The preparation and crystal structure of mercury(II) and nickel(II) complexes of 2-hydrazino-4-hydroxy-6-methylpyrimidine (LH) are described. The crystal of the mercury(II) complex, [HgCl₄](LHH)₂·2H₂O is triclinic with a=7.481(2), b=19.535(6), c=7.482(2)Å, α=94.77(3)°, β=106.28(5)°, γ=85.24(3)°, V=1043.8(6)ų, D_x=2.102g·cm^-3, Z=2, and space group P1^^-. The atomic parameters were refined to a final R value of 0.044 for 3115 reflections. In the mercury(II) complex, one [HgCl₄]^2- group which completes a regular tetrahedral coordination and two LHH⁺ molecules which take a keto form (>C(4)=O), constitute a double salt type structure, in which both units are bound together hydrogen bonds. It is notable that two different modes of stackings along the a and c axis are found between pyrimidine rings in the crystal. The crystal of the nickel(II) complex, [Ni(LH)₂(H₂O)₂]Cl₂·2H₂O is triclinic with a=8.911(2), b=9.197(2), c=6.791(1)Å, α=93.41(3)°, β=102.31(3)°, γ=114.32(4)°, V=490.1(3)ų, D_x=1.633g·cm^-3. Z=1, and space group P1^^-. The atomic parameters were refined to a final R value of 0.049 for 1310 reflections. The nickel(II) ion completes an octahedral coordination with two ring nitrogen N(3) and two hydrozino N_amino nitrogen atmos of the two neighboring ligand molecules and two water molecules. The chloride ion is not bonded to nickel(II) ion but is hydrogen bonded to N(1)-H of the pyrimidine base. The length of C(4)-O(9), 1.249, in the LH residue suggests the keto form. Therefore, in the same preparation method with excess protons, the mercury(II) complex forms a double salt type structure, [HgCl₄](LHH)₂·2H₂O, whereas the nickel(II) complex forms a chelate type structure, [Ni(LH)₂(H₂O)₂]Cl₂·2H₂O.

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As a series in the structural studies of tryptophan metabolites by an X-ray diffraction method, the crystal and molecular structure of 6-hydroxymelatonin, one of the final tryptophan metabolites, has been determined. The space group is Pbca with cell dimensions a=9.309(1), b=12.061(1) and c=22.301(1)Å. The structure was refined to R=0.053 for 2108[|Fo|>0.0) observed reflections. In contrast to a nearly planar trans conformation of melatonin, a precursor of 6-hydroxymelatonin, a folded conformation of the N-acetylaminoethyl side chain to the indole ring was observed, which is also energetically stable as shown by quantum chemical modified neglect of diatomic overlap calculations for melatonin and 6-hydroxymelatonin molecules. The oxygen atom of 6-hydroxy group participates in two intermolecular hydrogen bond formations as an electron donor and an acceptor. Three-dimensional molecular packing is essentially stabilized by these and NH (indole)…O (acetyl) hydrogen bonds.

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A chemical examination of the polyphenolic constituents of the fern, Dicranopteris pedata HOUTT., has led to the isolation of eight new proanthocyanidins possessing a doubly-linked (A-type) unit, together with known flavan-3-ols and proanthocyanidins. On the basis of chemical and spectroscopic evidence, they are characterized as epiafzelechin-(4β→8, 2β→O→7)-eniafzelechin-(4α→8)-epiafzelechin(8), epicatechin-(4β→8, 2β→O→7)-epiafzelechin-(4α→8)-epiafzelechin(9), epiafzelechin-(4β→8, 2β→O→7)-epizfzelechin-(4α→8)-epicatechin(10), epiafzelechin-(4β→8, 2β→O→7)-epicatechin-(4α→8)-epicatechin (11), epicatechin-(4β→8, 2β→O→7)-epiafzelechin-(4α→8)-epicatechin (12), epicatechin-(4β→8, 2β→O→7)-epicatechin-(4α→8)-epiafzelechin (13), epicatechin-(4β→8, 2β→O→7)-epicatechin-(4α→8)-epigallocatechin (14) and epiafzelechin-(4β→8)epicatechin-(4β→8, 2β→O→β→7)-epicatechin-(4α→8)-epicatechin (15).

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A chemical examination of the tannin ingredients in the leaves of the wood oil tree, Aleurites fordii HEMSLEY (Euphorbiaceae), has led to the isolation of three new ellagitannins named aleurinins A (4), B(5) and C(6), together with corilagin (1), geraniin (2) and chebulagic acid (3). on the basis of chemical and spectroscpic evidence, the structures of aleurinins A (4) and B (5) have been established as ellagitannins possessing a novel cyanopropylene alcohol glucoside core, while aleurinin C (6) has been characterized as an ellagitannin based on a hydroxyacetone glucoside core.

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Unsymmetrical N¹, N²-disubstituted amidines were prepared by conventional and newly developed methods. Reaction of N¹-tosyl-N¹, N²-diarylacetamidines and arylamines gave unsymmetrical acetamidines in the presence of basic catalysts, and N¹-acyl-N¹, N²-di(p-nitrophenyl)formamidines and arylamines gave unsymmetrical formamidines under neutral conditions. Unsymmetrical amidines exist as tautomeric mixtures in solution owing to proton transfer between the two nitrogen atoms, and it was proved on the basis of proton nuclear magnetic resonance (¹H-NMR) evidence that the tautomer in which the hydrogen is attached to the more basic nitrogen atom is predominant.

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10-Chloro-10, 9-(epoxyalkano)selenoxanthenes (12, 14-17) were prepared by the reaction of 9-(hydroxyalkyl)-selenoxanthenes (4, 9-11) with N-chlorosuccinimide, and 1-chloro-1-phenyl-3H-2, 1-benzoxaselenoles (32-34) were similarly synthesized. The selenurane structure of 14 was established by X-ray analysis. The proton nuclear magnetic resonance and electron impact mass spectral data supported the selenurane structures of these compounds. Reactions of the selenurane 16 with sodium acetylacetonide gave a selenoxantheniomethanide derivative 37. Thermal reaction of 14 provided 9-(1-chloro-2-hydroxyethylidene)selenoxanthene (41) together with 9-(2-hydroxyethyl)selenoxanthene (9), while thermal reaction in ethanol produced 9-(1-chloro-2-hydroxyethyl)-9-ethoxyselenoxanthene (42). On the other hand, the benzoxaselenole selenurane (32) was heated at 195-200°C to afford 2-(phenylseleno)benzyl chloride (45), 2-(phenylseleno)benzyl 2-(phenylseleno)benzoate (46) and 2-(phenylseleno)benzaldehyde (28).

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The direct resolution of (3aRS, 6SR, 6aSR)-1, 3-dibenzyl-6-hydroxy-3, 3a, 6, 6a-tetrahydro-1H-furo[3, 4-d]imidazole-2, 4-dione [(±)-9], a key intermediate for biotin, with optically active amines was examined. Reaction of (±)-9 with cinchonidine readili gave the cinchonidine salt of the (4S, 5R)-aldehyde-carboxylic acid (12), acidification of which gave (3aS.6R, 6aR)-9, convertible to biothin. N-alkyl-D-glucamines (14) were also found to be effective resolving agents for (±)-9 applicable for industrial use. Reutilizatin of the unwanted epimer [(3aR, 6S, 6aS)-9] was effected by facile oxidation to the meso-diacid (3) with sodium chlorite.

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Proanthocyanidins containing flavan-3-ol (epiafzelechin and epicatechin) units with an abnormal 2S-configuration have been isolated from the pods of Cassia fistula L. and the bark of C. javanica L. (Leguminosae), together with common flavan-3-ols and proanthocyanidins The structures of these compounds have been established on the basis of chemical and spectroscopic evidenve. In addition, the flavan-3-ols and proanthocyanidins obtained from C. fistula have been found to be partly racemic, and the proportions of each enantiomer have beem determined by high-performance liquid chromatography using an optical resolution column.

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Eight new tetranortriterpenoids, swietemahonin A-G and swietemahonolide, were isolated from the cotyledons of seeds of Swietenia mahagoni. The structures 1-8 are proposed for these compounds, respectively, based mainly on detailed analyses of the proton and carbon-13 nuclear magnetic resonance(¹H-and ¹³C-NMR)spectra by the use of two-dimensional NMR techniques(¹H-¹H chemical shift correlation spectroscopy (COSY), ¹H-¹³C COSY, and ¹H-¹³C long-range COSY.

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The reaction of lithiated ortho-toluamides and related species with vinylsilanes was examined in order to develop a new, convenient synthesis of 1-tetralones and 1-naphthols.

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The total synthesis of the Erythrina alkaloid (±)-3-demethoxyerythratidinone (20) has been accomplished in 39% overall yield from homoveratrylamine(1)by 8 chemical operations, using a tandem cationic cyclization of the Pummerer rearrangement intermediate derived from the sulfoxide 5 as the key step. Of particular interest is the observation that heating of 5 with p-toluenesulfonic acid provides the erythrinan 6 (and the deprotected derivative 7) as a single stereoisomer, whereas similar treatment of 5 in the presence of ethylene glycol gives initially the bicyclic lactam 8, which then cyclizes under the reaction conditions used to afford a mixture of two diastereomeric erythrinans 6 and 9.A possible explanation of these contrasting results is presented.

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The X-ray crystal structure of 9-benzyl-N⁶-methoxyadenine (2) has been determined. In the crystal, this compound exists in two different conformations with respect to the N(9)-benzyl group. Each conformer has been found to possess the syn-6-imino-1H-purine structure (13).

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Various structural types of monobactams bearing an (R)-1-hydroxyethyl and an (S)-1-carbamoyloxyethyl group at the C_{3, 4}-positions, respectively, could be synthesized from (3S, 4S)-4-[(S)-1-benzyloxyethyl]-3-[(R)-1-hydroxyethyl]-2-azetudubibe, These synthetic studies expored several novel methods applicable to construct substituted carbamoyloxy groups.

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dl-Griseofulvin (1a) was prepared by two synthetic pathways. New 6'-congeners (3 and 4) of griseofulvin were also prepared. Their antifungal activities were evaluated and compounds 3 and 4 were found to be less active than 1a.Molecular calculations on 1a, dl-epigriseofulvin (1b), 3 and 4 were undertaken.

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In order to study a new antitumor platinum complex, various platinum complexs were prepared from 2-aminomethylpyrrolidine derivatives synthesized to serve as carrier ligands and tested for their antitumor activity against Colon 26 carcinoma (s.c.-i.p. system) and P388 leukemia (i.p.-i.p. system) in mice. 2-Aminomethylpyrrolidine proved to be the most effective carrier ligand in its amine derivatives. The structureactivity relationships of the carrier ligands in the platinum complexes with dichloro, oxalato, 1, 1-cycldutanedicarboxylato and dichlorodihydroxo as leaving group were clearly shown on the Colon 26 carcinoma screen and were as follows : the antitumor activity of the platinum complexes with any leaving groups was considerably decreased by the substitution of hydrogen by alkyl group (Me, Et) on nitrogen of aminomethyl and the effects of 1, 1-cyclobutanedicarboxylato Pt(II) complexes completely disappeared with the same substitution on nitrogen of pyrrolidine. In all the tested platinum complexes 2-aminomethylpyrrolidine(1, 1-cyclobutanedicarboxylato)platinum(II) (15) exhibited the most potent antitumor activity. 15 was superior to 1, 1-cyclobutanedicarbocylatodiammineplatinum(II) (CBDCA) and similar to cis-diamminedichloroplatinum(II) (CDDP) on the Colon 26 carcinoma screen but it was inferior to CBDCA and CDDP on the P388 leukemia screen. Futhermore, 15 showed more potent antitumor activity than CBDCA against Colon 38 carcinoma (s.c.-i.p.system).

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SA2572 ((±)-1), 3-acetyl-2-[5-methoxy-2-[-[N-methyl-N-(3, 4, 5-trimethoxyphenethyl)amino]butoxy]phenyl]-benzothiazoline hydrocholoride is a newly synthesized Ca²⁺ antagonist having a inhibitory effect on the fast Na⁺ inward channel In order to clarify the absolute configurations and the pharmacological properties of both enantiomers, compounds ((+)-1 and (-)-1) were synthesized. The configurations of these compounds were assigned on the basis of an X-ray crystallographic analysis of synthetic precursor (5). The in vitro Ca²⁺ channel blocking activities of (+)-1 and (-)-1 were evaluated in terms of the inhibitory activities on depolarization-induced contraction of guinea pig taenia cecum and rabbit aorta. The in vivo efficacy of the enantiomers was evaluated with their hypotensive effects in spontaneously hypertensive rats. Compound (-)-1 showed more potent Ca²⁺ antagonistic activities on guinea pig taenia cecum and rabbit aorta and the hypotensive effect than those activities of (+)-1. In the electrophysiological study of Langendorff perfused rabbit hearts, compound (+)-1 showed more potent inhibitory effect on the fast Na⁺ inward channel than that of compound (-)-1, and an approximately equal potent inhibitory effect on the slow Ca²⁺ inward channel as compared (-)-1. Stereoselectivity of the pharmacological activity was found.

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Besides serratagenic acid, three new ursane-type triterpenes, named goreishic acids I (1), II (2), and III (3), were isolated from a Chinese medicine, Goreishi(the feces of Trogopterus xanthipes MILNE-EDWARDS). The structures of 1, 2 and 3 were respectively determined as 2α, 3β-dihydroxyursa-12, 18-dien-28-oic acid, 2α, 3β-dihydroxy-23-norursa12, 18-dien-28-oic acid and 2α, 3β-dihydroxy-24-norursa-12, 18-dien-28-oic acid on the basis of spectroscopic evidence.

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The structure and stereochemistry of scopadulin, a novel aphidicolane-type diterpene isolated from Scoparia dulcis L.have been established from spectral data and single-crystal X-ray analysis of its acetone solvate.

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Separation coefficients log γ for substituted halgenobenzene derivatives given by gas-liquid chromatography have been evaluated by regression analysis, using three kinds of descriptors, namely, σ_s°, μ²/α and Σσ^±_π. For the orthodisubstituted series, the descriptor Σσ^±_π, correcting the ortho effect due to the vicinal substituent group, is required. This correction can be achieved by evaluating the intensity drop of the p(¹La) band of ultraviolet absorption spectra. The Σσ^±_π of the regreession equation indicates the contribution of the charge-transfer interactionbetween the substrate and stationary liquid.

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Each testosterone-[¹²⁵I]iodinated histamine derivative where[¹²⁵I)iodinated histamines were linked to respective 15α- and 15β-carboxymethyltestosterone (15α-and 15β-CMT), testosterone-3-(O-carboxymethyl)oxime (T-3-CMO) and testosterone-17β-hemisuccinate (T-17-HS) were tested for their usefulness as radiotracers in testosterone immunoassay. In the use of anti-15α- and 15β-CMT antisera produced in rabbits against 15α- and 15β-CMT-bovine serum albumin (BSA) conjugates, the antisera with 15α- and 15β-CMT-[¹²⁵I]iodinated tracers showed low sensitivity and somewhat low specificity in comparison with those of the antisera with tritiated testosterone (T-³H). On the other hand, the antisear with T-3-CMO-[¹²⁵I]iodinated tracer showed high sensitivity but low specificity for 5α-dihydrotestosterone(5α-DHT)in comparison with T-³H. The T-17-HS-[¹²⁵I]iodinated tracer was not bound to the antisera. In the use of anti-15α- and 15β-CMT antisera produced in rabbits by pretreatment with 15α-carboxymethyl-5α-DHT linked to a copolymer of D-glutamic acid and D-lysine followed by immunization with 15α- and 15β-CMT-BSA, the antisera with homologous[¹²⁵I]iodinated tracer showed high sensitivity and specificity.

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A spectrophotometric method for the determination of albumin was established by using o-sulfophenylfluorone (SPF)-uranium(VI)(U(VI)) complex. This method can be used to determine 20-500μg/10 ml of human serum albumin (HSA), and is affected very little by the presence of globulin(as γ-globulin). Results obtained by the Bromocresol green (BCG) method and this method agree well with each other in artificial serum samples containing HSA and γglobulin, with the regression equation being Y (this method)=0.943X(BCG method)+ 1.20 (in mg HSA/dl, n=18, r=0.996).The propesed method is 6 times more sensitive than the BCG method, and has an advantage that deviation of responses of the reagent to albumins derived from the different animal species is small in comparison with that of Bromocresol purple. The binding parameters (n and K) were calculated from dual double-reciprocal plots. From the thermodynamic parameters (ΔG, ΔH and ΔS) obtained from a ven't Hoff plot, the binding between HSA and SPF-U(VI) complex or SPF was presumed to be a kind of hydrophobic interaction.

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A sensitive and specific enzyme immunoassay for vasoactive intestinal polypeptide (VIP)-like immunoreactivity was developed with the use of synthetic carboxy-terminal(C-terminal) fragment (residue 11-28) of porcine VIP conjugated with β-D-galactosidase and a second antibody-coated immunoplate. Using 4-methylumbelliferyl β-D-galactopyranoside as a fluorogenic substrate, the minimum amount of VIP-like immunoreactive substance (VIP-IS) detectable by this method was 0.1 fmol/well (2.5 pmol/l). The level of VIP-IS in bovine foremilk was above 100 pmol/l, which was more then eightfold higher than that in normal milk.

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A simple high-performance liquid chromatographic method for the determination of 2-deoxy-D-glucose and D-glucose in rat serum is described; this method is based on a post-column fluorescence derivatization. The sugars are automatically converted into fluorescent derivatives by reaction with meso-1, 2-bis(4-methoxyphenyl)ethylenediamine in an alkaline medium after their separation on a strong anion exchanger column (TSK gel Sugar AXG). The detection limits (S/N=3) for 2-deoxy-D-glucose and D-glucose in rat serum are 0.52 and 0.56 nmol/ml, respectively.

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To explore agents for differentiation therapy of leukemias, various combinations of cytokines and low-molecular-weight inducers were examined for differentiation-inducing activity toward three kinds of human leukemia-derived celllines. The strongest differentiation inducing activity on promyeloxytic HL60 cells and histiocytic U937 cells was obtained by combining recombinant tumor necrosis factor (rTNF), interferon-γ (IFN-γ), retinoic acid (RA), and 1α, 25-dihydroxyvitamin D₃ (1α, 25(OH)₂D₃). For myeloblastic ML1 cells, the combination of rTNF, IFN-γ, and RA had the strongest differentiation-inducing activity.

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The effects of ten 10-phenyl-[11]cytochalasans produced by Phomopsis sp. including novel compounds haing 5, 7-or 6, 7-glycol structures and their derivatives, on the cell morphology and actin distribution in C3H-2K cells, as well as on lymphocyte capping and actin polymerization, were examined. The structure-activity relationship reported in the previous papars has been confirmed. The novel glycol type compounds showed little or no activity, suggesting the importance of the perhydroisoindol-1-one nucleus for the manifestation of the cytochalasin actions.

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Salt and detergent extracts of acetone-dried powder of Xenopus laevis skin and eggs were fractionated on sugar-Sepharose columns, to which lactose, melibiose, galactose, rhamnose and mannose had been covalently linked, by successive elution with chelating reagent and specific sugars, resulting in separation of the different Ca²⁺ -dependent and Ca²⁺ -independent carbohydrate-binding proteins. The skin of X. laevis contains a salt-extractable Ca²⁺ -dependent lactose-binding lectin of 30 kilodalton (kDa) and the eggs a similar lectin of 43kDa, but they both lack Ca²⁺ -dependent galactose-binding lectins, The 30 kDa lactose-binding lectin which agglutinates human A erythrocytes was isolated by successive affinity chromatography on two linked sugar-Sepharose columns, i.e., a galactose-Sepharose-lactose-Sepharose (GL) column system. Since the 30 kDa lectin was not recovered in the Ca²⁺ -dependent lactose-binding protein fraction from the GL column system under the dithiothreitol (DTT)-free conditions, it was concluded that the lectin requires the presence of DTT and calcium for binding to the lactose-Sepharose column.

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Four photoactivable tetrodotoxin (TTX) derivatives and the corresponding tritiated compounds were synthesized and porified. The photoactivable groups introduced were a nitro-azidophenyl (NAP) group and a trifluoromethyl diazirinobenzoyl (TDB) group, as nitrene and carbene precursors, respectively, as well as two isomers of the fluoronitrophenoxy group, a new photpreactive group selective for nucleophiles. The binding affinities of the four derivatives to the sodium channel were similar to that of TTX, but the values of specific photoincorporation were unexpectedly low (up to 2.5%), suggesting that the photpactivable groups are likely to be oriented unfavorably for labeling reactions in the TTX binding site. Two of the labeled sodium channel proteins were purified and digested. Peptides labeled with TTXenNAP lost most of the label during high performance liquid chromatography in 0.1% trifluoroacetic acid-acetonitrile, while peptides labeled with TTXenTDB retained the labels during the procedures. The TTXenTDB-labeled peptides were eluted in four major fractions with 80% recovery of the amount applied on a reverse-phased C4 column.However, further purification is necessary to identify the labeled sites of the peptides.

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The chemical cross-linking of soluble (1→3)-β-D-glucans having molecular weights of 21000 (CL 3h) and 6400 (CL 6h), and laminarin (CL LAMI), which showed negligible biological activity, by epichlorohydrin provided rigid particles. These particles showed no gel-to-sol transition upon the addition of sodium hydroxide. We compared the effects of chemical cross-linking on the biological activities of glucans. The alternative complement pathway was not activated by any of the cross-linked glucans. Glucose consumption, lysosomal enzyme release, and interleukin-1 production by mouse resident peritoneal macrophages incubated in vitro were strongly induced by CL 3h, CL 6h and CL LAMI. However, cross-linked dextran, Sephadex, did not exhibit any of these biological activities. These results suggested that chemical cross-linking of (1→3)-β-D-glucans enhances macrophage activities without opsonization by complement components.

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The degradation of deoxyribose, an indicator of hydroxyl radiacal(HO·)generation, was observed in the reaction of alloxan with glutathione (GSH) in the presence of Fe³⁺-ethylenediaminetetraacetic acid (EDTA). Catalase and HO·scavengers strongly inhibited this degradation, but superoxide dismutase (SOD) did not do so effectively, suggesting that the HO· was generated via the Fenton reaction but not the Haber-Weiss reaction. The reduction of Fe³⁺-EDTA was rapid in the reaction of alloxan with GSH. The generation of alloxan radical in the reaction system was diminished by the addition of Fe³⁺-EDTA, indicating that Fe³⁺-EDTA was directly reduced by the alloxan radical . However, only a large amount of SOD inhibited both reduction of Fe³⁺-EDTA and generation of alloxan radical, suggesting that superoxide radical(O^-₂)may participate indirectly in both reactions. The generation of O^-₂ and H₂O₂ in the reaction was confirmed by the formation of compound III from lactoperoxidase and by partial regeneration of consumed oxygen upon addition of catalase, respectively, suggesting that O^-₂ may be a source of H₂O₂. From these results, we concluded that HO· was generated by alloxan radical-dependent Fenton reaction.

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N⁴-Trimethoxybenzoyl-5'-deoxy-5-fluorocytidine (Ro 09-1390), a new prodrug of 5'-deoxy-5-fluorouridine (5'-dFUrd), was synthesized for the purpose of finding a drug with less intestinal toxicity than tha parent compound. The present study compared the antitumor activity and immunotoxicity of Ro 09-1390 with those of 5'-dFUrd, 5-fluorouracil (5-FUra) and tegafur in various transplantable tumor models The antitumor efficacy of Ro 09-1390 was comparable to 5'-dFUrd and these two agents were much more effective than the others. However, Ro 09-1390 was much less toxic to the intestinal tract and less immunosuppressive in both humoral and cellular immune reactions than 5'-dFUrd. Consequently, Ro 09-1390 showed higher therapeutic indices and higher efficact than 5'-dFUrd at high dosages. The antitumor spectrum of Ro 09-1390 was somewhat different from that of 5'-dFUrd, though it shows the efficacy after it converts to 5'-dFUrd. The activity of Ro 09-1390 was partly associated with cytidine deaminase in the tumors treated. Ro 09-1390 appeared to be more effective against tumors with a high concentration of the enzyme by which the major metabolite 5'-deoxy-5-fluorocytidine (5'-dFCyd) is metabolized to 5'-dFUrd.

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Four hypotensive peptides called elapherine-A, -B, -C and -D were isolated from the body of Elaphe climacophora after removal of the internal organs. Elapherine-A, which had the lowest molecular weight, exhibited a prolonged fall for 5 min in the blood pressure of spontaneously hypertensive rats, wherase elapherin-B, -C and -D displayed a transient fall in the blood pressure. The molecular weights of elapherine-A--D estimated from sodium dodecyl sulfate (SDS) gel disk electrophoresis were 6600, 6900, 7000 and 7200, respectively. The isoelectric points of these peptides were 10.4, 10.6, 10.7 and 10.5, respectively. They possessed a single polypeptide chain of 34-35 (elapherine-A), 56-58 (elapherine-B), 56-57 (elapherine-C) and 52-53 (elapherine-D) amino acid residues.

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A series of tripeptidyl analogues carrying hydroxamic acid residue at the C-terminus of the molecule were synthesized, and their inhibitory activities against vertebrate collagenase and other metalloenzymes including bacterial collagenase were examined. Both Z-Pro-Leu-Ala-NHOH and Z-Pro-D-Leu-D-Ala-NHOH showed highly specific and potent inhibitory activity against tadpole and human skin collagenases with an IC₅₀ of 10^-6 M order.

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Pharmacokinetic profiles of canrenoic acid (CRA) and canrenone (CR), the reversible metabolite of CRA, were studied in the rat after intraportal (pv) administration in comparison with those after intravenous (iv) administration using an interconversion model In the clearances for the irreversible loss, CL₂₀ of CR was larger then CL₁₀ of CRA. Nevertheless, the real plasma clearance of CR was less than that of CRA. The distribution volume V₁ of CRA was almost close to the real distribution volume V_{ss, real, D} of CRA at the steady state. The hepatic available fraction of CRA, F_H1 and sequential hepatic available fraction of generated metabolite, F_H2, were estimated. Simultaneous computer multi-line fitting of plasma concentration-time data was carried out and the adequacy of pharmacokinetic parameters in this model was tested using the iterative nonlinear least-squares regression program, MULTI.

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High frequency pulse iontophoresis of diclofenac sodium across excised guinea-pig skin was carried out in vitro. An equivalent circuit model was constructed to simulate the time courses of voltage drop across the donor solution and the skin. Parameter values obtained by the least-squares adaptation of the model to observed data were consistent with expectation and validated the proposed model.

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Some of the factors affecting the steady-state transport rate of diclofenac sodium across excised guinea-pig skin during high-frequency pulse intophoresis were examined. The same mathematical expression was employed for enhancement ratio as a function of applied voltage as the one derived for direct-current iontophoresis. The effective voltage drop across the skin was only 1.1% of the applied voltage. The steady-state flux value increased with increase of the donor cocentration.

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The dissolution of log-normal particle-size-distributed model systems prepared with sieved n-propyl p-hydeoxybenzoate crystalline particles was conducted under the silk condition. The log-normal particle-size distributed systems were expressed as a generalized equation and distribution curve, and mixed systems were prepared following the generalized distribution curves. The dissolution of the mixed systems, composed of particles whose chenges of surface area during the dissolution were not easy to measure, was carried out under the silk condition. These dissolution processes were simulated by the use of the relationship between the surface-producing rate constant and the initial particle size deduced with some components. The simulated values for the dissolution showed fairly good coincidence with those measured, and it is considered that the relationship between the surface-producing rate constant and the initial particle size is useful for prediction of the dissolution behavior of mixed systems.

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We prepared indomethacin (IM) sustained-release suppositories using sugar ester (SE) as an additive. The suppositories were prepared by the fusion method with IM, SE, and Witepsol^[○!R] H-15 (H-15) and their availablities in vitro and in vivo were evaluated mainly by the drug release test and the absorption test in rabbits, respectively. The softening point of the suppositories increased with increasing SE content. In the release test with the Muranishi method, slow-release profiles were obtained when the SE content was more than 52.5%. The absorption of IM from these suppositories, however, was very little. In the other release test, e.g. immersion method with guaze, all of the suppositories with SE showed slow-release profiles, and the drug release rates clearly depended on the SE content. The drug was released from the suppositories by the following leaching-type mechanism proposed by Higuchi. The suppository with a 30% SE content showed a sustained-plasma level of IM, but the other suppositories did not. It was concluded that an appropriate content of SE (i.e. 30%) in the suppository base was required to obtain sustained-release because it reasonable regulated the infiltration of rectal fluid into the suppository and the mechanical strength of the suppository against disintegration.

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The vapor pressures of solid drugs were determined by the steam distillation method. Experiments using a series of benzoic acid derivatives indicated that this method consistent offered and satisfactory values for vapor pressure at about 100°C. The vapor pressures of two nonsterodial antiinflammatory drugs, flufenamic acid (FFA) and mefenamic acid (MFA), were found to be 3.8×10^-3 and 1.8×10^-4 mmHg, respectively. These values explain the difference in the rate of change to the amorphous state between mixtures of each with magnesium aluminum silicate (MAS) when they were stored under reduced pressure. It was concluded that the vapor pressures of solid drugs at about 100°C, as determined by steam distillation, may be suitable indices for predicting whether or not these drugs have an inherent propensity to become amorphous readily in mixtures with an adsorbent.

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A sensitive and simple fluorometric method for the determination of N, N'-bis(2-aminoethyl)-1, 2-ethanediamine dihydrochloride (triethylenetetramine) in human plasma by high-performance liquid chromatography is described. Free triethylenetetramine (TETA) obtained by passing the TETA-copper clelate compound through a solid-phase cation exchange resin was converted to its fluorescamine derivative in the presence of ethylenediaminetetraacetic acid to mask the interfering metal ions in the reactin solution, and the derivatives were separated on a nitrile high-performance liquid chromatograph column (Nucleosil 5-CN) using isocratic elution. The plasma levels of TETA were measured in eight patients receiving treatment for excess copper. Absorption rates of TETA were relatively slow and the peak levels were significantly different among patients. The bioavailability of TETA in the rat was also examined and the ratio of intestinal absorption was extremely low.

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The inhibitory effect of vexibinol, one of the flavanols found in Sophora, on gastric uncers induced by HCl-ethanol has been reported previously. In the present study, the effect of vexibinol was examined in various experimental ulcer models in order to determine the mechanism of its antiulcer action. The results indicated that the oral administration of vexibinol at 25-50 mg/kg significantly inhibited the development of ulcers induced by HCl-ethanol, 0.6 N HCl, 0.2N NaOH, absolute ethanol and 1% NH₃. In addition, an intraduodenal administraion of vexibinol at 300 mg/kg significantly inhibited Shay's ulcer. Further, intraduodenal administraion at 300 mg/kg significantly inhibited acid secretion caused by 2-deoxy-D-glucose. These results suggest that vexibinol has not only gastric mucosal protective action but also an inhibitory effect on the secretion of gastric acids.

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The rhizomes of Curcuma xanthorrhiza ROXB, are used in Indonesian folk medicine as cholagogues, aromatic stomachics, analgesics, a rheumatic remedy, etc. The present study was carried out to elucidate the antiinflammatory effect of the methanol extract obtained from these rhizomes and its active principles. The methanol extract was partitioned between ether and water, and then the ether-soluble fraction was extracted with n-hexane. The n-hexane-soluble fraction was chromatographed (fr. I-IV), fr. II was rechromatographed (fr. V-VII), and then fr. V was rechromatographed (fr.VIII-X) by silica gel column chromatography. The antiinflammatory activity of these fractions was investigated on carrageenin-induced edema in rats and acetic acid-induced vascular permeability as well as the writhing symptom in mice. The methanol extract (p.o.) showed both an antiinflammatory activity and an analgesic activity and these activities shifted successively to the ether-soluble fraction, the n-hexane-soluble fraction, fr. II, V and IX. The chemical structure of fr. IX was identified as germacrone. These results suggest that the antiinflammatory action of Curcuma xanthorrhiza is the result of the germacrone that it contains.

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The effects of persimmon tannin on pathophysiological changes in stroke-prone spontaneously hypertensive rats (SHRSP) were investigated. When the persimmon tannin was chronically ingested by SHRSP, the life span was significantly prolonged, yet the effect on blood pressure was slight. The incidences of brain hemorrhage and infarction were also significantly decreased by this treatment. To elucidate the mechanisms involved in these events, the effects of condensed tannins, including persimmon tannin, on free radicals and lipid peroxidation were examined in vitro. Using electron spin resonance analysis, we found that these tannins have a potent, concentration-dependent scavenging action toward active oxygen free radicals. These tannins strongly inhibited lipid peroxidation in rat brain homogenates, in a concentration-dependent manner. Persimmon tannin inhibited lipid peroxidation similarly to (-)-epigallocatechin.Persimmon tannin was 20 times more effective than α-tocopherol in terms of the 50%-inhibitory concentration. The radical scavenging action and inhibition of lipid peroxidation by persimmon tannin may explain, in part, the prolongation of the life span of the SHRSP ingesting persimmon tannin.

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The generation of a different type of β-kallikrein, designated Cβ-kallikrein, from α-kallikrein by chymotryptic action was ascertained by the following observations : 1) When α-kallikrein was incubated with chymotrypsin, an increase of esterolytic activity of kallikrein was observed. 2) In sodium dodecyl sulfate polyacrylamide gel electrophoresis, Cβ-kallikrein was found to be different from the β-kallikrein obtained from α-kallikrein by tryptic digestion, and was designated Tβ-kallikrein. 3) N-Terminal amino acid sequence analyses of internal light and heavy chains of Cβ-kallikrein indicated that N-termini of the light and the heavy chains were isoleucine and lysine, respectively, and that the heavy chain had most of the "kallikrein autolysis loop" sequence in its N-terminal end. In the case of Tβ-kallikrein, N-termini of the light and the heavy chains were isoleucine and alanine, respectively, and the light chain retained the "kallikrein autolysis loop" region in its C-terminal end. These observations demonstrated that Cβ-kallikrein was different from the β-kallikrein prepared from autolyzed pancreas, Aβ-kallikrein, which had lost the "kallikrein autolysis loop" sequence. Structural differences of the above four kallikreins (α-, Tβ-, Cβ- and Aβ-) result in somewhat different enzyme properties. The kinetic constants for the hydrolysis of synthetic substrates (N^α-benzoyl-L-arginine ethyl ester and N^α-tosyl-L-arginine methyl ester) of these kallikreins differed from each other, and inhibitory profiles against α₁-antitrypsin were also different. These observations suggest that the "kallikrein autolysis loop" region may play an important role in the regulation of kallikrein activity in vivo.

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To clarify the origin of nitrogen of vitamin B₁₂, ¹⁵N-labeled aminolevulinic acid (ALA) was prepared and administered to Propionibacterium shermanii. Vitamin B₁₂ thus isolated showed four signals in the nitrogen-15 nuclear magnetic resonance (¹⁵N-NMR) spectrum. The nitrogen of [5-¹⁵N]riboflavine was incorporated into the benzimidazole part of vitamin B₁₂. Hydroxycobalamin was transformed into cyanocobalamin by treatment with [¹⁵N]potassium cyanide, and the ¹⁵N-NMR spwctrum was measured. The results of these experiments revealed the origin of the nitrogen atoms of vitamin B₁₂, and allowed the ¹⁵N-NMR signals to be assigned.

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The reactions of (S)-4-amino-1-phenylbutanones (3a-e) with methyllithium, methylmagnesium bromide, and methyltitanium triisopropoxide were studied. The reaction of the (S)-4-hydroxyethylamino derivatives (3a and 3d) with methyltitanium triisopropoxide gave 4a and 4d by 1, 6-asymmetric induction with diastereoselectivities of 78 and 70%.

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Three acidic metabolites (5-7) of 6, 11-dihydro-11-(3-dimethylaminopropylidene)dibenzo[b, e]thiepin(dothiepin) were prepared. In the synthetic course, a reaction of 6, 11-dihydro-11-vinyldibenzo[b, e]thiepin-11-ol (2) with SOCl₂ stereoselectively afforded (E)-11-(2-chloroethylidene)-6, 11-dihydrodibenzo[b, e]thiepin (3). The mechanism of this reaction is discussed.

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A new class of sulfonamides, N²-arylsulfonyl-N¹, N¹-disubstituted ethoxalamidines, was synthesized by reaction of arylsulfonyl isocyanates with N, N-disubstituted ethyl oxamates. It was suggested that the reacion might proceed through [2+2] cycloaddition of the isocyanates to an amide carbonyl moiety with high selectivity.

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α-Rat atrial natriuretic peptide (α-rANP) was synthesized by assembling five peptide fragments in solution, followed by HF-dimethylselenide-m-cresol deprotection and subsewuent air-oxidation. Synthetic α-rANP exhibited more potent diuretic and natriuretic activity in rats than syntheric α-hANP.

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Synthesis of 3-alkylthio-4-methyl-4H-1, 2, 4-benzothiadiazine 1, 1-dioxides was conveniently achieved by [2+2] cycloaddition reaction of S-alkyl N-methyl-N-phenyldithiocarbamates with chlorosulfonyl isocyanate with subsequent loss of carbonyl sulfide, followed by cyclization of the resulting chlorosulfonyl isothioureas under Friedel-Crafts conditions.

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An orally active penem antibiotic (5-methyl-2-oxo-1, 3-dioxol-4-yl)methyl(5R, 6S)-2-(fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3-carboxylate (1) was synthesized in 3 steps with a 50% yield from (3S, 4R)-3-[(1R)-1-tertbutyldimethylsilyloxyethyl]-4-[[(2-fluoroethylthio)thiocarbonyl]thio]azetidin-2-one (4) and a new building block, (5-methyl-2-oxo-1, 3-dioxol-4-yl)methyloxyoxalyl chloride (3).

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