The reaction of 14 C-labelled platinum ethylenediamine dichloride with nucleic acid constituents

The anti-tumour agent platinum ethylenediamine dichloride [Pt(en)Cl₂] reacts in 0.1 M NaClO₄ with adenine, guanine, cytosine and their nucleosides and nucleotides, but not with thymine and its derivatives. Such reactions have been followed by spectral changes and by chromatographic separation of reactants and products, using Pt(¹⁴C-en)Cl₂.In general, guanine derivatives reacted the most rapidly, notably guanosine. From double-labelling experiments using tritiated nucleic acid components, reaction products showed a Pt(en)Cl₂: base ratio of close to unity. An exception was ATP where an additional product was observed with Pt: base = 2. Here the phosphate moiety may also have been involved. A comparison of guanine and derivatives in which the N-7, N-9 or both positions were blocked indicates that probably more than one site is available for reaction with Pt(en)Cl₂.     

The binding of platinum ethylenediamine dichloride to proteins,in vitro and in vivo

The binding to proteins of platinum ethylenediamine dichloride (PtenCl₂) labelled with carbon-14 has been studied in vitro and in vivo. The metal complex binds to proteins in plasma with a half-time of about 1 h and is distributed over all protein classes. At pharmacologically relevant levels the binding of platinum does not affect the biological function of the protein, e.g. the immunoglobulins.Although the in vitro toxicity of PtenCl₂ is decreased by binding to the proteins of the culture medium, it has not yet proved possible to determine whether binding in vivo, e.g. to tumour cytosol proteins, leads to loss in toxicity and whether it is reversible.     

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.     

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.     

Arapen: a secondary complex between platinum ethylenediamine dichloride and cytosine arabinoside. I. Preparations and reactivity towards nucleic acid constituents.

An equimolecular complex between platinum ethylenediamine dichloride (PtenCl2) and 1-beta-D-arabinofuranosyl cytosine (araC) has been prepared (arapen). This 1 : 1 complex in which both ethylenediamine and araC moieties carried a radioactive label was found to be unreactive towards cytosine and guanine derivatives, but to react to the extent of 30% with deoxyadenosine, adenosine 5' -monophosphate, polyadenylic acid, poly a(AT) and DNA at comparable rates. It is suggested that adenine compounds react with platinum complexes such as PtenCl2 in a bidentate manner, but are still able to react with arapen as monodentate ligands. However, hydrolysis of the last chloride ion from arapen may not be complete, and the incoming adenine nucleophile is only able to react to a limited extent.     

A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor

A strategy is described for the re-design of DNA damaging platinum(II) complexes to afford elevated toxicity towards cancer cells expressing the estrogen receptor (ER). Two platinum-based toxicants are described in which a DNA damaging warhead, [Pt(en)Cl₂] (en, ethylenediamine), is tethered to either of two functional groups. The first agent, [6-(2-amino-ethylamino)-hexyl]-carbamic acid 2-[6-(7α-estra-1,3,5,(10)-triene)-hexylamino]-ethyl ester platinum(II) dichloride ((Est-en)PtCl₂), terminates in a ligand for the ER. The second agent is a control compound lacking the steroid; this compound, N-[6-(2-amino-ethylamino)-hexyl]-benzamide platinum(II) dichloride ((Bz-en)PtCl₂)), terminates in a benzamide moiety, which lacks affinity for the ER. Using a competitive binding assay, Est-en had 28% relative binding affinity (RBA) for the ER as compared to 17β-estradiol. After covalent binding to a synthetic DNA duplex 16-mer, the compound retained its affinity for the ER; specificity of the binding event was demonstrated by the ability of free 17β-estradiol as a competitor to disrupt the DNA adduct-ER complex. The (Est-en)PtCl₂ compound showed higher toxicity against the ER positive ovarian cancer cell line CAOV3 than did the control compound. (Est-en)PtCl₂ was also more toxic to the ER positive breast cancer line, MCF-7, than to an ER negative line, MDA-MB231.     

Intracellular formation of analogues of cyclic AMP: Studies with brain slices labeled with radioactive derivatives of adenine and adenosine

A variety of radioactive analogs of adenine and adenosine were incubated with guinea pig cerebral cortical slices. Neither 1,N⁶-ethano[¹⁴C]adenosine nor 1,N⁶-ethanol[¹⁴C]adenine were significantly incorporated into intracellular nucleotides. 2-chloro[8-³H]adenine was incorporated, but at a very low rate and conclusive evidence for the formation of intracellular radioactive 2-chlorocyclic AMP was not obtained. N⁶-Benzyl[¹⁴C]adenosine was converted only to intracellular monophosphates and significant formation of radioactive N⁶-benzylcyclic AMP was not detected during a subsequent incubation. 2′-Deoxy-[8-¹⁴C] adenosine was converted to both intracellular radioactive 2′-deoxyadenine nucleotides and radioactive adenine nucleotides. Stimulation of these labeled slices with a variety of agents resulted in formation of both radioactive 2′-deoxycyclic AMP and cyclic AMP. Investigation of the effect of various other compounds on uptake of adenine or adenosine suggested that certain other adenosine analogs might serve as precursors of abnormal cyclic nucleotides in intact cells.     

Fast cleavage of a diselenide induced by a platinum(II)-methionine complex and its biological implications

Platinum-based anticancer drugs such as cisplatin induce increased oxidative stress and oxidative damage of DNA and other cellular components, while selenium plays an important role in the antioxidant defense system. In this study, the interaction between a platinum(II) methionine (Met) complex [Pt(Met)Cl₂] and a diselenide compound selenocystine [(Sec)₂] was studied by electrospray ionization mass spectrometry, high performance liquid chromatography mass spectrometry, and ¹H NMR spectroscopy. The results demonstrate that the diselenide bond in (Sec)₂ can readily and quickly be cleaved by the platinum complex. Formation of the selenocysteine (Sec) bridged dinuclear complex [Pt₂(Met-S,N)₂(μ-Sec-Se,Cl)]³⁺ and Sec chelated species [Pt(Met-S,N)(Sec-Se,N)]²⁺ was identified at neutral and acidic media, which seems to result from the intermediate [Pt(Met-S,N)(Sec-Se)Cl]⁺. An accelerated formation of S-Se and S-S bonds was also observed when (Sec)₂ reacted with excessive glutathione in the presence of [Pt(Met)Cl₂]. These results imply that the mechanism of activity and toxicity of platinum drugs may be related to their fast reaction with seleno-containing biomolecules, and the chemoprotective property of selenium agents against cisplatin-induced toxicity could also be connected with such reactions.     

Reactions of [PtCl(dien)]Cl with glutathione,oxidized glutathione and S-methyl glutathione. Formation of an S-bridged dinuclear unit

The reaction of the monofunctional platinum compound [PtCl(dien)]Cl with the tripeptide glutathione (GSH), oxidized glutathione (GSSG) and S-methyl glutathione (GS-Me) has been investigated by ¹H, ¹³C and ¹⁹⁵Pt magnetic resonance spectroscopy and by potentiometric titrations. It appears that platinum binds with a high degree of specificity to the GSH sulfhydryl group. The reaction of platinum with GSH proceeds in two steps. In the first step only one platinum binds to the sulfur atom and, in the second step, another [Pt(dien)]²⁺ unit binds to [Pt(dien)GS]⁺ forming an S-bridged dinuclear unit [{Pt(dien)}₂GS]³⁺. The rate of the first binding step is pH-dependent, whereas the rate of the second step is not. At pH < 7 the rate of the first binding step is slow compared to the rate of the second binding step. At pH > 10, on the other hand, the rate of the first binding step is faster than the rate of the second binding step. Consequently, at pH < 7 one can only isolate the [{Pt(dien)}₂GS]³⁺ complex. In the presence of free GSH, at pH > 7, one [Pt(dien)]²⁺ unit of [{Pt(dien)}₂GS]³⁺ dissociates forming [Pt(dien)GS]⁺. The mechanism of the pH-dependent rate of the first platinum binding step and the ligand-exchange reaction are discussed. GSSG reacts with [Pt(dien)]²⁺, also forming the S-bridged dinuclear unit [{Pt(dien)}₂GS]³⁺, probably through a redox disproportionation reaction with a catalytic function of [PtCl(dien)]Cl. GS-Me reacts with [Pt(dien)]²⁺ forming the S-coordinated [Pt(dien)GS-Me]²⁺. [Pt(dien)GS-Me]²⁺ exists as a pair of diastereomers due to different configurations about sulfur. The rate of the inversion of configuration at the coordinated sulfur atom is slow on the NMR time-scale.     

Discrepancy between cytotoxicity,platinum accumulation,and DNA platination in MCF-7 breast cancer cells treated with diaqua(1,2-diphenylethylenediamine) platinum(II) sulfates and cisplatin

Cisplatin (cis), raceme-diaqua[1,2-bis(4-fluorophenyl)ethylenedi-amine]platinum(II) sulfate (r-4F-PtSO₄), meso-diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) sulfate (m-4F-PtSO₄), and meso-diaqua[1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]platinum(II) sulfate (m-2,6Cl₂-4OH-PtSO₄) were compared with regard to their growth inhibitory effect on MCF-7 breast cancer cells. At concentrations of 5 μM, cis, r-4F-PtSO₄, and m-4F-PtSO₄ were essentially equiactive, whereas m-2,6Cl₂-4OH-PtSO₄ was ineffective. Platinum measurements by neutron activation analysis showed that a 24-h treatment of the MCF-7 cells with r-4F-PtSO₄ and m-4F-PtSO₄ caused a 22.3- and 10.3-fold accumulation, respectively, whereas the accumulation factors for cis (2.55) and m-2,6Cl₂-4OH-PtSO₄ (1.83) were very low. The comparison of DNA-associated platinum revealed a similar tendency. After 24 h of drug exposure, the base pair/platinum ratios were: 2.1·10⁴ for r-4F-PtSO₄, 3.7·10⁴ for m-4F-PtSO₄, 6.1·10⁴ for cisplatin, and 8.1·10⁴ for m-2,6Cl₂-4OH-PtSO₄. Thus, the grade of cytotoxicity was correlated neither with the extent of cellular platinum enrichment nor with the degree of genomic DNA platination.     

Proton-NMR study of the interaction of trans-dichloro-diamine-platinum(II) with poly(I) and poly(I).poly(C)

The fixation of trans-(NH₃)₂Cl₂ Pt(II) to poly(I)·poly(C) at low r_b (< 0.05) leads to the formation of two complexed species. The major species (ca. 82% of bound platinum) involves coordination of platinum to a single hypoxanthine base, while the other species involves coordination of two hypoxanthine bases, which are either far apart on the same strand or on separate poly(I) strands, to the platinum. These same two species are found after reaction with poly(I), as are two other species throughout the entire r_b range studied (r_b = 0–0.30). The latter two species are assigned to trans-Pt bound to two bases on a poly(I) strand with (a) one or (b) two free bases between the two bound bases. These two species, (a) and (b), account for ca. 35% of the bound platinum, although the 1:1 species remains dominant (ca. 55%). These two additional species are observed at high r_b (>0.075) after reaction with poly(I)·poly(C) but as very minor species. They are formed by reaction with melted poly(I) loops. Also at high r_b, we have observed a shifted cytidine H⁵ resonance arising from interaction of trans-Pt with a melted loop of poly(C). Most probably, this arises from an intramolecular poly(I) to poly(C) crosslink. Results from the reaction of trans-Pt with poly(C) are presented for comparison.     

A proton magnetic resonance study of the interaction of adenylyl (3' is greater than 5') adenosine with polyuridylic acid

The interaction of adenylyl (3′ → 5′) adenosine (ApA) with polyuridylic acid in D₂O solution at neutral pD has been studied by high resolution proton magnetic, resonance spectroscopy. At temperatures above ～32°C, no evidence was obtained for the interaction of ApA with poly U. Below this temperature, a rigid triple-stranded complex involving a stoichiometry of 1 adenine to 2 uracil bases is formed, presumably via specific adenine–uracil base-pairing and cooperative base stacking of the adenine bases in a manner similar to that previously reported for the adenosine–poly U complex.     

Different relationships between cellular adenosine or 3′-phosphorylation and cellular adenine ribonucleotide catabolism may be obtained

Treatment of BALB/c-3T3 mouse fibroblasts with 3′-led to a rapid accumulation of 3′-phosphates and the kinetics of this process has been determined. Concomitant with accumulation of these compounds, the adenine ribonucleotide pool was reduced. The kinetics of the two processes suggested that they were tightly coupled. The inhibitory effect of relatively high concentrations of coformycin indicated that IMP was an intermediate in the catabolic pathway. Similar experiments with Ehrlich ascites tumor cells were performed in Ringer-Hepes solution at pH 6.5 or 7.5 and with varying concentrations of orthophosphate. The experiments were performed with cells where ATP was [³H]-. This allowed the determination of the catabolism of adenine ribonucleotides to labeled nucleosides under conditions where added adenosine was phosphorylated. The results showed that at low phosphate concentration (5.8 mM) at pH 6.5 adenosine may be phosphorylated at a rate that was completely balanced to the concomitant catabolism of adenine ribonucleotides; that is, there was apparently a tight kinetic coupling between anabolism of adenosine and catabolism of adenine ribonucleotides. With 3′-a corresponding effect was obtained although the apparent coupling between phosphorylation of 3′-and catabolism of adenine ribonucleotides was not complete. When experiments were performed at the same pH but at high concentration of phosphate (45 mM) there was in contrast no coupling between the two processes; that is, ATP was present in constant amounts while 3′-phosphates accumulated at a high rate. In experiments with adenosine under these conditions there was still some although a relatively limited degree of apparent coupling between phosphorylation of adenosine and catabolism of adenine ribonucleotides. In both lines of cells used and with both adenosine and 3′-, the main products of the catabolism of adenine ribonucleotides were inosine and hypoxanthine. With 3′-there was in addition (about 20%) formation of xanthosine, suggesting that IMP dehydrogenase had also been activated. These results lead to the suggestion that adenosine (or 3′-) may be phosphorylated in two ways. 1) Phosphorylation may depend on an adenosine kinase unrelated to catabolism of adenine ribonucleotides. 2) Phosphorylation may be tightly coupled to catabolism of adenine ribonucleotides. A nucleoside phosphotransferase may catalyze the transfer of a phosphoryl group from IMP to adenosine (or 3′-) to form AMP (or 3′-) and inosine, a process that may be tightly coupled to an AMP deaminase reaction. The IMP formed in the latter reaction may not be released but transferred to the phosphotransferase. In contrast, the AMP formed in the phosphotransferase reaction should be in equilibrium with soluble AMP. It is assumed that a physical complex may exist, possibly in a membrane bound form, between AMP deaminase and the nucleoside phosphotransferase. © 1993 Wiley-Liss, Inc.     

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⁻.     

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 binding of Ni2+ to adenylyl-3',5'-adenosine and to poly(adenylic acid)

Studies of the binding of Ni²⁺ to adenylyl-3',5'-adenosine (ApA) at pH 6-0 by ultraviolet spectrophotometry indicate the formation of a 1:1 complex in the presence of a large excess of metal ion. At 25 °C. and ionic strength μ = 0.5 M, the stability constant of Ni(ApA) is evaluated to be K = 2.6 (±0.6) M^?1. The low stability is taken as evidence that the predominant complex species is one in which the ApA acts as a monodentate ligand, mainly through the adenine group. The rate constants for complex formation and dissociation, k_f = 1430 M^?1 s^?1 and k_b = 665 s^?1 (25°C. μ = 0.5M). determined by the temperature-jump relaxation technique, are consistent with this interpretation. The binding strength of Ni²⁺ to poly(adenylic acid) [poly(A)] has been studied at pH 7.0 using murexide as an indicator of the concentration of free Ni²⁺. Within the concentration range [Ni²⁺ = 1 × 10^?5 × 10^?3 M the data can be represented in the form of a linear Scatchard plot. i.e., the process can be described as the binding of Ni²⁺ to one class of independent binding sites. The number of binding sites per monomer is 0.26, and the stability constant K = 8.2×10³ M^?1 (25°C μ = 0.1 M). In kinetic studies of the reaction of Ni²⁺ with poly(A), two relaxation effects due to complex formation were detected, one with a concentration-independent time constant of about 0.4 ms, the other with a concentration-dependent time constant in the millisecond range. The concentration dependence of the longer relaxation time can be accounted for by a three-step mechanism which consists of a fast second-order association reaction followed by two first-order steps. There is evidence, however, that the overall process is more complicated than expressed by the three-step mechanism.     

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.     

A comparison of the inhibitory potency of reversibly acting inhibitors of anion transport on chloride and sulfate movements across the human red cell membrane

The effects of a variety of chemically diverse, reversibly acting inhibitors have been measured on both Cl^? and SO₄^2? equilibrium exchange across the human red cell membrane. The measurements were carried out under the same conditions (pH 6.3, 8°C) and in the same medium for both the Cl^? and SO₂⁴ tracer fluxes. Under these conditions the rate constant for Cl^?-Cl^? exchange is about 20 000 times larger than that for SO₄^2?-SO₄^2? exchange. Despite this large difference in the rates of transport of the two anions, eight different reversibly acting inhibitors have virtually the same effect on the Cl^? and SO₄^2? transport. The proteolytic enzyme papain also has the same inhibitory effect on both the Cl^? and SO₄^2? self-exchange. In addition, the slowly penetrating disulfonate 2-(4′-aminophenyl)-6-methylbenzenethiazol-3′,7-disulfonic acid (APMB) is 5-fold more effective from the outer than from the inner membrane surface in inhibiting both Cl^? and SO₄^2? self-exchange. We interpret these results as evidence that the rapidly penetrating monovalent anion Cl^? and the slowly penetrating divalent anion SO₄^2? are transported by the same system.     

Synthesis and crystal structures of platinum (II) complexes with phosphine sulfide: cis-Dichloro[dimethylsulfoxide](triphenylphosphine sulfide) platinum (II) and (−)-cis-dichloro[(S)-methyl-p-tolylsulfoxide](triphenylphosphine sulfide) platinum (II)

The addition of triphenylphosphine sulfide (Ph₃PS) to bis-sulfoxide platinum (II) complexes [Pt(Me₂SO)₂Cl₂] and (−)-[Pt(Me-p-TolSO)₂Cl₂] yields mixed ligand complexes [Pt(Ph₃PS)(Me₂SO)Cl₂] (1) and (−)-[Pt(Ph₃PS)(Me-p-TolSO)Cl₂] (2), which are effective catalysts for hydrosilylation reaction. These mixed-ligand complexes were obtained in crystal state and analyzed by X-ray diffraction, ¹H, ³¹P and ¹⁹⁵Pt NMR; 2 was also studied by circular dichroism spectroscopy. Both complexes exist in CDCl₃ solution as a dynamic equilibrium of two geometric isomers with an approximate 1:10 ratio, but only cis-isomer is obtained on crystallization. The X-ray structures of the complexes have classical geometry, and phosphine sulfide and sulfoxides are coordinated via sulfur. The new structural data for simple platinum–Ph₃PS coordination bond, unaffected by chelation or bridging, were evaluated. The lengths of this bond are 2.300(4) Å in 1 and 2.305(3) Å in 2, respectively. PtSP angle equals 105.7(2)° in 1 and 104.05(13)° in 2, the PtSP plane is almost perpendicular to the coordination plane. The static trans-influence of Ph₃PS is estimated to be strong and close to that of S-coordinated Me₂SO. The complex 2 exhibits strong circular dichroism at a wavelength below 330 nm, caused both by inherent Me-p-TolSO stereogenic center and induced asymmetry of Ph₃PS.     

Coordination chemistry of 7,9-disubstituted 6-oxopurine metal compounds. 4. Platinum(II) coordination at N(1). Molecular and crystal structure of [(ethylenediamine)bis(7,9-dimethylhypoxanthine)platinum(II)] hexafluorophosphate

The preparation and molecular and crystal structure of the complex [(ethylenediamine)bis(7,9,-dimethylhypoxanthine)platinum(II)] hexafluorophosphate, [Pt(C₂H₈N₂)(C₇H₈N₄O)₂] (PF₆)₂, are reported. The complex crystallizes in the monoclinic system, space group C2/c, with a = 12.334(2)Å, b = 10.256(2)Å, c = 22.339(3)Å, β = 101.31(1)°, V = 2771.0ų, Z = 4, D_measd = 2.087(3) g cm^?3, D_calc = 2.094 g cm^?3. Intensities for 3992 symmetry-averaged reflections were collected in the θ-2o scan mode on an automated diffractometer employing graphite-monochromatized MoKα radiation. The structure was solved by standard heavy-atom Patterson and Fourier methods. Full matrix least-squares refinement led to a final R value of 0.051. Both the ethylenediamine chelate and the PF₆^? anion are disordered. The primary coordination sphere about the Pt(II) center is approximately square planar with the bidentate ethylenediamine ligand and the N(1) atoms [Pt(II) ? N(1) = 2.020(5)Å] of two 7,9-dimethylhypoxanthine bases (related by a crystallographic twofold axis of symmetry) occupying the four coordination sites. The exocyclic O(6) carbonyl oxygen atoms of the two 7,9-dimethylhypoxanthine ligands participate in intracomplex hydrogen bonding with the amino groups of the ethylenediamine chelate [N(ethylenediamine) ? O(6) = 2.89( )Å]. The observed Pt ? O(6) intramolecular distances of 3.074(6)Å are similar to those found in other Pt(II) N(1)-bound 6-oxopurine complexes and in several Pt(II) N(3)-bound cytosine systems.