Improvement of some pharmaceutical properties of nocloprost by β- and γ-Cyclodextrin Complexation

Inclusion complexation of nocloprost, a potent antiulcer prostaglandin derivative, with -, -, and -cyclodextrins (CyDs) in aqueous solutions has been studied by the solubility method and¹³C-NMR spectroscopy. The steric requirement of host-guest interaction was reflected in the magnitude of the stability constants and the thermodynamic parameters of the inclusion complexes. Solid complexes of nocloprost with - and -CyDs in a molar ratio of 1 : 2 were obtained on the basis of aBs-type phase solubility diagram. The X-ray diffraction data suggested that nocloprost is included in the cylindrical channel formed by coaxial alignment of -CyD molecules to give a channel type structure. Release and thermal behavior of the solid complexes was examined and compared with nocloprost itself. The results indicated that the -CyD complex may have great utility among the three CyDs, being a rapid dissolving form of nocloprost with improved thermal stability.     

Radiation-induced reactions of cholesterol in an aqueous medium

⁶⁰Co -ray radiolysis of cholesterol /3-hydroxy-5-cholestene/ /I/ in the two-phase system /water-ethyl acetate/ and in the presence of air has been studied using TLC and GC methods. The following products were observed in the irradiated mixture: 3, 7-dihydroxy-5-cholestene /II/, G O. 36, 3-hydroxy-7-keto-5-cholestene /III/, G 1.48, 3-hydroxy-7-keto-5-cholestane /IV/, G 0.22, 3,5,6-trihydroxy-5-cholestane /V/, G 0.83, 5,6-epoxy-3-hydroxy-5-cholestane /VIa/, G 0.26, 5,6-epoxy-3-hydroxy-5-cholestane /VIb/, G 0.24, and 2, 3-dihydroxy-5-cholestene /VII/, G 0.22. The dose dependence of the formation of these products shows that the cholesterol derivatives substituted in the position 7 /II–IV/ are formed from a common precursor — the radical Ia. On the other hand, the products of the 5–C=C double bond reactions /V and VI/ are formed independently. Also the product VII is formed independently. A reaction scheme that is in agreement with these results is proposed.     

Crystal and molecular structures of the sesquiterpene lactone ajafinin

An x-ray structural analysis has been made with the aim of reliably determining the spatial structure of the sesquiterpene lactone ajafinin. It has been established that it has the structure and configuration of 1,2--epoxy-3,4,10-trihydroxy-5,6(H),7(H)-guai-11(13)-en-6,12-olide.Institute of the Chemistry of Plant Substances, Academy of Sciences of the Uzbek SSR, Tashkent. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 291–295, May–June, 1986.     

A molecular mechanics study of the effect of substitution in position 1 on the conformational space of the oxytocin/vasopressin ring

Summary The effect of the substitution in position 1 on the low-energy conformations of the oxytocin/vasopressin 20-membered ring was investigated by means of molecular mechanics. Three representative substitutions were considered: -mercapto-,-dimethyl)propionic acid (Dmp), (-mercapto-,-cyclopentamethylene)propionic acid (Cpp), both forming strong antagonists, and (,-dimethyl--mercapto)propionic acid (-Dmp), forming analogs of strongly reduced biological activity, with the -mercaptopropionic (Mpa) residue taken as reference. Both ECEPP/2 (rigid valence geometry) and AMBER (flexible valence geometry) force fields were employed in the calculations. Three basic types of backbone conformations were taken into account which are distinguished by the type of -turn at residues 3 and 4: 1/III, II, and I/III, all types containing one or two intra-annular hydrogen bonds. The allowed (ring-closed) disulfide-bridge conformations were searched by an algorithm formulated in terms of scanning the disulfide-bridge torsional angle C-S-S-C. The ECEPP/2 and AMBER energies of the obtained conformations were found to be in reasonable agreement. Two of the low-energy conformers of the [Mpa¹]-compound agreed very well with the cyclic part of the two conformers found in the crystal structure of [Mpa¹]-oxytocin. An analysis of the effect of -substitution on relative energies showed that the conformations with the N-C-CH₂-CH₂ (₁) and C-CH₂-CH₂-S (₁) angles of the first residue around (–100°, 60°) and (100°, –60°) are not affected; this in most cases implies a left-handed disulfide bridge. In the case of -substitution the allowed values of ₁ are close to ± 60°. This requirement, being in contradiction to the one concerning -substitution, could explain the very low biological activity of the -substituted analogs. The conformational preferences of substituted compounds can largely be explained by the analysis of local interactions within the first residue. Based on the selection of the conformations which are low in energy for both the reference and -substituted compounds, two distinct types of possible binding conformations were proposed, the first one being similar to the crystal conformer with a left-handed disulfide bridge, the second one having a right-handed bridge, but a geometry different from that of the crystal conformer with the right-handed bridge. The first type of disulfide-bridge arrangement is equally favorable for both I/III and II types of backbone structure, while the second one is allowed only for the II type of backbone. No conformation of the I/III type has a low enough energy to be considered as a possible binding conformation for all of the active compounds studied in this work.     

Radiometric measurements of fallout under accidental conditions

Empirical expression for experimentally obtained functional dependence between the results of total -activity and integral -activity activity of fallout, measured during May, 1986, at a control point: 44°47 northern latitude and 20°32 eastern longitude, has been established in order to enable estimation of the level of fallout contamination by -emitters when total -activity values are known.     

Radiochemical determination of lead-210 in environmental water samples using Cerenkov counting

A relatively simple method has been developed for the determination of²¹⁰Pb via its -emitting daughter,²¹⁰Bi. Lead-210 was separated from interfering elements as lead sulphate. The precipitate was dissolved in an alkaline solution of EDTA and the Cerenkov signal produced by the build-up of²¹⁰Bi was counted 30 days after storage using tritium channel of a liquid scintillation counter. Cerenkov counting efficiency was found to be approximately 20%. A lower limit of detection of 5.1 mBq/1 (based on 3 of the background with 500 minute counting time) was achieved. Chemical recoveries in the range of 70–100% were determined gravimetrically. Interference associated with currently used methods is avoided. Data from from both spiked samples and natural samples are presented.     

Pulse-chromatographic determination of molybdenum surface by oxygen adsorption in Co?Mo catalysts

A pulse-chromatographic method has been developed for the estimation of molybdenum surface by selective adsorption of oxygen at –78°C in cobalt-molybdenum-alumina catalysts. The surface concentrations of molybdenum in a series of catalysts of different compositions were compared with the activities for cyclohexene hydrogenation and for thiophene hydrogenolysis.

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- –78°C -- . - .

     

Complexation of Vinpocetine with Cyclodextrins in the Presence or Absence of Polymers. Binary and Ternary Complexes Preparation and Characterization

Inclusion complexation between -cyclodextrin (-CD),hydroxypropyl--cyclodextrin (HP--CD), water-solublepolymers (PVP and HPMC) and vinpocetine was studied in aqueous solution and in the solid state.Phase solubility studies were used to evaluate the complexation in aqueous solution at roomtemperature. Stability constants (K_c) of binary and ternary complexes were determined spectrophotometrically. Differential scanning calorimetry (DSC)was used to characterize kneaded, co-evaporated and lyophilised binary and ternary systems.The K_c values obtained were 70.14 M^-1 and 35.01 M^-1 for vinpocetine--CD and vinpocetine-HP--CD and increased in a range of 17% to 94%by addition of water-soluble polymers. Some preliminary evidences ofinclusion complexation were obtained from DSC suggesting that co-evaporated and lyophilised binary andternary systems were truly inclusion complexes.     

Electron Delocalization in 3d Complexes Caused by Dimethylurea Checked by Positron Annihilation

The rate constants, k _CR, of ortho- into para-positronium conversion reactions promoted by paramagnetic 3d complexes are linearly correlated with the electron delocalization, , of unpaired metal electrons caused by ligands, being the ratio between the inter-electronic repulsion parameters in complexes and in the free gaseous ions. By applying a procedure previously described the values of Mn^II, Co^II, Ni^II complexes with dimethylurea were deduced from the mentioned correlations and compared with those of complexes with urea obtained both by the method of Ps reactions here applied and that based on UV-Vis absorption spectroscopy.     

Electric moments and polarizabilities for LiH (X1Σ+)

Near Hartree-Fock values have been obtained for all independent components of electric multipole moment and polarizability tensors up to the fourth rank for the ground state of LiH. The dependence of the electric properties on internuclear separation is inferred from calculations at three different bond lengths. The calculation of the interaction potential LiH. e^– leads to deductions about the relative importance of the polarizability tensors in intermolecular interaction studies. The independent components of the tensors at r _e =3.034286 a₀ are, in atomic units, _zz =22.0884, _xx =25.2846, _zzz =224.3, _zxx =203.1, _zzzz =76848, _xxxx =21472, and _xxzz =19485.Member of the Ottawa-Carleton Chemistry Institute     

Interaction of tri-O-methyl-β-cyclodextrin with drugs

Summary The effect of tri-O-methyl--cyclodextrin(methyl--CD) on the partition coefficients of drugs, such as p-nitrophenol, salicylic acid, benzoic acid, and aspirin, was studied at 25°C. The partition coefficients of these drugs were increased linearly with methyl--CD concentration. The increase of partition coefficients was interpreted by the 11 complex formation between methyl--CD and the drug in CHCl₃ phase.The interaction between p-nitrophenol and methyl--CD in solution was studied by UV and PMR spectroscopies. It was concluded that p-nitrophenol is included in the cavity of methyl--CD in both aqueous solution and CHCl₃ solution.Inclusion compounds of these drugs with methyl--CD in the solid state were studied by X-ray diffractometry, IR spectroscopy, and DSC measurements. 11 crystalline inclusion compounds were obtained from hot water. It is also suggested that amorphous inclusion compound was obtained by the grinding of drug with methyl--CD.The dissolution rate and the bioavailability of ketoprofen were significantly increased in the presence of methyl--CD. The bioavailability of ketoprofen after oral administration with methyl--CD to rats was 3.7 times that of ketoprofen alone.     

Polyhydroxysteroids from the Far-Eastern starfishCtenodiscus crispatus

Four new polyhydroxysteroids, 5-cholesta-3,5,6,15,16,25,26-heptaol, 24-ethyl-5-cholesta-3,5,6,15,28,29-heptaol-29-sulfate, (22E)-24-methyl-5-cholest-22-ene-3,5,6,15,25,26-hexaol-26-sulfate, 24-propyl-5-cholesta-3,5,6,8,15,28,29-heptaol, and the known 5-cholesta-3,5,6,15,16,26-hexaol, have been isolated from the starfishCtenodiscus crispatus.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1821–1825, October, 1994.     

Stereoselective Hydrogenation of Thymol over Rh/alumina in the Presence of β:-cyclodextrin and its Derivatives

Stereoselective hydrogenation of thymol over Rh/alumina in the presence of various equivalents of -cyclodextrin (-CD) and itsderivatives in the solid state was studied. Hydrogenation of thymol in the absence of -CD gave 76.8% epimeric alcohols with a menthol/neomenthol (M/N) ratio of 5.6 and an alcohol/ketone ratio of 4.5, whereas the presence of 0.1 equivalent (to thymol) of -CD gave rise to 94.6% of epimeric alcohols with a M/N ratio of 6.3 and an alcohol/ketone ratio of 45.4. The effect of -cyclodextrin and its derivatives on the modification of the yield and the proportion of epimeric alcohols formed were found to be the salient features of this investigation. Inclusion complexation of thymol by -CD studied by UV-Visible spectroscopyindicated a 2:1 stoichiometry ofthymol: -CD complex with a binding constant value of 480 ±40 M^-2.     

Reaction of the nitrile of 3,3-diphenyl-2-propenic acid with the carbanions of some α-branched nitriles Short communication

Reaction of the nitrile of 3,3-diphenyl-2-propenic acid with -branched nitriles in the presence of lithium amide in liquid ammonia does not give the correspondingMichael adducts but the ,-unsaturated nitriles6. Conc. sulfuric acid transforms these nitriles into the -lactones7.

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Reaktion von 3,3-Diphenyl-2-propensäurenitril mit den Carbanionen einiger -verzweigter Nitrile (Kurze Mitteilung)

Zusammenfassung Die Reaktion von 3,3-Diphenyl-2-propensäurenitril mit -verzweigten Nitrilen in Gegenwart von Lithiumamid in flüssigem Ammoniak führt nicht zu den entsprechendenMichael-Addukten, sondern zu den ,-ungesättigten Nitrilen6. Durch Einwirkung von konz. Schwefelsäure entstehen aus diesen Nitrilen die -Lactone7.

     

Glycosylation of triterpene alcohols of the lupane series

The glycosylation of lupeol, allobetulin, 3-28-dihydroxy-18-lupene, 3-28-dihydroxy-18, 19-epoxylupane and of betulin monoacetates in acetonitrile with mercury cyanide has been studied. The 3- and 28-mono- and the 3,28-di-O--D-glucopyranosides of 3-28-dihydroxy-18-lupene and of 3-28-dihydroxy-18, 19-epoxylupane have been synthesized for the first time. Preparative methods for the synthesis of glucosides of lupeol, of allobetulin, and of betulin 3- and 28-monoacetates are proposed.Pacific Ocean Institute of Bioorganic Chemistry, Far Eastern Branch, USSR Academy of Sciences, Vladivostok. Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 212–217, March–April, 1988.     

Contribution de l'analyse thermique a l'etude des acides humiques et de leurs sels de sodium

Résumé On a étudié le comportement thermique sous oxygène des acides humiques et de leurs sels de sodium. On prépare les humates de sodium, soit par neutralisation des acides humiques, soit par dialyse de leurs pseudo-solutions dans la soude. L'examen des spectres infrarouges et de diffraction X des prélèvements effectués entre les étapes de dissociation (suivie par ATD-TG -TGD) suggère un double mécanisme. Au-dessous de 500°, il s'est formé du carbonate de sodium et du carbone. Dès 600°, débute la dissociation du carbonate. Le carbone restant s'oxyde brutalement à 770°. L'importance de la réaction varie avec la teneur initiale en sodium.

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The thermal behaviour of humic acids and their sodium salts in oxygen has been studied. The sodium humates were prepared by neutralization of humic acids or by dialysis of their pseudosolutions in sodium hydroxide. Infrared and X-ray diffraction spectra of samples taken between the dissociation steps obtained from the DTA-TG-DTG curves suggest a double mechanism. Below 500°, sodium carbonate and carbon are formed. At 600°, the dissociation of carbonate starts. The residual carbon burns at once at 770°. The extent of reaction changes with the amount of sodium initially present.

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Zusammenfassung Es wird über die Untersuchung der thermischen Eigenschaften von Huminsäuren und ihren Natriumsalzen unter Sauerstoff berichtet Letztere wurden entweder durch Neutralisation der entsprechenden Huminsäuren oder durch Dialyse ihrer Pseudolösungen in Natriumhydroxyd erzeugt. Die infrarotspektroskopische und röntgenanalytische Prüfung von zwischen zwei (durch DTA, TG und DTG verfolgte) Dissoziationen entnommenen Proben zeigt zwei Vorgänge. Unter 500° werden Natriumkarbonat und Kohle gebildet. Bei 600° beginnt die Dissoziation des Karbonats. Die zurückbleibende Kohle wird bei 770° plötzlich oxidiert.

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Na- . . - , ( — ), . 500° . 600° . 770°. .

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En l'honneur du 70^e anniversaire du Professeur Clément Duval. Etude entreprise dans le cadre des travaux de l'Equipe de Recherche Associée du C. N. R. S. n 220 (Pédologie des Pays Atlantiques).     

Synthesen von kernsubstituierten N,N-Diphenyl-β-alaninen

Zusammenfassung N,N-Diphenyl--alanine mit Substituenten in einem oder in beiden Phenylresten wurden durch Umsetzung von entsprechenden Diphenylaminderivaten mit -Propiolacton erhalten. In ähnlicher Weise reagierte Diphenylamin mit -Butyrolacton zu -(N,N-Diphenylamino)-buttersäure. 4,4-Diäthyldiphenylamin und 2-Chlor-6-methyl-diphenylamin wurden als Ausgangsmaterialien für die entsprechenden -Alanine hergestellt.

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N.N-Diphenyl--alanines with substituents in one or in both of the phenyl groups were synthesized by reactions of the corresponding diphenylamine derivatives with -propiolactone. Similarly diphenylamine reacted with -butyrolactone to give -(N.N-diphenylamino)-butyric acid. 4.4-Diethyldiphenylamine and 2-chloro-6-methyldiphenylamine were prepared as starting materials for the corresponding -alanines.

     

Inclusion Complexes of Cyclodextrins with Tetrakis(4-carboxyphenyl)porphyrin and Tetrakis(4-sulfonatophenyl)porphyrin in Aqueous Solutions

In neutral and alkaline solutions, tetrakis(4-carboxyphenyl)porphyrin (TCPP) and tetrakis(4-sulfonatophenyl)porphyrin (TSPP) form 1:1 and 2:1 host–guest inclusion complexes with -cyclodextrin (-CD), -cyclodextrin (-CD), and 6-deoxy-6-diethylamino--CD (DEA--CD), except for DEA--CD in alkaline solution. On the other hand, TCPP and TSPP form only 1:1 inclusion complexes with 6-deoxy-6-dihexylamino--CD (DHA--CD). The limited solubilities of DEA--CD in alkaline solution and DHA--CD are likely responsible for no observation of the 2:1 inclusion complex containing DEA--CD in alkaline solution and that containing DHA--CD. The equilibrium constants (Ks) of TCPP and TSPP for the formation of the inclusion complexes have been estimated from the absorption and/or fluorescence intensity changes in neutral and alkaline solutions. The K₂ values, which are the equilibrium constants for the formation of the 2:1 host–guest inclusion complex from the 1:1 inclusion complex, are about one tenth the corresponding K₁ values, except for the -CD–TSPP system in alkaline solution. In neutral solution, where DEA--CD and DHA--CD are in protonated forms, the electrostatic force operates between DEA--CD (DHA--CD) and TCPP (TSPP), leading to the greater K values than those in alkaline solution, where DEA--CD and DHA--CD exist as neutral species.     

Cardiac glycosides of theCheiranthus allioni. XII

The seeds ofCheiranthus allioni hort. have yielded three new cardenolides the structures of which have been established and which have been named as 4-dehydrosarmentogenin (II), 4-dehydrosarmentogenin rhamnoside (I), and 4-dehydrosarmentogenin rhamnoglucoside (IV). (II) — C₂₃H₃₂O₅. m.p. 296–302°, [] _D ²⁰ +26.2±3° (in pyridine) is 3,11,14-trihydroxy-14-card-4,20(22)-dienolide. (I) C₂₉-H₄₂O₉, m.p. 268–275°, [] _D ²⁰ –38.2±3° (chloroform-ethanol) is 11,14-dihydroxy-3--L-rhamnopyranosyloxy-14-card-4,20(22)-dienolide.(IV) C₃₅H₅₂O₁₄, [] _D ^20D –44.1±3° (methanol), is 3-(4-O--D-glucopyranosyl--L-rhamnopyranosyloxy)-14-card-4, 20(22)-dienolide. An independent synthesis of 4-dehydrosarmentogenin (II) has been carried out, starting from 3,5,11,14-tetrahydroxy-5,14-card-20(22)-enolide, which has confirmed its structure.For Communication XI, see [1].All-Union Scientific-Research Drug Institute, Kharkov. Kharkov State Pharmaceutical Institute. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 119–125, January–February, 1987.