Chelating chiral diphosphines are often used as ligands of organometallic complexes. However monophosphines, or more generally ligands with one phosphorus linked to one or several heteroatom, may also be useful.This review gives the main results obtained in that area, by considering the classes of monodentate chiral ligands bearing one P(III) atom and involved in asymmetric catalysis with organometallic complexes.

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Remote loading of insulin and bovine serum albumin (BSA) into neutral or positively-charged liposomes by incubation under a transmembrane pH gradient or non-pH gradient was investigated. Trapping efficiencies in several incubation conditions were compared with those of the conventional reverse-phase evaporation vesicle method (c-REV method). For neutral liposomes, insulin could not be effectively loaded into the liposomes by incubation, regardless of the incubation conditions.The trapping efficiency of insulin into positively-charged liposomes was higher than that of neutral liposomes, especially by the pH-gradient method. Insulin could be loaded into positively-charged liposomes about twofold more efficiently than by the pH-gradient method, compared with the c-REV method. Insulin distributed more on the surface of liposomes by the pH-gradient method than by the c-REV method. BSA showed significantly higher affinity to positively-charged liposomes than to neutral ones by various methods. However, the transmembrane pH-gradient method did not increase BSA loading into liposomes, compared with the c-REV and the non-pH-gradient methods. Our results suggest that the pH-gradient method, combining electrostatic interactions, may be useful for preparation of liposomal insulin and that the high hydrophobicity of BSA may not increase the remote loading of BSA into liposomes by the pH-gradiet method.

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The effect of L-ascorbic acid 2-[3, 4-dihydro-2, 5, 7, 8-tetramethyl-2-(4, 8, 12-trimethyltridecyl)-2H-1-benzopyran-6-yl-hydrogen phosphate] potassium salt (EPC-K₁) on hydroxyl radical (·OH) elimination was studied using electron spin resonance (ESR) and spectrophotometric experiments. The addition of EPC-K₁ and ·OH scavengers eliminated the ·OH generated from Cu²⁺/H₂O₂, Fe²⁺/H₂O₂ and H₂/UV-irradiation reaction systems. However, in competitive reactions using different concentrations of a spin-trap agent, the addition of the ·OH scavenger altered the IC₅₀ values, whereas the addition of EPC-K₁ and a metal chelater did not change the value in the Cu²⁺/H₂O₂ and Fe²⁺/H₂O₂ reaction systems. The addition of EPC-K₁ and metal chelater changed the ESR signal for free Cu²⁺. The spectrophotometric experiments confirmed that the addition of EPC-K₁ and metal chelater altered the absorption spectra due to CuCl₂ and FeSO₄, whereas the ·OH scavenger did not alter the spectra.Therefore, it was demonstrated that EPC-K₁ has the ability both to scavenge ·OH directly and to inhibit the generation of ·OH by the chelation of Cu²⁺ and Fe²⁺.

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The chemical constituents of an acetone extract of the stems of Micromelum minutum WIGHT et ARN (Rutaceae), collected at Nakorn-Rachasima province in Thailand, were studied. Six new coumarins, named micro-marin-A (1), -B (2), -C (3), -F (4), -G (5), and -H (6), were isolated along with six known coumarins, and their structures were elucidated by chemical and spectroscopic methods.

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Three new naphthoquinones and their analogues, named avicequinone-A (1), -B (2), -C (3), and avicenol-A (4), -B (5), -C (6), respectively, were isolated from the stem bark of Avicennia alba (Avicenniaceae) collected in Singapore, and their structures were elucidated by means of spectral methods.Gillan and co-workers have proposed that the structures of the new phytoalexins isolated from Avicennia marina are 1, 2-naphthoquinones 8 and 9. Our synthetic and spectrometric studies showed that these structures should be revised respectively to 1, 4-naphthoquinones 2 and 3, named avicequinone-B and -C by us.

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Feeding synthetic [2β-²H]- and [2α-²H]-cholesterols to the hairy roots of Ajuga reptans var. atropurpurea and ²H-NMR analysis of the biosynthesized 20-hydroxyecdysone revealed that hydroxylation at C-2 proceeds with retantion of configuration. Feeding [2α, 3α-²H₂]cholesterol followed by ²H-NMR analysis of the 2, 3, 22-triacetate of the resulting 20-hydroxyecdysone ruled out a mechanism which involves a partial loss of the 2α-hydrogen. The steric course of C-2 hydroxylation in Ajuga hairy roots is identical with that reported in the insect, Schistocerca gregaria.

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Cardenolide glucohydrolase II (CGH II) is a cardenolide-specific glucohydrolase obtained from Digitalis lanata leaves. We investigated the structure-specificity relationship of several cardenolide disaccharides as a substrate for CGH II. Conformation analysis of the substrates was performed using molecular mechanics calculations. The sugar chain conformation of two inert glycosides was significantly different from that of the other glycosides. The other two glycosides, which were weak substrates of CGH II, were suggested to have an intramolecular hydrogen bond between the sugar groups. It was deduced that this hydrogen bond restricts the conformational change of the sugar chain and prevents the glycosides from enzymatic recognition.

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Four novel prenyl-furocoumarin type sesquiterpenoid derivatives, 2, 3-dihydro-7-hydroxy-2S^*, 3R^*-dimethyl-3-[4, 8-dimethyl-3(E), 7-nonadienyl]-furo[3, 2-c]coumarin, 2, 3-dihydro-7-hydroxy-2R^*, 3R^*-dimethyl-3-[4, 8-dimethyl-3(E), 7-nonadienyl]-furo[3, 2-c]coumarin, 2, 3-dihydro-7-hydroxy-2S^*, 3R^*-dimethyl-3-[4-methyl-5-(4-methyl-2-furyl)-3(E)-pentenyl]-furo[3, 2-c]coumarin, and 2, 3-dihydro-7-methoxy-2S^*, 3S^*-dimethyl-3-[4, 8-dimethyl-3(E), 7-nonadienyl]-furo[3, 2-c]coumarin were isolated from the roots of Ferula ferulioides. Their structures were established by detailed spectral analysis and the biosynthetic pathway leading to these prenyl-furocoumarin type sesquiter-penoids is proposed based on these structures.

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Seven new compounds, sodium aristolochate-VII (1), aristolactam-CIV (2), madolin-I (3), -J (4), -K (5), -L (6) and -M (7) together with 71 known compounds were isolated and characterized from the fresh root and stem of Aristolochia heterophylla Hemsl. Their structures were determined by spectral methods. Compound 8 was revised as aromadendrane-4β, 10β-diol by spectral data and single-crystal X-ray analysis.

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Three new spirostanol steroidal oligoglycosides, together with a known oligoglycoside, were obtained from the seeds of Allium tuberosum after enzymatic hydrolysis of furostanol saponin fraction by β-glucosidase. On the basis of spectroscopic analysis, the structure of new spirostanol oligoglycosides were elucidated as (25S)-spirost-5-ene-2α, 3β-diol 3-O-α-L-rhamnopyranosyl-(1→4)-[α-L-rhamnopyranosyl)-(1→2)]-β-D-glucopyranoside, (25S)-spirostane-3β, 5β, 6α-triol 3-O-α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranoside, and (25S)-5β-spirostane-3β, 6α-diol 3-O-α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranoside.

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For 4-amino-5-chloro-2-methoxy-N-[(2S, 4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide (TKS159), two polymorphs, forms α and β, were prepared and characterized by means of X-ray powder diffractometry, thermal analysis, infrared spectroscopy and ¹³C-NMR spectroscoy, both in the solution and solid phases. The X-ray powder diffraction analysis gave different patterns for forms α and β. In the thermogravimetry and differential thermal analysis profiles, form β exhibited characteristic endo- and exothermic peaks at 112.7°C and 116.2°C, respectively, due to the partial melting-induced phase transition to form α without accompanying weight loss, and these were followed by an additional endothermic peak at 138.2°C due to fusion. For form α, only an endothermic peak at 137.8°C due to fusion was observed. The IR spectroscopic analyses of forms α and β gave different absorption bands assigned to N-H and O-H stretching, N-H bending, and C=O stretching vibrations. From the data obtained by thermal analysis, form α was shown to be thermodynamically more stable than form β.

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From the quaternay alkaloidal fraction of the dried tubers of Stephania cepharantha, two new isoquinoline alkaloids, stecepharine and tetradehydroreticuline have been isolated along with the known compounds, magnoflorine, menisperine, steponine, cyclanoline, oblongine, cis-N-methylcapaurine and 2'-N-methylisotetrandrine.cis-N-Methylcapaurine (=9-O-methylstecepharine) was isolated as a natural product for the first time. Their structures were determined on the basis of spectroscopic evidence.

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As part of the series investigating the structural features of C-terminal amidated amino acids and peptides, three crystal structures of Z-Gly-Phe-NH₂, Tyr-Lys-NH₂, and Asp-Phe-NH₂ were analyzed by the X-ray diffraction method, and their molecular conformations and intermolecular interactions were investigated. Although the respective dipeptides exhibited an energetically allowable torsion angle concerning each backbone or side chain, the observed extended (Z-Gly-Phe-NH₂, Asp-Phe-NH₂) and folded (Tyr-Lys-NH₂) conformations were considerably different from those of the corresponding unamidated peptides, due to the conformational flexiblility of the respective dipeptides. The comparison between the crystal packings of the amidated and unamidated dipeptides indicated that the C-terminal amides tend to associate with the same neighboring group through hydrogen bonds, in which both the amide NH and O=C groups participate, while the unamidated peptides prefer a linear molecular connection, where both or either of the two carboxyl oxygens participate in the hydrogen bond formation. The difference in hydrogen bonding ability between the C-terminal amide and carboxyl groups has been considered to be based on the structural data of the related peptides analyzed so far.

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In a search for novel nonsteroidal inhibitors of human prostatic 5α-reductase, we found a new series of indole derivatives that showed potent inhibitory activities for the human enzyme. Among them, 4-[(1-benzyl-1H-indol-5-yl)oxy]-3-chlorobenzoic aicd (2d, YM-32906) showed more potent inhibitory activity than finasteride with an IC₅₀ value of 0.44 nM. 3-Chloro-4-{[1-(4-phenoxybenzyl)-1H-indol-5-yl]oxy}benzoic acid (2m) showed inhibitory activities for both human and rat prostatic 5α-reductase with IC₅₀ values of 2.1 and 73 nM, respectively. The synthesis and structure-activity relationships of these indole derivatives are presented.

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Naturally occurring phenylpropanoids, hinokiresinol (trans-hinokiresinol) and nyasol (cis-hinokiresinol) were found to possess appreciable estrogen receptor binding activity. Strong differences in activity were observed between the geometrical isomers and enantiomers. Among these, (3S)-cis-hinokiresinol displayed the highest activity, one order of magnitude greater than the activity of genistein. Furthermore, cis- and trans-hinokiresinol stimulated the proliferation of estrogen-dependent T47D breast cancer cells, and their stimulatory effects were blocked by an estrogen antagonist, indicating that the compounds are estrogen agonists. In addition, the absolute configuration of C-3 in (+)-cis-hinokiresinol has been assigned as S by comparison with the circular dichroism spectra of the hydrogenated products prepared from cis and trans ((3S)-trans-hinokiresinol : previously assigned) isomers. These results incidentally provide us with an unambiguous answer to contradictory reports regarding the assignment of the full stereochemisry of cis-and trans-hinokiresinol that have existed in the literature for more than two decades.

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Application of the scanning probe microscopy technique for quantitative measurement of the surface roughness of lactose carriers was evaluated. The roughness values of four different lactose carriers were related to the in vitro deposition results of the drug, sulbutamol sulphate. The rugosity values of the lactose carriers were represented by Ra values which were in the order of DCL-40>DCL-11>lactose 325M>lactose 200 M. In vitro deposition results using a twin impinger showed that rougher carrier surfaces generally allowed more drug particles to be emitted from the capsules and inhaler but the availability of the drug to stage 2 was reduced, as detachment of drug particles from the carrier surfaces was more hindered. There was an optimum Ra value for greater delivery of the drug particles to stage 2 of the twin impinger. A balance between adherence and detachment of the drug from the carrier surface was needed in order to optimize the delivery of a drug to the desired target sites using a dry powder inhaler.

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New and convenient synthesis of 2, 3, 9, 10-tetraoxygenated protoberberine alkaloids and their 13-methyl alkaloids through the same intermediates was developed. Acylation of the brominated benzylphenethylamine (13) with α-chloro-α-(methylthio)acetyl chloride, followed by cyclization with stannic chloride, furnished tha key intermediates 4-methylthio-3-phenethylisoquinolin-3-ones (14), which were methylated to provide their methyl derivatives (17). Both isoquinolin-3-ones (14, 17) were easily transformed into protoberberine alkaloids (16) and their 13-methyl alkaloids (21) in good yield.

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The Lewis acid-mediated reactions of allene-ene compounds, derived from 3-methylcitronellal or dimethyl malonate, were carried out using various Lewis acids such as ethylaluminum dichloride, diethylaluminum chloride, titanium chloride, zinc chloride etherate, or boron trifluoride etherate, affording unexpectedly intramolecular [2+2]cycloaddition products under some particular reaction conditions without any formation of intramolecular ene reaction products.

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Mesoionic 4-trifluoroacetyl-1, 3-oxazolium-5-olates (1), obtained from the reaction of N-acyl-N-alkylglycines (2) with trifluoroacetic anhydride, react with amidines to give 5-trifluoroacetylimidazoles (3) in moderate yield. The novel ring trandformations of 1 into 3 occur via an initial attack of amidines on the C-2 position of the ring.

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From the leaves of Alangium kurzii, a new tetrahydroisoquinoline-monoterpene glucoside, 6-O-methyl-N-deacetylipecosidic acid and a new iridoid glucoside, 10-O-benzoyladoxosidic acid, were isolated along with alangiside, demethylalangiside, 6"-O-β-D-glucosylhenryoside, uridine and four known flavonoid glycosides. The structures of new glucosides were determined on the basis of spectroscopic and chemical methods.

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This paper reports the influence of post-melt impeller speed, post-melt processing time, binder concentration and particle size of bulk material on the sphericity of pellets produced by melt pelletization in a high shear mixer. Lactose was used as the bulk material with polyethylene glycol 3000 as a meltable binder. The sphericity of pellets was found to be affected by post-melt impeller speed and post-melt processing time. Binder concentration and particle size of bulk material had a lesser effect on pellet sphericity. The melt pelletization process can be divided into two spheronization phases (a fast initial rate, followed by a slower rate). The change in the spheronization rate was associated with the pellet size, porosity and flow pattern of the processing material. The present study established a bi-exponential mathematical model to relate the pellet sphericity with post-melt specific energy consumption. The relationship of pellet sphericity with post-melt specific energy consumption was independent of the effects of the production variables.

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A new 9, 19-cyclolanostane-type triterpene xyloside (1), from the rhizomes of Cimicifuga racemosa, has been isolated together with four known saponins; cimiaceroside A, 25-O-methylcimigenol-3-O-β-D-xylopyranoside, 27-deoxyactein and 23-O-acetylshengmanol-3-O-β-D-xylopyranoside. The structure of the new compound was established as 16β, 23 : 22β, 25-diepoxy-12-acetoxy-3β, 23, 24β-trihydroxy-9, 19-cyclolanost-7-ene-3-O-β-D-xylopyranoside. For the structure elucidation, 1D-and 2D-NMR experiments and high resolution electrospray ionzation Fourier transformation mass spectrometry (HRESIFTMS) were used.

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A new series of 3, 4-dihydro-2H-1, 4-benzoxazine derivatives, where various substituents were introduced into one of the geminal dimethyl groups at the 2 position, were synthesized and their potassium channel-activating activity was evaluated. Introduction of a hydroxyl group, as in compound 5, resulted in good solubility in water and a long duration of action compared with the parent compound 1. Introduction of a nitrato group, as in compound 8, produced typical nitrate activity such as exhibited by nitroglycerine in addition to potassium channel-activating activity. X-ray structural analysis of compound 5 showed that the sum of the bond angles around the N atom at the 4 position was 357.8°, suggesting that the N atom had an approximately sp²-like planar bond configuration.

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Two novel migrated pimarane-type diterpenes named neoorthosiphols A (1) and B (2) were isolated from the water decoction of the leaves of Orthosiphon aristatus (Lamiaceae), which has been prescribed in Javanese traditional medicine (jamu) for the treatment of hypertension, etc. The absolute chemical structures have been elucidated on the basis of physicochemical properties.It has been found that two migrated pimarane-type diterpenes (1, 2), four isopimarane-type diterpenes (3, 4, 5, 6), three benzochromenes (7, 8, 9) and two flavones (12, 13) exhibit a suppressive effect on contractile responses in rat throacic aorta, among thirteen chemical constituents (1-13) isolated from the leaves.

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The reaction of a sec-nitrodienamine 3 with aldehyde compounds afforded 2-substituted 3-nitro-1, 2-dihydropyridines 5, providing a heterocyclic annulation reaction.

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Bioassay-directed fractionation of an ethanolic extract of Cephalotaxus wilsoniana has resulted in the isolation of a novel C-methylated biflavone, taiwanhomoflavone-A (1). Its structure was elucidated on the basis of spectroscopic analysis. Taiwanhomoflavone-A is cytotoxic with ED₅₀ values of 3.4, 1.0, 2.0 and 2.5 μg/ml, respectively, against KB epidermoid carcinoma of nasopharynx, COLO-205 colon carcinoma, Hepa-3B hepatoma, and Hela cervix tumor cells.

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Simultaneous use of N-hydroxysuccinimide (HOSu) and CuCl₂ with a HOSu-based uronium coupling reagent, O-(N-succinimidyl)-1, 1, 3, 3-tetramethyluronium tetrafluoroborate, has been found to eliminate the racemization of the carboxy-terminal N-methylamino acid residue during the segment condensation.

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A ne catalytic asymmetric oxidation of sulfides to sulfoxides in water using the hypervalent iodine(V) reagent iodoxybenzene (PhIO₂) has been developed. This methodology is distinctly different from the previously reported use of cyclodextrins or biological catalysts and provides a new route to asymmetric sulfoxidation in water.

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