The thermodynamics of partitioning of benzocaine (BZC) were studied in octanol/buffer (ROH/W), isopropyl myristate/buffer (IPM/W), cyclohexane/buffer (CH/W), and dimyristoyl phosphatidylcholine (DMPC) and dipalmitoyl phosphatidylcholine (DPPC) liposome systems. In all cases the partition coefficients were greater than unity; therefore the free energies of transfer were negative, that is, the processes of transfer of BZC from aqueous media to organic systems were spontaneous. The partition coefficients were approximately three-fold higher in DMPC liposomes compared with the ROH/W system in the 30°—40 °C temperature range. The enthalpies of transfer from aqueous media to ROH and IPM were negative, but positive for CH, while this property was negative for DMPC liposomes and positive for DPPC liposomes. The entropies of transfer were positive in almost all cases, except for DMPC. The results presented here confirm the lipophilic nature of BZC.

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The effects of antimalarial drugs halofantrine and lumefantrine on the fluoresence anisotropy of diphenylhexatriene (DPH)-containing phospholipid vesicles have been examined. Lumefantrine increases DPH anisotropy, indicating a condensing effect on bilayers of dipalmitoylphosphatidyl choline (DPPC), dioleoylphosphatidylcholine (DOPC), egg lecithin and mouse erythrocyte membranes (including membranes isolated from plasmodial-infected mice). Its condensing effect is more pronounced in bilayers of lower microviscosity. In contrast, increases or decreases in DPH anisotropy are observed with halofantrine, depending on the nature of the lipid. Decreases in anisotropy, which reflect a perturbing effect, are observed in bilayers of high microviscosity (for example, gel state of DPPC bilayers). Increases in anisotropy are observed in bilayers of low microviscosity (such as DOPC and egg lecithin bilayers). The perturbing effect of halofantrine is further confirmed by the increases in permeability of calcein-containing DPPC vesicles in the presence of the drug. However the perturbative effects of halofantrine are observed to the same magnitude in uninfected and plasmodial-infected erythrocyte membranes, and may not be relevant to the antimalarial action of the drug. In contrast, the condensing effect of lumefantrine is significantly greater in infected erythrocyte membranes and may contribute to its antimalarial action.

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A screening study focusing on monoamine oxidase inhibitory activity on the EtOAc extract of an Ascomycete Chaetomium quadrangulatum, which previously gave five unique chromones possessing this activity (chaetoquadrins A—E (1—5)), this time afforded six new constituents termed chaetoquadrins F—K (6—11) in addition to 1—5. The structures of 6—11 have been deduced on the basis of spectral and chemical data, and 7 and 8 have shown appreciable monoamine oxidase inhibitory activity.

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Paeonins A and B, new monoterpene galactosides have been isolated from the chloroform-soluble fraction of the roots of Paeonia emodi and showed potent lipoxygenase inhibitory activity. The structures of 1 and 2 have been assigned on the basis of spectral analysis including one- and two-dimensional NMR techniques.

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Two new podophillotoxin glucosides, L-picropodophillotpxin 7′-O-(β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside) (2) and L-picropodophillotpxin 7′-O-β-D-glucopyranoside (3), were isolated from Chinese medicinal plant, Sinopodophillum emodi, together with 4 known compounds, podophillotoxin (1), podorhizol 4′-O-β-D-glucopyranoside (4), deoxypodophillotoxin (5), and dehydropodophillotoxin (6). The structures of 2 and 3 were finally determined by the extensive decouping and nuclear Overhauser effect (NOE) experiments in NMR spectra and circular dichroism (CD) spectra. Compound 2 is the second example of podophillotoxin diglucoside, and both the first one and 2 were isolated from S. emodi. X-ray crystal structure analysis of 1, 5, and 6 was carried out. Compounds 1 and 5 showed the different conformations from those reported.

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Four new diarylheptanoids (1—4), along with two known tetralones (5, 6), were isolated from the roots of Juglans mandshurica and their structures were elucidated on the basis of spectroscopic studies.

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We have synthesized novel axially chiral ligand with two chiral centers, (R)-(R)₂- and (S)-(S)₂-2,2′-bis(2,2,2-trifluoro-1-hydroxyethyl)biphenyl (1), which showed a high asymmetric induction when used as ligand. Here, another new approach to 1 by kinetic and thermodynamic resolution is presented which gave these ligands in a much shorter steps, in a higher yield, and in a higher enantiomeric excess.

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From the methanolic extract of Indonesian Orthosiphon stamineus, nine new highly-oxygenated isopimarane-type diterpenes [7-O-deacetylorthosiphol B (1), 6-hydroxyorthosiphol B (2), 3-O-deacetylorthosiphol I (3), 2-O-deacetylorthosiphol J (4), siphonols A—E (5—9)] have been isolated together with nine known diterpenes [orthosiphols H (10), K (11), M (12) and N (13); staminols A (14) and B (15); neoorthosiphols A (16) and B (17); norstaminol A (18)]. Their structures were determined based on the spectroscopic data. The isolated diterpenes inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-activated macrophage-like J774.1 cells. Compounds 4—7, 9, 10, 14, and 17 showed inhibitory activities more potent (IC₅₀, 10.8—25.5 μM) than a positive control N^G-monomethyl-L-arginine (L-NMMA; IC₅₀, 26.0 μM).

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A series of erythrose, ribose, and substituted pyrrolidine containing 2,4-thiazolidinediones were synthesized. Among them, thirteen unsaturated thiazolidinediones, six saturated thiazolidinediones and two unsaturated malonates were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. On the basis of the in vitro activity, 5-{4-[2-(1-benzyl-3,4-bis-benzyloxypyrrolidin-2-yl)ethoxy]benzylidene}thiazolidine-2,4-dione 24b was selected as the candidate for further pharmacological studies.

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Five megastigmane glucosides were isolated from the leaves of Glochidion zeylanicum. One of them was a known compound, blumenol C O-β-D-glucopyranoside (1), and the structures of the four new compounds, glochidionionosides A—D (2—5), were mainly elucidated by spectroscopic methods, including a modified Mosher's method. The absolute configurations of the six-membered ring of glochidionionoside D (5) were deduced by β-D-glucopyranosylation-induced shift trends in the ¹³C-NMR spectra and confirmed by X-ray analysis as its p-bromobenzoate (5b), and the axis chirality of C-7 was determined to be R.

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Oxidation products of cyclopropanoid terpenes, (−)-carane (4), (+)-cyclosativene (5), laurinterol methyl ether (6), and thujopsane (7), with ruthenium tetraoxide were investigated.

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Cycloadditions of 1,3-butadiene derivatives having an electron-rich group at the 1-position with 4- or 3-substituted 2(1H)-quinolones were carried out to give the richly functionalized phenanthridines under both atmospheric and high pressure conditions. Furthermore, the reactivity of 4- or 3-substituted 2(1H)-quinolones acting as a dienophile with 1-substituted dienes was examined using MO calculation.

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The influence of fluoride (F⁻), bromide (Br⁻), iodide (I⁻), thiocyanate (SCN⁻) and nitrite (NO₂⁻) on the reaction of a myeloperoxidase–H₂O₂–Cl⁻ system with a nucleoside mixture was studied. The reaction was carried out under mildly acidic conditions and terminated by N-acetylcysteine. Without the additional anions, quantity of nucleosides consumed fell in the following order: 2′-deoxyguanosine>2′-deoxycytidine>>2′-deoxythymidine>2′-deoxyadenosine≈0. F⁻ did not affect the reaction. Br⁻ increased the consumption of 2′-deoxycytidine and 2′-deoxythymidine, but decreased that of 2′-deoxyguanosine. I⁻, SCN⁻ and NO₂⁻ suppressed the reaction. These results suggest that Br⁻ has a unique effect in relation to nucleoside damage caused by myeloperoxidase.

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Chemical examination of the fresh rhizomes of Tupistra wattii HOOK. f. led to the isolation of three new steroidal saponins, wattoside G (1), H (2), and I (3), together with one known steroidal saponin, (25S)-1β,3β,4β-trihydroxyspirotan-5β-yl-O-β-D-glucopyranoside (4). The structures of 1—3 were established to be (25R)-1β,2β,3β,5β-tetrahydroxyspirostan-4β-yl-O-β-D-xylopyranoside (1), (24S,25S)-24-[(β-D-glucopyranosyl)oxy]-1β,2β,3β,4β,5β,7β-hexahydroxyspirostan-6-one (2), and (24S,25S)-1β,3β-dihydroxy-5β-spirostan-24-yl-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside (3) on the basis of detailed analyses of physical, chemical, and spectral data. The isolated compounds were evaluated for cytotoxic activity against the cancer cell line K562 in vitro.

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In order to obtain novel topically applied anti-inflammatory compounds containing an inexpensive anti-oxidative moiety without chirality, we synthesized compound 2c derivatives having a di-tert-butylphenol moiety, and evaluated by topical administration their anti-inflammatory potentials on picryl chloride-(PC) induced contact hypersensitivity reaction (CHR) in mice. In the course of our structure–activity relationship (SAR) studies on the pyrimidine or the anti-oxidative moiety and the linker between them, the most potent compounds (10, 11) were obtained by the insertion of a C2 unit in compound 2c. The potencies of these compounds were 2-fold greater than that of 1. Compounds 10 and 11 were considered to be useful lead compounds having inexpensive anti-oxidative moieties without chirality.

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A series of leflunomide (1a) analogues were examined for antiinflammatory activity using the carrageenan-induced paw edema assay. Some of the compounds were significantly more potent than leflunomide, particularly those with electron-donating or negative inductive groups situated in the phenyl rings. In contrast, all the nonsubstituted compounds or with further chain-extension in the 4-position of the rings led to a decrease in activity. The LD₅₀ values of the most active compounds (1d, g—j) in male ICR mice were significantly greater than those of either 1a or its active metabolite 2 and therefore merit further study.

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Thirteen alkaloids have been isolated from dried bulbs and leaves of flowering Eucharis amazonica (Amaryllidaceae). The alkaloids, 7-methoxyoxoassoanine, 6-O-methylpretazettine and apohaemanthamine, are reported for the first time from a natural source.

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A new stilbene, 4-[(2″E)-7″-hydroxy-3″,7″-dimethyloct-2″-enyl]-2′,3,4′,5-tetrahydroxy-trans-stilbene (1), and the known compound chlorophorin (2) were isolated from the heartwood of Chlorophora excelsa. Both 1 and 2 showed tyrosinase inhibitory activity with IC₅₀ values of 96 and 1.3 μM, respectively.

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Employment of a Pd/C–pyridine combination as a catalyst is a very useful method for the selective removal (hydrogenolysis) of phenolic O-benzyl, N-Cbz and benzyl ester protective groups and for the selective hydrogenation of nitro and olefin functions of phenol derivatives protected with the MPM group. These discriminatory results are apparently attributable to the effect of pyridine. The MPM group could be extensively applied to chemoselective hydrogenation as a protective group for phenolic hydroxyl functions.

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The (±)-trans- or cis-4(5)-(5-aminomethyltetrahydrofuranyl)imidazole [1 and 2] were synthesized by the Mitsunobu cyclization, starting from L-glutamic acid.

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Two novel butenolides, isoravenelone (1) and ravenelone (2), and a large amount of a known compound, vulpinic acid (3), were isolated from the methanolic extract of the Japanese fungus Pulveroboletus ravenelii (Boletales). These structures were elucidated by two dimensional (2D) NMR, MS, IR and UV spectra, and X-ray crystallographic analysis.

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A new triterpenoid saponin, loniceroside C was isolated from the aerial parts of Lonicera japonica. Its structure was established to be 3-O-β-D-glucopyranosyl hederagenin 28-O-α-L-rhamnopyranosyl (1→2)-[β-D-xylopyranosyl(1→6)]-β-D-glucopyranosyl ester by spectroscopic techniques and chemical transformations. Loniceroside C showed in vivo antiinflammatory activity against mouse ear edema provoked by croton oil.

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Newly formulated cationic liposomes (TRX-liposomes) with four different mean diameters were injected into twelve male rats via the lateral tail vein in order to evaluate the effect of liposomal size on pharmacokinetic parameters. TRX-liposomes disappeared from the blood according to the one-compartment model and demonstrated maximum and minimum half-lives of ca. 14 h (mean diameter of 114.3 nm) and ca. 5 h (mean diameter of 285.9 nm), respectively. This prolonged half-life tended to decrease at the boundary of 114.3 nm mean diameter. The optimal size (114.3 nm) for prolonged circulation of TRX-liposomes was consistent with that of pegylated liposomes such as Doxil^®, however, the half-life was different among these liposomes. The electric charge of the TRX-liposomal surface is assumed to be responsible for this difference. The results of the present study will be very useful in the design of long-circulating cationic liposomes.

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A concise and efficient total synthesis of the flavonoids baicalein, oroxylin A and wogonin was described. Intramolecular oxidative cyclization followed by demethylation of chalcone 1, readily prepared from trimethoxyphenol, afforded, depending upon the controlled conditions, baicalein or oroxylin A in excellent yields. Demethylation of 1 yielded 3, which, by oxidation with I₂/dimethyl sulfoxide (DMSO), was readily converted to oroxylin A and wogonin after column chromatography.

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Two new furanoditerpene-lactones, LS-1 (1) and LS-2 (2), were isolated along with four known furanoditerpene-lactones 3, 4, 5 and 6 from the aerial part of Leonurus sibiricus L. The structures of the new compounds were determined by spectroscopic means. Compounds 1—6 isolated here exhibited moderate cytotoxic activity (IC₅₀=50—60 μg/ml) against leukemia cells (L 1210) in tissue culture.

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Six fatty acids (1—6), two xanthines (7, 8), two flavonol glycosides (9, 10), one monoterpene glucoside (11), one lignan glycoside (12), and four flavanes (13—16) were clarified by a bioassay-guided separation as chemical constituents of Scurrula atropurpurea (Loranthaceae), a parasitic plant of the tea plant Thea sinensis (Theaceae). Among these constituents, it was found that the alkynic fatty acid octadeca-8,10,12-triynoic acid (6) exhibits a more potent inhibitory effect on cancer cell invasion in vitro than flavanes [(+)-catechin (13), (−)-epicatechin (14), (−)-epicatechin-3-O-gallate (15) and (−)-epigallocatechin-3-O-gallate (16)].

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Decomposition of protected hydrazine diol (1) hemi-oxalate, a key intermediate of the potent indolocarbazole-based DNA topoisomerase I inhibitor (2), was investigated. Spectroscopic analysis revealed that the main decomposition compounds of the hydrazine derivative were a peroxide (3) and an alcohol derivative (4). The peroxide derivative (3) was proposed to form in the presence of oxygen- and/or H₂O-generated radicals, which was subsequently reduced to the more stable alcohol derivative (4). A plausible decomposition mechanism was proposed and our findings were substantiated by chemical conversion.

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Novel 9α and 9β-hydroxy grayanotoxin II derivatives were prepared by photo-sensitized oxygenation of iso-grayanotoxin II and oxidation of grayanotoxin II tetraacetate with selenium dioxide respectively. The lethal dosage of 9α and 9β-hydroxy grayanotoxin II were lower than that of grayanotoxin II. In addition, the lethal dosage of 9β-hydroxy-dihydro grayanotoxin II was higher than that of dihydro grayanotoxin II.

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One known (1) and two new cycloartane triglycosides, 20S,22R,23S,24R-16β,23;22,25-diepoxy-cycloartane-3β,23,24-triol 3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-(1→2)-β-D-xylopyranoside (2) and 20S,22R,23S,24R-16β,23;22,25-diepoxy-cycloartane-3β,23,24-triol 3-O-(6-O-trans-isoferuloyl-β-D-glucopyranosyl)-(1→2)-β-D-glucopyranosyl-(1→2)-β-D-xylopyranoside (3), were isolated from a commercial Cimicifuga Rhizome. Their structures were determined by two dimensional (2D) NMR spectroscopic analysis and chemical evidence. These compounds suppressed the proliferation of lymphocytes in mouse allogeneic mixed lymphocyte reaction.

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Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder caused by mutations in the vitamin D receptor, which lead to resistance to 1α,25-dihydroxyvitamin D₃ [1α,25(OH)₂D₃]. We found that the A ring-modified analogues, 2α-(3-hydroxypropyl)- and 2α-(3-hydroxypropoxy)-1α,25(OH)₂D₃, (O1C3 and O2C3) can bind better than the natural hormone to the mutant VDR (R274A), which similar to the HVDRR mutant, R274L, had lost the hydrogen bond to the 1α-hydroxyl group of 1α,25(OH)₂D₃.

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