SIMP/II, a revised version of SIMP which is a simulater of intermolecular potentials based on modified neglect of diatomic overlap (MNDO) approximation, has been developed. SIMP/D, which can approximately estimate dispersion energies using the second order sum-of-state perturbation method based on neglect of diatomic differential overlap (NDDO) approximation, has also been developed. The SIMP/II and SIMP/D systems were used to calculate the stacking energies between the two bases in nucleic acids. The results were in fair agreement with the ab initio calculations, thus confirming the utility benefits of the new versions.

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Glycyrrhetinate α-monoglycoside derivatives 8, 10 and 12, all having a trichloroacetyl group at the C-2 position of the pyranose ring, were treated with NH₃-saturated ether at 0°C to give the corresponding alcohols 13, 15 and 17, accompanied by 2'-chloroderivatives, 14, 16 and 18, respectively. Glycosylations of the alcohols 13, 15 and 17 with methyl 2, 3, 4-tri-O-acetyl-α-D-glucuronatopyranosyl bromide 19 in the presence of AgOTf in dry CH₂Cl₂ gave the corresponding α-diglycosides 20, 22 and 24 together with the enol α-glycosides 21, 23 and 25, respectively. Glycosylations of the diglycoside derivatives 20, 22 and 35 having no reactive OH group in the molecules with 19 for longer reaction times gave quantitatively the enol α-glycoside derivatives 21, 23 and 36, respectively. Glycosylation of the monoglycoside derivative 37, which has a poorly reactive OH group at the C-4 position on the pyranose ring, with 19 gave an enol α-glycoside 38. The mechanism of the formation of enol α-glycosides was investigated. Removal of the protecting groups of 20, 22 and 24 by successive treatment with 1.5N NaOMe in MeOH and 5% KOH in EtOH-H₂O (1 : 1) gave the free α-diglycosides 26-28, and removal of those of 31, 21, 23, 25 and 36 by treatment with 5% KOH in EtOH-H₂O (1 : 1) under reflux gave the free enol α-glycosides 41-45, respectively.

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Incubation of (25RS)-, (25R)- and (25S)-3α, 7α, 12α-trihydroxy-5β-cholestan-26-oic acid (THCA, 6, 6a, 6b) and (24E)-3α, 7α, 12α-trihydroxy-5β-cholest-24-en-26-oic acid (7) with rat liver mitochondria gave all four stereoisomers (9a, 9b, 9c, 9d) of 3α, 7α, 12α, 24-Tetrahydroxy-5β-cholestan-26-oic acid (TeHCA). The corresponding 27-nor analogs (10, 11) were also converted non-stereoselectively to a 1 : 1 mixture of the epimeric 24-hydroxy compounds (12).

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A palladium-catalyzed intramolecular asymmetric metallo-ene reaction was accomplished using a chiral allylic sulfone (prepared by thermal rearrangement of an optically active allylic sulfinate) as an enophile. The stereoselectivity of the reaction was determined by high-performance liquid chromatography with a chiral column. A plausible mechanistic pathway for this asymmetric cyclization is presented.

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Constant-current electrolysis (CCE) of Ph₃P and a carboxylic acid (RCO₂H, 1) in CH₂Cl₂ using a one-compartment cell equipped with two graphite plates as an anode and a cathode under a nitrogen atmosphere gave the corresponding aldehyde (2) when Ph₃P⁺H·ClO^-₄ was used as a supporting electrolyte. The partial reduction was affected by the choice of electrolysis conditions, especially temperature and current density, depending on the structure of 1. Thus, the CCE of 1 with R=Ph-, o-Cl-Ph-, p-MeO-Ph-, Ph(CH₂)₂-, CH₃(CH₂)₈-, Ph₂CH-proceeded smoothly at -30°C in fair yields. In the case of 1 with R=cyclo-C₆H₁1- and (CH₃)₂CH-, the electrolysis had to be carried out under reflux, and with R=(CH₃)₃C- the aldehyde was obtained only in a poor yield even under reflux. Based on the results of cyclic voltammetry of the anolyte obtained by the CCE of CH₂Cl₂ solutions of Ph₃P, Ph₃P⁺H·ClO^-₄, and 1 in a divided cell, the sequence of the partial reduction is proposed to be as follows : formation of acyloxy triphenylphosphonium ion (3) at the anode; the reaction of 3 with Ph₃P to afford the corresponding acyl triphenylphosphonium ion (4); reduction of 4 to the α-hydroxyalkyl triphenylphosphonium ion (7) at the cathode; decomposition of 7 to 2 and Ph₃P during the aqueous work-up after the CCE. The voltammetric study also suggested that the ease of the transformation of 3 to 4 is reflected in the required CCE conditions and may determine the yield of 2.

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Both enantiomers [(1'R)-6 and (1'S)-6] of N⁶-(1, 3-dimethyl-2-butenyl)adenine and their 9-β-D-ribofuranosides [(1"R)-16 and (1"S)-16] have been synthesized for the first time from both enantiomers of alanine (15) in nine steps. These aglycones and nucleosides, together with N⁶-(3-methyl-2-butenyl)adenine (5) and its 9-β-D-ribofuranoside (18) as well as 9-β-D-ribofuranosyl-cis-zeatin (20) and 9-(2-deoxy-β-D-ribofuranosyl)-cis-zeatin (19), were tested for cytokinin activity in the tobacco callus bioassay. The order of their activity was 5>(1'R)-6>(1"R)-16≈18>(1'S)-6>(1"S)-16>20>19. The bioassay results are compared with those obtained previously for the derivatives modified analogously in the N⁶-substituent in the cis- and trans-zeatin series.

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Seven new clerodane-type diterpenoids, named peronemins B₂ (1), A₂ (2), B₁ (3), C₁ (4), B₃ (5), A₃ (6), and D₁ (7), were isolated from the leaves of Peronema canescens (Verbenaceae), an Indonesian medicinal plant collected in Bengkulu, Sumatera Island, Indonesia. The chemical structures of 1-7 have been elucidated on the basis of their chemical and physicochemical properties.

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From the air-dried roots of Glycyrrhiza glabra L. (Leguminosae) collected in Xinjiang province, China ("Shinkyo-Kanzo" in Japanese), five new flavonoid compounds named glucoliquiritin apioside (1) (a flavanone bisdesmoside), prenyllicoflavone A (5) (a bisprenylflavone), shinflavanone (7) (a prenylated pyranoflavanone), shinpterocarpin (9) and 1-methoxyphaseollin (12) (both pyranopterocarpans), were isolated together with eight known saponins, seven known flavonoid glycosides, and eloven flavonoids. The structures of the new compounds have been elucidated on the basis of their chemical and physicochemical properties.

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Hypelcin B is a mixture of antibiotic peptides produced by Hypocrea peltata. Hypelcins B-I, B-II, B-III, B-IV and B-V are components of this mixture purified by reversed-phase high-performance liquid chromatography. The amino acid sequences of these peptides were determined by electrospray mass spectrometry and electrospray mass spectrometry/mass spectrometry. The molecular weights of these peptides were all ca. 2000 and the structures were very similar.

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New peptaibols, trichokindins I-VII, have been isolated from the fungus Trichoderma harzianum. Their structures were characterized by spectrometric methods. Trichokindins, which are 18-residue peptides containing one to three isovaline residues, were found to induce Ca²⁺-dependent catecholamine secretion from bovine adrenal medullary chromaffin cells.

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A series of 6, 8-dioxo-3-thia-1, 7-diazabicyclo[3.3.0]octanes and a series of 6, 8-dioxo-3-thia-1, 7-diazabicyclo[3.3.0]octane 2-spiro derivatives were synthesized from L-(-)-R-cysteine ethyl ester in two steps. The synthetic route involved condensation of the amino acid with an appropriate aldehyde or ketone, then a further condensation of the resultant ethyl tiazolidine-4-carboxylate with an isocyanate or an isotiocyanate. The proliferative response to human lymphocyte mitogen (phytohemagglutinin) was used as a primary screening assay for most of the thiadiazabicyclic compounds in comparison with levamisole. Furthermore, the most active compounds were tested for ability to release soluble receptors (sRIL-2) after mitogenic stimulation of T cells and for ability to activate macrophage oxidative metabolism measured by chemiluminescence. Most compounds were active in all three tests and some showed dose-dependent activity.

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The molecular geometry, acid dissociation constants and partition coefficients of the anilinoquinoline (I), indolo[3, 2-c]quinoline (II) and tetrahydroindolo[3, 2-d] [1]benzazepine (III) ring systems have been determined using representative compounds : 7-chloro-4-(p-anisidino)quinoline (Ia), 3-chloro-8-methoxy-11H-indolo[3, 2-c]quinoline (IIa) and 3-chloro-9-methoxy-5, 6, 7, 12-tetrahydroindolo[3, 2-d] [1]benzazepine (IIIa). Ring systems II and III are cyclic analogues of I. The minimum energy conformation was determined by molecular mechanics. Compound IIa is the most planar and conformationally restricted, followed by IIIa and Ia. The acid dissociation constants (pK_a) were determined by the solubility method. The ring nitrogen of Ia is most basic, followed by that of IIa and IIIa. The partition coefficient (log P) was determined between octanol and appropriate aqueous buffers by the shaken flask method. Hydrophobicity decreases in the order of Ia>IIa>IIIa. Factors contributing to the different molecular geometry, pK_a and hydrophobicity of these related compounds are discussed. The present study may contribute to the design of better drugs with ring system I, II or III.

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In order to develop new-generation macrolide antibiotics active against erythromycin (EM)-resistant strains, a series of 6-O-methyl EM 9-O-substituted oxime derivatives was synthesized and evaluated for antibacterial activity against EM-resistant (S. aureus J-109) and susceptible (S. aureus 209P) strains. To understand how substituents affect the biological activity, the quantitative structure-activity relationships (QSAR) was analyzed using the Hansch-Fujita method. With the EM-resistant strain, the positive coefficient for log P may indicate that higher hydrophobicity of molecules is favorable for antibacterial activity. The negative coefficients of the Sterimol parameters L, B₁, and B₅ may indicate that long, bulky substituents are unfavorable. With the EM-susceptible strain, the negative coefficient for log P may indicate that hydrophilicity is important for antibacterial activity. A short substituent is also required to improve the activity. Based on the QSAR model, a derivative (87) having an anthracenylmethyl moiety was synthesized to reinforce and confirm the correlation. The activity of 87 against the EM-resistant strain was significant. In QSARs of 6-O-methyl EM-A 9-O-substituted oxime derivatives, the difference of the contribution of log P to the antibacterial activity between EM-resistant and susceptible strains was clearly recognized.

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Three new antitumor sesquiterpenoids, achimillic acids A, B and C, were isolated as methyl esters from Achillea millefolium and their structures were determined spectroscopically. The compounds were found to be active against mouse P-388 leukemia cells in vivo.

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Five triterpenes with a D : C-friedo-oleanane skeleton, D : C-friedo-oleana-7, 9(11)-diene-3β, 29-diol (3-epikarounidiol), 7-oxo-D : C-friedo-olean-8-en-3β-ol (7-oxoisomultiflorenol), 7-oxo-8β-D : C-friedo-olean-9(11)-ene-3α, 29-diol, D : C-friedo-olean-8-ene-3α, 29-diol (3-epibryonolol), and D : C-friedo-olean-8-ene-3β, 29-diol (bryonolol), the first four of which are new naturally occurring compounds, were isolated from the seeds of Trichosanthes kirilowii MAXIM. The structures were determined by spectral and chemical methods. 3-Epikarounidiol, 7-oxoisomultiflorenol, and 3-epibryonolol showed marked inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear inflammation in mice. The 50% inhibitory dose of these triterpenes for TPA-induced inflammation (1 μg) was 0.2-0.6 mg/ear.

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A new xyloside (I), mp 252-253°C, C₃₇H<58>O<11>, [α]_D -51.4°, obtained from the methanolic extract of the aerial parts of Cimicifuga simplex was characterized as 7β-hydroxy-23-O-acetylshengmanol 3-O-β-D-xylopyranoside. A new triterpene (V), 7β-hydroxycimigenol, was also obtained as an aglycone of a glycoside mixture.

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Four new triterpenoidal saponins, called calliandra saponins B (8), C (9), D (10), and F (12), were isolated from the branches of Calliandra anomala (KUNTH) MACBR. The structures of these compounds were established on the basis of NMR spectra, FAB-MS, and the chemical evidence.These saponins, interestingly, have a N-acetyl glucosamine at the 3 position of the genin, and one or two monoterpene glycosides at the position of the sugar chain.

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Phytochemical screening of the bulbs of Ipheion uniflorum (Liliaceae) has led to the isolation of three new furostanol saponins (2-4) along with a known phytoecdysteroid, ecdysterone (1). The structures of the new compounds were determined by two-dimensional NMR techniques, ¹H-¹H correlation spectroscopy (COSY), homonuclear Hartmann-Hahn (HOHAHA), phase-sensitive nuclear Overhauser effect spectroscopy (NOESY), heteronuclear multiple quantum coherence (HMQC) and heteronuclear multiple-bond correlation (HMBC) spectra, and hydrolysis to be 3β-hydroxy-22α-methoxy-26-O-β-D-glucopyranosyloxy-5α-furost-25(27)-en-2-one 3-O-{O-α-L-rhamnopyranosyl-(1→2)-O-[O-α-L-arabinopyranosyl-(1→2)-O-[β-D-xylopyranosyl-(1→3)]-β-D-glucopyranosyl-(1→4)]-β-D-galactopyranoside} (2) and its 25(27)-dihydro derivatives (3 : 25S; 4 : 25R). The inhibitory activity exhibited by compounds 1-4 and the corresponding spirostanol saponins (2a and 3a) of 2 and 3 on cAMP phosphodiesterase was assayed as a primary screening test to identify new compounds with medicinal potential.

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Piretanide polymorphs were prepared by recrystallization using 27 organic solvents. We identified a new polymorphism, forms A and B, and 6 solvates. They were characterized by X-ray powder diffractometry, differential scanning calorimetry (DSC), thermogravimetry (TG), Fourier-transform infrared (FTIR) spectroscopy, elemental analysis and scanning electron microscopy. After heating, some solvates transformed to the stable form A, and others to form B. X-ray powder diffraction patterns and FTIR spectra of forms A and B were significantly different. However, the X-ray powder diffraction patterns and FTIR spectra of form A and the bulk sample were similar. The DSC curve of form A showed only an endothermic peak at 227°C corresponding to the melting point. The DSC curve of form B showed endothermic and exothermic peaks at 213 and 216°C, respectively, as well as a subsequent endothermic peak at 227°C. The metastable form B transformed to form A. The dissolution profiles of the bulk sample and form B in JP XII, 1st fluid (pH 1.2) at 37°C were measured by means of the dispersed amount. The solubilities of the bulk sample and form B were estimated to be 8.3 and 13.3mg/100ml, respectively.

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A quantitative approach is used in this work to reproduce the solubility profile of drugs in solvent mixtures showing two solubility maxima. The solubilities of sulfanilamide and sulfamethazine were determined at 25°C in two mixtures of varying polarity (ethyl acetate-ethanol and ethanol-water). A plot of the mole fraction of the drugs versus the solubility parameter of the solvent mixtures shows two solubility peaks. This unusual behavior cannot be described using the Extended Hildebrand method; it is probably a result of the chameleonic effect first described by Hoy. An equation including solute-solvent interaction terms represented by the acidec and basic partial solubility parameters, together with the Hildebrand solubility parameters of the solvent mixtures, is used to reproduce the experimental solubilities. The equation yields the two solubility maxima as found experimentally.Furthermore, the solubilities of sulfanilamide and sulfamethazine in two solvent mixtures are combined into a single equation to reproduce the two solubility maxima found for each drug. The equation is also able to predict the solubility curve of sulfamethoxypyridazine. The results show that the chameleonic effect can be described in a quantitative way in terms of Lewis acid-base interactions as represented by acidic and basic solubility parameters. Hildebrand solubility parameters, as well as the acidic and basic solubility parameters, are tabulated and they can be calculated for solvent mixtures, making easier the prediction of the best solvent mixture for a drug.

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The interaction between warfarin (WF) and ionic synthetic polymer was investigated using an equilibrium dialysis method. Polymers used were quaternized poly(4-vinylpyridinium bromide)s (QPV), in which N-alkyl groups were butyl (QBu), methyl (QMe) and benzyl (QBz), and degree of quaternization of polymer was shown in parentheses as a percentage. The nature of bindings depended on both the hydrophilic property of the pyridinium part and the hydrophobic property of the alkyl and pyridine parts. The bindings of WF to QBu(100) and QMe(100) were assumed to be due to hydrophilic interaction. The binding capacity of WF to QBu decreased with increase of the degree of quaternization of QBu. The binding of WF to QBu(24) was attributed to both hydrophobic and hydrophilic parts. The binding of WF to QBz(80) was due to hydrophobic interaction because of the hydrophobic property of the benzyl group. N-Butyl-4-ethylpyridinium bromide (BEP) monomer and WF formed an equimolar complex. Phenylbutazone (PB) competed with WF for the hydrophobic binding to QBz(80).

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The effect of formaldehyde (FA) on three physicochemical properties of soft gelatin capsule shells was studied to interpret a change in the internal structure of those capsule shells whose disintegration time was remarkably prolonged by long-term storage at 40°C or more. Shells with different degrees of crosslinking were prepared by immersing the shells in 0-3% FA solutions for 10 min. These shells were evaluated by measuring the following three physicochemical properties : equilibrium swelling ratio (S_eq), the gel strength of the swollen shells, and the percent of gelatin dissolved after 10 min (D₁₀) from the shells.When the soft gelatin capsule shells were crosslinked by the treatment with FA, S_eq determined by second-order kinetics in the swelling of the shells decreased linearly with an increase in the amount of FA. The gel strength of the swollen shells increased with an increasing amount of FA, whereas the D₁₀ of gelatin from the shells was diminished drastically at a given small amount of FA. From these findings, we confirmed that a three-dimensional network was formed tightly by interchain covalent crosslinking in the shells by treatment with FA.These results were, on the whole, closely similar to the phenomenon observed in the disintegration test for the soft gelatin capsules stored long-term at 40°C or more. Therefore, it was suggested that the evaluations of these physicochemical properties were available also for capsule shells treated by heating to clarify a mechanism for the prolongation of the disintegration time of the soft gelatin capsules.

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Novel molecular conformation of racemic hesperetin, (±)-2, 3-dihydro-5, 7, -dihydroxy-2-(3-hydroxy-4-methoxy-phenyl)-4H-1-benzopyran-4-one, was determined by X-ray analysis. A new form was crystallized from ethanol solution and its molecular conformation is quite different from that of monohydrate crystal (Acta Crystallogr., C43, 1946 (1987)). The aromatic ring part of benzopyrone and the phenyl ring form the twist orientation (dihedral angle of two rings, Φ is 53.1(3)°), in contrast to the parallel arrangement in the monohydrate form (Φ=0.6°). The pyrone ring forms a slightly flattened sofa conformation, where C(2) is displaced by 0.40(2) Å from the pyrone plane, in contrast to the large displacement in the monohydrate form (0.54Å). There is a strong intramolecular hydrogen bond between keto O(4) atom and hydroxy H(O5)-O(5) group which forms a six-membered ring conjugated with benzopyrone rings. The degree of conjugation is also slightly different of the two forms and may relate to the difference of hydrogen bonding network and stacking mode of aromatic rings.

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The ¹³C-NMR spectrum of cyclo(L-Phe-L-Pro)₄ (1) and DL-noradrenaline hydrochloride (DL-NA·HCl) in a mixture of CDCl₃ and CD₃OD suggested the formation of a complex, which was demonstrated to be 1 : 1 from examination of the titration curves. The complex retained the C₂-symmetric conformation of 1 containing two cis-peptide bonds, and was linked through hydrogen bonds between the carbonyl groups of the Phe¹ and Pro² residues, and the ammonium moiety of NA·HCl.

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Reaction of enaminones with benzyltrimethylammonium dichloroiodate (BTMA·ICl₂) in methylene chloride-methanol in the presence of sodium bicarbonate at room temperature gave iodinated products at the α-position of the carbonyl group in good yields within 1 h.

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Incorporation of hydrophobic poly(amino acid) into liposomal membranes was achieved by the polymerization of N-carboxy anhydrides of amino acids in the egg yolk phosphatidylcholine (EyPC) bilayer under reduced pressure at 30°C. The trapped volumes for the liposomes with and without polypeptides were 8.1 - 10.3 lmol^-1 and 11.4 lmol^-1, respectively. The permeability barrier abilities of liposomal membranes were lowered by the incorporation of polypeptides into the membrane bilayers. Water permeation across the membrane bilayer was more effective for the liposome with the α-helical polypeptide than for that with the β-sheeted one.

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1-Ethoxycarbonyl-3-methylbenzimidazolium salts, which have two possible reactive sites toward superoxide, were allowed to react with KO₂ and electrogenerated superoxide to give the ring-opened products and 1-methylbenzimidazoles. The former compounds were specific products for superoxide, and the product distributions were revealed to depend on the counter cation of superoxide.

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The rate of racemization of N(α)-phthalimidoglutarimide (thalidomide) was determined as its half life to be 566 min at pH 7.4/37°C. This fast racemization of thalidomide resulted in no apparent difference between (S)- and (R)-forms of the compound on enhancing activity of phorbol ester-induced tumor necrosis factor (TNF)-α production by human leukemia HL-60 cells. Optically pure forms of structurally related analog of thalidomide, (S)- and (R)-α -methyl-N(α)-phthalimidoglutarimides (methylthalidomides), which do not racemize under the physiological condition, were prepared. Only (S)-form of methylthalidomide, but not its (R)-form, elicited TNF-α production-enhancing effect, suggesting that the (S)-isomer of thalidomide would be the active form in terms of thalidomidal biological response modifying effects.

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(4S, 5R)-Epoxy-(3S)-hydroxy-(10S)-7α, 11βH-eudesman-6α, 12-olide 4__- and (4R, 5S)-epoxy-(3S)-hydroxy-(10R)-7β, 11αH-eudesman-6β, 12-olide 5__- were obtained from (±)-3__- using yeast and (3S)-acetoxy-(4S, 5R)-epoxy-(10S)-7α, 11βH-eudesman-6α, 12-olide 8__- was produced from (±)-8__- using lipase, respectively. New total syntheses of l-α-santonin (9) and its Δ⁴⁽¹⁴⁾-isomers (10 and 11) were accomplished by a short step synthesis using the optically active key intermediate (10S)-8__- (prepared by asymmetric hydrolysis of (±)-8__-).

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