Yoshinori Kidani

The crystal structures and absolute configurations of the anti-tumor complexes Pt(oxalato)(1R,2R-cyclohexanediamine) and Pt(malonato)(1R,2R-cyclohexanediamine)

Abstract The absolute configurations of the anti-tumor complexes [Pt(oxalato)(trans-l-dach)] and [Pt(malonato) (trans-l-dach)] (trans-l-dach = 1R,2R-cyclohexanediamine) have been determined by X-ray anomalous scattering techniques. These complexes are particularly interesting because they show higher anti-tumor activity than the corresponding Pt complexes with other 1,2-cyclohexanediamine(dach) ligands, namely those with trans-d-dach (1S,2S-dach) or cis-dach (1R,2S-dach). The oxalato and malonato ligands are found to bind to the Pt atom in a chelating fashion, through one oxygen atom from each of the two carboxylate groups. Crystallographic details: Pt(oxalato)(trans-l-dach): space group P2 1 (monoclinic); a = 11.230(11) A, b = 9.914(5) A, c = 4.716(3) A, β = 90.86(6)°; R = 4.0% for 1256 reflections. Pt(malonato)(trans-l-dach): space group P2 1 (monoclinic); a = 11.568(5) A, b = 10.007(5) A, c = 5.187(3) A, β = 99.16(4)°; R = 4.8% for 1675 reflections.

Complex of cis-(NH3)2PtCl2 with guanylyl(3′-5′)-cytidine

Abstract The predominant complex formed by the reaction of cis-(NH3)2PtCl2 and guanylyl(3′-5′)cytidine has been isolated. The molar ratio of the binding of cis-(NH3)2PtCl2 to guanylyl(3′-5′)-cytidine is 1:2. The values of proton dissociation constant due to guanine and cytosine bases provide useful information for determining the binding site of the isolated complex. In addition, nmr and ir spectral data were used to determine the binding site. cis-(NH3)2PtCl2 coordinates to guanylyl(3′-5′)cytidine through N(7) position of the guanine base, but cytosine base does not participate in the binding to cis-(NH3)2Pt2+. Interbase crosslink has not been detected. The binding specificity of cis-(NH3)2PtCl2 to guanine base is discussed.

Ultraviolet difference spectral study of the interaction of DNA with platinum complexes

Abstract Ultraviolet difference spectral data provided useful information to differentiate the binding modes between antitumor-active and -inactive platinum complexes. The uv difference spectra for the DNA samples treated with platinum complexes exhibit a band at 295 nm due to the change in electron distribution of nucleic acid bases and a band at 270 nm due to the change in the secondary structure of DNA. The absorption ratio, ΔA 270 /ΔA 295 , is an index for the change of the secondary structure of DNA induced by binding with platinum. Changes in the DNA secondary structure induced by antitumor-active platinum complexes are greater than those induced by antitumor-inactive platinum complexes, and the uv difference spectral behavior of antitumor-active platinum complexes is similar. A tendency for preferential binding toward the guanine residues in DNA was confirmed in this study. Melting profiles for the DNA samples treated with platinum complexes showed a decrease in hyperchromicity and a broadening of transition width. The platinum complexes, other than trans -Pt(NH 3 ) 2 Cl 2 , decreased the melting temperature.

Cis-dichlorodiammineplatinum(II) has a binding specificity for adjoining guanine bases

Abstract Self complementary deoxyribooctanucleotides, [5′-d(GpGpTpCpGpApCpC)-3′] 2 and [5’-d(CpGpGp- ApTpCpCpG)-3’] 2 , were allowed to react with cis - PtCl 2 (NH 3 ) 2 , and the reaction mixture was treated with exonuclease (snake venom phosphodiesterase and/or calf spleen phosphodiesterase). Semi-quantitative analysis by HPLC showed that the adjoining guanine bases have a specific binding affinity to cis -PtCl 2 (NH 3 ) 2 .

The pH dependence of apparent binding constants between apo-superoxide dismutase and cupric ions

Abstract Apo-superoxide dismutase can bind four copper ions to two native copper- and two native zinc-binding sites. Four, stepwise, apparent binding constants of copper ions to the apo-enzyme were obtained from the equilibrium dialysis data at various pH values. These binding constants are pH dependent. In the low pH region, the binding of copper ions to the native copper binding sites has much larger apparent binding constants than to the native zinc sites. But the difference between apparent binding constants of copper ions to the native copper sites and those to the native zinc sites decreased with an increase of pH. At pH 10.0, it is impossible to distinguish between the binding of copper ions to the native copper sites and to the native zinc sites. The relationship between logarithm of apparent binding constants of copper sites and pH was linear with a slope of 2 in the pH region from 4.0 to 7.0. Above pH 7.0, apparent binding constants at the copper sites were almost pH independent. These results indicate that copper ions compete with two protons in the native copper-binding sites and that p K a values of the protons were almost 7. From apparent binding constants of copper ions to the apo-enzyme at pH 7.0 and 10.0, theoretical EPR-detectable copper contents were calculated and compared with EPR data obtained by J. S. Valentine, M. W. Pantoliano, P. J. McDonnell, A. R. Burger, and S. J. Lippard ( Proc. Nat. Acad. Sci. USA , 1979 , 76 , 4245–4249).

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

Abstract The reaction products of adenosine with [Pt(NH 3 ) 3 Cl]Cl or cis -Pt(NH 3 ) 2 Cl 2 have been studied using high performance liquid chromatography and uv spectroscopy. The reaction of [Pt(NH 3 ) 3 Cl]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(NH 3 ) 3 Cl]Cl. The reaction of cis -Pt(NH 3 ) 2 Cl 2 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(NH 3 ) 2 2+ 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(NH 3 ) 2 2+ bound to two adenosine molecules through the N(7) sites. cis -Pt(NH 3 ) 2 Cl 2 is stronger affinity to the N(7) site than of adenosine to the N(1) site.

Pharmacokinetics of (1R,2R-diaminocyclohexane)oxalatoplatinum(II) in comparison with cisplatin following a single intravenous injection in rabbits.

SummaryThe pharmacokinetics of (1R,2R-diaminocyclohexane)oxalatoplatinum(II) (1-OHP, NSC-266046), a second-generation antitumor platinum complex, was studied in rabbits and compared with that of cisplatin. The rabbits were given a single i.v. dose of 1-OHP or cisplatin (10 μmol/kg). A comparison of tissue platinum levels at 24 h postinjection showed that platinum levels were lower in the eight organs examined, which included the kidney and liver, after the injection of 1-OHP than following cis-platin administration. Plasma-decay profiles of three platinum species, that is, the unchanged species, filterable platinum, and total platinum, were examined. Plasma levels of the unchanged species and filterable platinum for 1-OHP declined more rapidly than those for cisplatin. The ratio of plasma filterable-to-total platinum indicated that the protein-binding ability of 1-OHP was greater than that of cisplatin. As for urinary excretion, amounts of the unchanged species and total platinum excreted during the 24 h period postinjection were 28% and 76% of the dose for 1-OHP and 23% and 57% of the dose for cisplatin, respectively. The renal clearance of both the unchanged species and filterable platinum in plasma for 1-OHP was about 2-fold that for cisplatin. 1-OHP is reported to be much less nephrotoxic than cisplatin. This may be due in part to its pharmacokinetic behavior or to pharmacokinetic differences resulting from chemical reactions that make 1-OHP less toxic than cisplatin.

Significance of water solubility in the gastrointestinal absorption of trans-bis(n-valerato)(1R,2R-cyclohexanediamine)(oxalato)platinum(IV), an orally active antitumor platinum complex, and its analogs.

Trans-bis(n-valerato)(1R,2R-cyclohexanediamine)(oxalato)-platinum (IV) (C5-OHP) is an orally active platinum complex we prepared. The gastrointestinal absorption of C5-OHP was examined in rats and compared with those of C5-OHP analogs which have a general formula of trans-bis(n-OCOCnH2n+1 )(1R,2R-cyclohexanediamine)(oxalato)platinum (IV) as well as C5-OHP. The complexes did not show significant differences in pharmacokinetic behavior after i.v. injection. Plasma platinum level after a single oral administration at a dose was higher for a complex with higher water solubility. The intestinal absorption rate measured by an in situ recirculating perfusion technique was higher for a complex with higher lipophilicity. These results indicate that the water solubility is a more dominant factor than the lipophilicity in the gastrointestinal absorption of the complexes. Then, the effects of surfactants and x-cyclodextrin (x-CD) on the solubility of C5-OHP was studied. Among the agents tested, x-CD showed the highest effect in increasing the solubility. Administration of C5-OHP together with x-CD gave approximately three times higher plasma platinum levels than administration of C5-OHP alone. Water solubility was found to be a dominant factor in the gastrointestinal absorption of C5-OHP and its analogs.

Binding sites between platinum (II) and uracil derivatives.

The complexes of triammineplatinum with uracil, 6-methyluracil, or uridine were prepared in aqueous solution at pH 7. The reaction of uracil with triammineplatinum gave two complexes at the same time. One was a complex in which triammineplatinum displaced a proton from uracil and coordinated to the N(3) position, and the other the complex coordinated to the N(1) position by displacing a proton. When triammineplatinum was treated with 6-methyluracil or uridine in aqueous solution at pH7, only a complex coordinated to the N(3) position was obtained. The ultraviolet (UV), NMR, and infrared (IR) spectral data provide useful information for determining the binding site of these complexes. The UV and IR spectral behaviors of the complex coordinated to the N(3) of uracil are very similar to those of 3-methyluracil. The NMR spectrum of the complex coordinated to the N(1) of uracil exhibits satellite peaks of 195Pt-proton and its coupling constant (39 Hz) gives good evidence for determining the binding site at the N(1) position.

Studies on the reaction products of guanylyl(3′–5′)adenosine with cis-Pt(NH2)2Cl2 and [Pt(NH3)3Cl]Cl

Abstract The reaction products of dinucleotide, GpA, with [Pt(NH3)3Cl]Cl and cis-Pt(NH3)2Cl2 have been separated by means of high performance liquid chromatography with a strong cation exchange column. Each peak fractionated has been characterized by UV spectral analysis. The reaction of GpA with [Pt(NH3)3Cl]Cl gave four products, but three of them are minor ones. The main product is found to be the 1:1 complex in which Pt(NH3)2+3 binds to GpA only through the N(7) site of the guanine residue. The reaction of cis-Pt(NH3)2Cl2 with GpA gave two products. One of the products is the 1:1 complex in which cis-Pt(NH3)2+2 binds to GpA through the N(7) sites of the guanine and adenine residues. The effect of pH on the reaction of cis-Pt(NH3)2Cl2 with GpA has been studied using high performance liquid chromatography.