and the occurrence of adjacent adenines will be low. The reaction of PtenCl₂ with DNA seems to involve a rapid attack on deoxyguanosine (GdR) and a slow reaction with deoxyadenosine (AdR) and deoxycytidine (CdR).     

Reaction of 3′,5′-di-O-acetyl-2′-deoxyguansoine with hypobromous acid

Hypobromous acid (HOBr) is formed by eosinophil peroxidase and myeloperoxidase in the presence of H₂O₂, Cl^?, and Br^? in the host defense system of humans, protecting against invading bacteria. However, the formed HOBr may cause damage to DNA and its components in the host. When a guanine nucleoside (3′,5′-di-O-acetyl-2′-deoxyguansoine) was treated with HOBr at pH 7.4, spiroiminodihydantoin, guanidinohydantoin/iminoallantoin, dehydro-iminoallantoin, diimino-imidazole, amino-imidazolone, and diamino-oxazolone nucleosides were generated in addition to an 8-bromoguanine nucleoside. The major products were spiroiminodihydantoin under neutral conditions and guanidinohydantoin/iminoallantoin under mildly acidic conditions. All the products were formed in the reaction with HOCl in the presence of Br^?. These products were also produced by eosinophil peroxidase or myeloperoxidase in the presence of H₂O₂, Cl^?, and Br^?. The results suggest that the products other than 8-bromoguanine may also have importance for mutagenesis by the reaction of HOBr with guanine residues in nucleotides and DNA.     

Reactions of platinum(IV) amine compounds with 9-methylhypoxanthine at high temperature result in both platinum(II) and platinum(IV) amine adducts

The products obtained from the reaction of Pt(IV)Cl₄(LL) compounds (LL denotes the chelating ligands ethylenediamine (en) and 2,2-dimethyl-1,3-diaminopropane (dmdap), or two cis- or trans-coordinated ammines) with 9-methylhypoxanthine (mHyp) at high temperature (80°C) have been characterized by proton NMR spectroscopy. It appeared that both platinum(II) and platinum(IV) adducts were present in the reaction mixtures. After cation-exchange chromatography, the Pt(II) compound could be characterized as Pt(II)(LL)(mHyp)₂, whereas the Pt(TV) fractions appeared to contain mainly one or two adducts for the chelating diamine compound but more adducts for the ammine compounds. A ³J(¹⁹⁵Pt-¹H) coupling was observed for the Pt(IV), but not for the Pt(II) compounds at the used spectrometer frequency. This supplies a useful tool to discriminate between these two types of platinum adducts.     

Synthesis and characterization of the novel Pt(II) complexes of the types cis- and trans-Pt(Ypy)(pyrazine)Cl2, K2[Cl3Pt(μ-pyrazine)PtCl3] and trans, trans-(Ypy)Cl2Pt(μ-pyrazine)Pt(Ypy)Cl2 (Ypy = pyridine derivative)

New types of Pt(II) mixed-ligand complexes containing a pyridine derivative (Ypy) and pyrazine (pz) were synthesized. The compounds were characterized by infrared spectroscopy and by multinuclear (¹H, ¹³C and ¹⁹⁵Pt) magnetic resonance. The complexes cis-Pt(Ypy)(pz)Cl₂ were synthesized from the reaction of K[Pt(Ypy)Cl₃] with pyrazine (1:1 proportion) in water. When the reaction was carried on in a 2:1 ratio, a mixture of compounds was obtained, which was refluxed in CH₂Cl₂ for several days. The final product was found to be pure and it was identified as trans,trans-Cl₂(Ypy)Pt(μ-pyrazine)Pt(Ypy)Cl₂. The cis monomers isomerize to the trans isomers in organic solvents. Different methyl derivatives of pyridine were studied in order to determine the influence of substitution in ortho position on the pyridine ligand in the complexes. In IR spectroscopy, the cis monomers showed two ν(Pt-Cl) bands, while the trans monomers and dinuclear species showed only one ν(Pt-Cl) band. The NMR results were interpreted in relation to the solvent effect, which seems important in these complexes. The ¹⁹⁵Pt NMR signals of the cis monomers were found at slightly higher fields than those of the corresponding trans isomers. The coupling constants J(¹⁹⁵Pt-¹H) and J(¹⁹⁵Pt-¹³C) are larger in the cis geometry. The δ(¹⁹⁵Pt) of the dinuclear species were found close to those of the trans monomers and the coupling constants are similar to those of the trans monomers, strongly suggesting a trans-trans configuration for the dinuclear compounds. The pyrazine-bridged complex K₂[Cl₃Pt(μ-pz)PtCl₃] was also synthesized and spectroscopically studied. The crystal structures of the compounds cis-Pt(3,5-lut)(pz)Cl₂ and trans-Pt(2,4,6-col)(pz)Cl₂ were determined by X-ray diffraction methods.     

Synthesis and NMR characterization of the novel mixed-ligands Pt(II) complexes Pt(amine)(pyrimidine)X2 and trans,trans-X2(amine)Pt(μ-pyrimidine)Pt(amine)X2 (X = I and Cl)

Mixed-ligand complexes of the type Pt(amine)(pm)I₂, (pm = pyrimidine) were synthesized and characterized by IR spectroscopy and by multinuclear (¹⁹⁵Pt, ¹H and ¹³C) magnetic resonance spectroscopy. The cis compounds were prepared from the reaction of I(amine)Pt(μ-I)₂Pt(amine)I with pyrimidine (1:2 proportion) in water, while the trans isomers were synthesized from the isomerization of the cis complexes in acetone. The cis isomers could not be isolated with several amines, especially the more bulky ones. In ¹H NMR, the pyrimidine protons of the cis compounds were found at lower fields than those of the trans analogs and the J(¹⁹⁵Pt-¹H) coupling constants are slightly larger in the cis geometry. For n-butylamine, the reaction produced also I₂(n-butylamine)Pt(μ-pm)Pt(n-butylamine)I₂. No such dimer could be isolated with the other amines. The compounds Pt(amine)(pm)Cl₂ were also prepared (amine = methylamine and t-butylamine) from the ionic complex K[Pt(amine)Cl₃] using an excess of pyrimidine. The IR and NMR characterization showed that the methylamine compound was a cis-trans mixture, while only the trans isomer was isolated with t-butylamine. When the same reaction was performed using a Pt:pm ratio of 2:1, Cl₂(amine)Pt(μ-pm)Pt(amine)Cl₂ was isolated. The pyrimidine-bridged dimers were identified by IR and multinuclear magnetic resonance spectroscopies as the trans-trans isomers. The trans monomers and dimers showed only one ν(Pt-Cl) band. The ¹⁹⁵Pt NMR signals of the dimers were found close to those of the monomer trans-Pt(amine)(pm)Cl₂.     

Reaction of platinum(II) diamine and triamine complexes with selenomethionine

We have reacted [Pt(dien)Cl]Cl, [Pt(en)(D₂O)₂]²⁺, and [Pt(Me₄en)(D₂O)₂]²⁺ [Me₄en = N,N,N′,N′-tetramethylethylenediamine] with selenomethionine (SeMet). When [Pt(dien)Cl]Cl is reacted with SeMet, [Pt(dien)(SeMet-Se)]²⁺ is formed; two Se-CH₃ resonances are observed due to the different chiralities at the Se atom upon platination. In a reaction of [Pt(dien)Cl]Cl with an equimolar mixture of SeMet and Met, the SeMet product forms more quickly though a slow equilibrium with approximately equal amounts of both products is reached. [Pt(Me₄en)(D₂O)₂]²⁺ reacts with SeMet to form [Pt(Me₄en)(SeMet-Se)(D₂O)]²⁺ initially but forms [Pt(Me₄en)(SeMet-Se,N)]⁺ ultimately. One stereoisomer of the chelate, assigned to the R chirality at the Se atom, dominates within the first few minutes of reaction. [Pt(en)(D₂O)₂]²⁺ forms a variety of products depending on reaction stoichiometry; when one equivalent or less of SeMet is added, the dominant product is [Pt(en)(SeMet-Se,N)]⁺. In the presence of excess SeMet, [Pt(en)(SeMet-Se)₂]²⁺ is the dominant initially, but displacement of the en ligand occurs leading to [Pt(SeMet-Se,N)₂] as the eventual product. Displacement of the en ligand from [Pt(en)(SeMet-Se,N)]⁺ does not occur. In reactions of K₂PtCl₄ with two equivalents of SeMet, [Pt(SeMet-Se,N)₂] is formed, and three sets of resonances are observed due to different chiralities at the Se atoms. Only the cis geometric isomers are observed by ¹H and ¹⁹⁵Pt NMR spectroscopy.     

Direct measurement of interaction forces between a platinum dichloride complex and DNA molecules

The interaction forces between a platinum dichloride complex and DNA molecules have been studied using atomic force microscopy (AFM). The platinum dichloride complex, di-dimethylsulfoxide-dichloroplatinum (II) (Pt(DMSO)₂Cl₂), was immobilized on an AFM probe by coordinating the platinum to two amino groups to form a complex similar to Pt(en)Cl₂, which is structurally similar to cisplatin. The retraction forces were measured between the platinum complex and DNA molecules immobilized on mica plates using force curve measurements. The histogram of the retraction force for λ-DNA showed several peaks; the unit retraction force was estimated to be 130 pN for a pulling rate of 60 nm/s. The retraction forces were also measured separately for four single-base DNA oligomers (adenine, guanine, thymine, and cytosine). Retraction forces were frequently observed in the force curves for the DNA oligomers of guanine and adenine. For the guanine DNA oligomer, the most frequent retraction force was slightly lower than but very similar to the retraction force for λ-DNA. A higher retraction force was obtained for the adenine DNA oligomer than for the guanine oligomer. This result is consistent with a higher retraction activation energy of adenine with the Pt complex being than that of guanine because the kinetic rate constant for retraction correlates to exp(FΔx – ΔE) where ΔE is an activation energy, F is an applied force, and Δx is a displacement of distance.     

High performance liquid chromatography studies on the interactions of cis-Pt(NH3)2−(H2O)22+ with guanine and methylated g

Time dependence studies, using high performance liquid chromatography (HPLC), on the reaction between cis-diamminediaquoplatinum and guanine, N1-methylguanine, N7-methylguanine, N9-methylguanine, and N1 ,N7-dimethylguanine are reported. Each reaction gave rise to eight or more compounds; the major components have been prepared and characterization by ¹H and ¹⁹⁵Pt nuclear magnetic resonance has been attempted. Species of the form ((NH₃)₂Pt(NO₃)-(G-H)-(NO₃)-Pt(NH₃)₂)⁺, (NH₃)₂,Pt(G-H)(NO₃) monomer and (NH₃)₂Pt(G-H)(NO₃) dimer, where G-H indicates the guanine monoanion, are postulated.     

Synthesis and NMR characterization of the novel mixed-ligand Pt(II) complexes cis- and trans-Pt(Ypy)(pyrimidine)Cl2 and trans,trans-Cl2(Ypy)Pt(μ-pyrimidine)Pt(Ypy)Cl2 (Ypy = pyridine derivative)

Mixed-ligand complexes of the type cis- and trans-Pt(Ypy)(pm)Cl₂ where Ypy = pyridine derivative and pm = pyrimidine were synthesized and characterized by IR spectroscopy and by multinuclear (¹⁹⁵Pt, ¹H and ¹³C) magnetic resonance spectroscopy. The cis compounds were prepared from the reaction of K[Pt(Ypy)Cl₃] with pyrimidine (1:1 proportion) in water, while most of the trans isomers were synthesized from the isomerization of the cis compounds. The cis isomers could not be isolated with the Ypy ligands containing two -CH₃ groups in ortho positions. When the aqueous reaction of K[Pt(Ypy)Cl₃] with pyrimidine was performed in a Pt:pm ratio = 2:1, the pyrimidine-bridged dinuclear species were formed. Only the most stable trans-trans isomers could be isolated pure. In IR spectroscopy, the cis monomers showed two ν(Pt-Cl) bands, while the trans monomers and dimers showed only one ν(Pt-Cl) band. The ¹⁹⁵Pt NMR signals of the cis monomers were found at slightly higher fields than those of the corresponding trans isomers. The δ(¹⁹⁵Pt) of the dimers were found close to those of the trans monomers. The NMR results were interpreted in relation to the solvent effect, which seems important in these complexes. The coupling constants J(¹⁹⁵Pt-¹H) and J(¹⁹⁵Pt-¹³C) are larger in the cis geometry. The crystal structures of the compounds cis-Pt(2,4-lut)(pm)Cl₂, trans-Pt(2,6-lut)(pm)Cl₂ and trans,trans-Cl₂(2,6-lut)Pt(μ-pm)Pt(Ypy)Cl₂ were studied by X-ray diffraction methods and the results have confirmed the configurations suggested by IR and NMR spectroscopies.     

The Reaction of Pt-Antitumor Drugs with Selected Nucleophiles.: II. Preparation and Characterization of Coordination Compounds of Pt(II) andl-Histidine

Various His-Pt(II) coordination compounds were prepared by reaction of K₂PtCl₄ or cis-[Pt(NH₃)₂Cl₂](cis-DDP) with His and analyzed by ¹H and ¹³C NMR spectroscopy, electrophoresis, and ion-exchange chromatography. His may be coordinated to Pt by the imidazol iminogroup and/or the α-aminogroup; the carboxy group remains always free. Both bidentate as well as monodentate ligands were identified. Cis-DDP reacts with His to give a mixture of compounds where all these possibilities are present: cis-diamine-(histidine-N,N-)Pt(II) and three different types of cis-diammine-bis(histidine). HCl trans cleavage of compounds with bidentate His ligands leads to a mixture of two compounds having His ligated to Pt by an amino or imin group. The methods applied are suitable for analyzing reactions of His with cis-DDP under model conditions similar to physiological conditions.     

Specificity of the interaction of DNA-platinum, amount of platinum, and pH measurement]

Interaction between the sodium salt of a DNA extracted from salmon sperm (41% GC) with [Pt(NH₃)₄]Cl₂, [Pt(NH₂? (CH₂)₂? NH? (CH₂)₂? NH₂Cl]Cl, cis-Pt(NH₂? (CH₂)₂? NH₂)Cl₂, cis-Pt(NH₃)₂Cl₂, trans-Pt(NH₃)₂Cl₂, K[Pt(C₂H₄)Cl₃], and K₂[PtCl₄) indicates at least three types of complexation. A correlation is found between the change of pH and the number of platinum atoms fixed per (AT + GC) unit. The first binding site is located on the G-C pairs (guanine–cytosine), most likely the N-7(G) site, as it was shown in a previous study of the guanosine-platinum salts. The fixation of the second platinum atom by the pair (AT + GC) takes place with liberation of protons. In the case of the complexes cis-Pt(NH₂? (CH₂)₂? NH₂)Cl₂, cis-Pt(NH₃)₂Cl₂, and trans-Pt(NH₃)₂Cl₂ the second interaction seems to involve simultaneously the N-7(A) and the N-1(G) and N-3(C) sites. This latter intercrosslink between guanine and cytosine obviously liberates protons and the decrease of pH is related in this case to the trans effect of the platinum compounds. The first two platinum atoms in the reaction of K₂PtCl₄] or the Zeise salt, K[Pt(C₂H₄)Cl₃] with DNA are fixed on the G-C pairs. A maximum of six platinum atoms per (AT + GC) unit were fixed in this case. Preliminary experiments with a DNA extracted from bacteria Micrococcus lysodeikticus (72% GC) give similar results.     

Coordination of 9-methyladenine to [cis-Pt(NH3)2]2+ and [Pt(dien)]2+ as studied by proton NMR

Reaction products of 9-methyladenine (mAde) with [Pt(dien)Cl]Cl and cis-Pt(NH₃)₂Cl₂ have been separated using CM-Sephadex C25 cation exchange chromatography. NMR and UV characteristics are presented; the platinum binding sites were established by studying the pH dependence of the ¹H-NMR chemical shifts and of UV difference absorption. It is shown that the N 1 atom of the ligand can be protonated in Pt(mAde-N7) adducts, while the N7 atom can be protonated in Pt(mAde-N1).     

Dinuclear complexes with a μ-cyano ligand. Part X. Synthesis and characterization of several derivatives of cis-diaquaamminecobalt(III) complexes. Influence of pH

Six new dinuclear complexes, derived from cis-[Co(H₂O)₂(NH₃)₄]³⁺, cis-[Co(H₂O)₂(en)₂]³⁺ and [M(CN)₄^2? (M = Ni, Pd, Pt) were prepared and characterized by means of chemical analysis, electronic and IR measurements. The influence of the pH on the rate of the reaction was studied for the two derivatives of [Pd(CN)₄]^2?, showing that the best conditions to obtain the dinuclear compounds are at pH near 6, where the predominant species are cis-[Co(OH)(H₂O)(amine)₂]²⁺. The [Pt(CN)₄]^2? derivatives show PtPt interactions both in the solid state and in solution.     

Participation of alkaline phosphatase in the active transport of phosphates in brush border membrane vesicles

This paper reports the separation and preliminary characterization of the products formed by the reaction of the antitumor compound cis-Pt(NH₃)₂Cl₂ with DNA. Electrophoresis of the acid hydrolysed platinum-DNA complex gave a profile of platinum concentration which contained 5 peaks whose relative intensities varied with the amount of cis-Pt(NH₃)₂Cl₂ fixed on the DNA. Similar analysis of the products formed between DNA and trans-Pt(NH₃)₂Cl₂ or [Pt(dien)Cl]Cl, which are not active antitumor agents, indicated that these compounds bound to DNA in a different manner than cis-Pt(NH₃)₂Cl₂. DNA isolated from Escherichia coli which had been treated with cis-Pt(NH₃)₂Cl₂ or [Pt(dien)Cl]Cl did not give the same electrophoresis profiles as the corresponding platinum-DNA complexes formed in vitro.     

Mechanisms for acceleration of halide anation reactions of platinum(IV) complexes. REOA versus ligand assistance and platinum(II) catalysis Without central ion exchange

Chloride anation of trans-Pt(CN)₄ClOH₂⁻ has been studied with and without Pt(CN)₄²⁻ present at 25.0°C by use of stopped-flow and conventional spectrophotometry and a 1.00 M perchlorate medium. The rate law in the absence of Pt(CN)₄²⁻ is Rate=(p₁ + p₂ [H⁺] ) [Cl⁻]² [complex]/(1 + q [Cl₋]) with p₁=(3.0 ± 0.1) × 10⁻⁵ M⁻²s⁻¹, p₂=(3.6 ± 0.1) × 10⁻⁵ M⁻³ s⁻¹ and q=(0.62 ± 0.02) M⁻¹. It is compatible with a chloride assistance via an intermediate of the type Cl-Cl-Pt(CN)₄···OH₂²⁻, in which the reactivity of the aqua ligand is enhanced due to a partial reduction of the platinum. This mechanism of halide assistance is in principle the same as the modified reductive elimination oxidative addition (REOA) mechanism proposed by Poë, in which the intermediate is not split into free halogen, platinum(II) and water, and in which electron transfer not necessarily involves complete reduction to platinum(II). To avoid confusion with complete reductive eliminations, reactions without split of the intermediates are here termed halide-assisted reactions. The pH-dependence indicates acid catalysis via a protonated intermediate ClClPt(CN)₄···OH₃⁻.The Pt(CN)₄²⁻accelerated path has the rate law Rate=

[Cl-] [Pt(CN)₄²⁻] [complex] where k=(39.9±0.5) M⁻² s⁻¹ and K_a=(4.0±0.2)10⁻² M is the protolysis constant of trans-Pt(CN)₄ClOH²⁻.Reaction between PtCl₅OH₂⁻ and chloride is accelerated by Pt(CN)₄²⁻ and gives PtCl₆²⁻ as the reaction product. The rate law is Rate=k [Cl⁻] [Pt(CN)₄²⁻] [PtCl₅OH₂⁻] with k=(5.6 ± 0.2)10⁻³ M⁻² s⁻¹ at 35.0°C and for a 1.50 M perchlorate acid medium. The reaction takes place without central ion exchange. Alternative mechanisms with two consecutive central ion exchanges can be excluded. The role of Pt(CN)₄²⁻ in this reaction is very similar to that of the assisting halide in the halide assisted anations. [p ]Reaction between trans-Pt(CN)₄ClOH₂⁻ and PtCl₄²⁻ gives Pt(CN)₄²⁻ and PtCl₅OH₂⁻ as products and has the rate law Rate=k[PtCl₄²⁻] [trans-Pt(CN)₄ClOH₂⁻] with k=(3.32 ± 0.02) M⁻¹ s⁻¹ at 25 °C for a 1.00 M perchloric acid medium. The formation of an aqua complex as the primary reaction product and the rate independent of [Cl⁻] shows that formation of a bridged intermediate of the type Pt(II)Cl₄ClPt(IV)(CN)₄OH₂³⁻ is formed in the initial reaction step, not five-coordinated PtCl₅³⁻.     

Pyrazine-bridged Pt(II)-sulfoxide complexes: multinuclear magnetic resonance spectroscopy and crystal structures of trans,trans-{Pt(R2SO)Cl2}2(μ-pyrazine)

A new type of pyrazine-bridged platinum(II) complexes, trans,trans-Pt(R₂SO)Cl₂(μ-pyrazine)Pt(R₂SO)Cl₂ was synthesized and characterized mainly by IR and multinuclear magnetic resonance spectroscopies (¹H, ¹³C and ¹⁹⁵Pt) and by crystallographic methods. Compounds with dimethylsulfoxide, tetramethylenesulfoxide, di-n-propylsulfoxide, di-n-butylsulfoxide, dibenzylsulfoxide and diphenylsulfoxide were prepared. The compounds were synthezised in good yields from the aqueous reaction of K[Pt(R₂SO)Cl₃] with pyrazine. IR spectroscopy showed only one ν(Pt-Cl) band suggesting trans isomers. The ¹⁹⁵Pt NMR signals of the dimeric species were observed between −3041 and −3113 ppm. The resonance of the diphenylsulfoxide complex was found at higher fields than the other compounds. In ¹H NMR, the pyrazine protons are more deshielded (ave. 0.52 ppm) than in free pyrazine. The coupling constants with the pyrazine protons 3J(¹⁹⁵Pt-¹H) are between 28 and 35 Hz. The crystal structures of three pyrazine-bridged dimers, {trans-Pt(R₂SO)Cl₂}₂(μ-pyrazine) were studied by X-ray diffraction methods. The results confirmed the trans,trans configuration of the compounds. All the molecules contain an inversion centre.     

The interactions of cis- and trans-diammineplatinum compounds with 5′-guanosine monophosphate and 5′-deoxyguanosine monophosphate. A proton nmr investigation

The interactions of cis- and trans-diammineplatinum compounds with 5′-GMP and 5′-dGMP in dilute aqueous solution at neutral pH were investigated by ¹H nmr. In addition to the 1:2 Pt nucleotide complexes cis- and trans-Pt(NH₃)₂(GMP)₂, it was possible to study the formation of the 1:1 Pt-nucleotide complexes with either one coordinated water or chloride ion. At 5°C GMP reacts with a stoichiometric amount of cis-diaquodiammine-platinum to yield cis-Pt(NH₃)₂(GMP) (H₂O) as a sole reaction product. From the present results it is concluded that such a complex may play an important role as the initial reaction product between antitumor compounds like cis-Pt(NH₃)₂Cl₂ and guanine in DNA in living organisms. The coupling constant ³J(H(1′)-H(2′)) of the H(1′) sugar proton in cis-Pt(NH₃)₂(GMP)₂ is temperature dependent, indicating a conformational change in the sugar moiety.     

Multinuclear magnetic resonance study of Pt(II) compounds with sulfoxide ligands and crystal structures of complexes of the types [Pt(R2SO)X3] and Pt(R2SO)2Cl2

Pt(II) complexes of the types K[Pt(R₂SO)X₃], NR₄[Pt(R₂SO)X₃] and Pt(R₂SO)₂Cl₂ (where X = Cl or Br) were characterized by multinuclear magnetic resonance spectroscopy (¹⁹⁵Pt, ¹H and ¹³C). In ¹⁹⁵Pt NMR, the chloro ionic compounds have shown signals between −2979 and −3106 ppm, while the cis disubstituted complexes were observed at higher fields, between −3450 and −3546 ppm. The signal of the compound trans-Pt(DPrSO)₂Cl₂ was found at higher field (−3666 ppm) than its cis analogue (−3517 ppm), since π-back-donation is considerably less effective in the trans geometry. In ¹H NMR, a single signal was observed for the sulfoxide in [Pt(DMSO)Cl₃]⁻, but for the other more sterically hindered ligands, two series of resonances were observed for the protons in α and β positions. The coupling constant ³J(¹⁹⁵Pt-¹H) are between 15 and 33 Hz. The ¹³C NMR results were interpreted in relation to the concept of inversed polarization of the π sulfoxide bond. The ²J(¹⁹⁵Pt-¹³C) values vary between 35 and 66 Hz, while a few ³J(¹⁹⁵Pt-¹³C) couplings were observed (13-26 Hz). The crystal structures of five monosubstituted ionic compounds N(n-Bu)₄[Pt(TMSO)Cl₃], N(Me)₄[Pt(DPrSO)Cl₃], K[Pt(EMSO)Cl₃], K[Pt(TMSO)Br₃] · H₂O and N(Et)₄[Pt(DPrSO)Br₃] and one disubstituted complex cis-Pt(DBuSO)₂Cl₂ were determined. The trans influence of the different ligands is discussed.     

Synthesis, characterization and cytotoxic activity of palladium (II) dithiocarbamate complexes with α,ω-diamines

The polymeric [PdCl(dithiocarbamate)]_n complexes, in which the ligand ion is dimethyldithiocarbamate (DMDT), pyrrolidine dithiocarbamate (PyDT, (CH₂)₄NCS₂⁻) and sarcosine ethyl ester dithiocarbamate (ESDT, EtO₂CCH₂N(CH₃)CS₂⁻), have been reacted with chelating diamines, like ethylenediamine (en) or 1,3-diaminopropane (dap) and long chain diamines, like 1,4-diaminobutane (dab) or 1,7-diaminoheptane (dah). The reaction products depend on either diamine chain length or molar ratio. By operating at PdCl(dithiocarbamate)/diamine molar ratio 1:1 chelating diamines yielded the ionic [Pd(dithiocarbamate)(diamine)]Cl species (diamine = en or dap), whereas with long chain diamines species of the type [Pd(dithiocarbamate)(diamine)]_nCl_n (diamine = dab or dah) were obtained, in which each Pd(dithiocarbamate)⁺ unit binds to the NH₂ group of two different molecules, in a network of bridging diamines. At molar ratio 1:0.5, the long chain diamines yielded the binuclear [Pd₂Cl₂(dithiocarbamate)₂(diamine)] complexes (diamine = dab or dah), whereas exchange reactions take place generally in the presence of en or dap. The reaction trend is described on the basis of IR and proton NMR spectra. The new dithiocarbamate complexes were preliminarily tested for their cytotoxicity on human cancer cells.