Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
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ISSN-L : 0009-2363
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Volume 49, Issue 9
Displaying 1-40 of 40 articles from this issue
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Regular Articles
  • DNA Topology on an Increase in Positive Writhing Number of DNA: Conformation Changes in the Time Course of cis-Diamminedichloroplatinum(II)—DNA Adducts
    Shigeki KOBAYASHI, Yoshihide NAKAMURA, Tamae MAEHARA, Hajime HAMASHIMA ...
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1053-1060
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1053
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    We show that the topological significance of the gel mobility of cis-diamminedichloroplatinum(II) (DDP)-closed circular DNA (ccDNA) adducts decreases with reaction time, until a point at which it joins relaxed DNA, and that the mobility of the adducts increases again. There is no relationship between the relative length of the adducts and the gel mobility. Although the significance of the decrease of gel mobility is due to the unwinding of cis-DDP-DNA (or trans-DDP-DNA) adducts, the conformational significance of the subsequent increase in mobility is unclear. To elucidate the conformational significance for unwinding of the adducts, we measured the writhing number (Wκ) of the adducts using electron microscopy and analyzed the topological states of cis-DDP (or trans-DDP) adducts based on the White rule, Lκ=Wκ+Tκ. Where, Lκ and Tκ represent the linking and twisting number in the ring, respectively. From the data, we found that the Wκ of cis-DDP-ccDNA adducts in comparison with trans-DDP-ccDNA adducts increases from a negative to a positive number with time. This suggests that cis-DDP plays a role in the chaneg of the topological state of ccDNA. In the abstraction of platinum from the adducts with CN- ion, the differences in both topological states may explain why Pt in trans-DDP is abstracted more easily than in cis-DDP. To explain the abstraction of Pt ion, we also discuss the findings based on the thermodynamic cycle in a intermolecular crosslink model Pt(NH3)2(guanine)22+→Pt(CN)42- using the Pt parametrized PM3 method.
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  • Synthesis and in Vitro Cytotoxic Evaluation of New Derivatives of Pyrido[1,2-a]benzimidazolic Ring System: The Pyrido[1',2':1,2]imidazo[4,5-h]quinazolines
    Marianne DUPUY, Frederic PINGUET, Olivier CHAVIGNON, Jean-Michel CHEZA ...
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1061-1065
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1061
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    Access to the original series of pyrido[1',2':1,2]imidazo[4,5-h]quinazoline was developed from a 1,3-dicarbonyl unit with some “N-C-N” bisnucleophilic reagents and the derivatives obtained were evaluated for in vitro cytotoxic activities against HL60 and A2780 cells. All compounds exhibited cytotoxic activitise on resistant cell lines (MDR+; HL60R and A2780R) with no resistance phenomena.
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  • Quantitative Study of the Structural Requirements of Phthalazine/Quinazoline Derivatives for Interaction with Human Liver Aldehyde Oxidase
    Taravat GHAFOURIAN, Mohammad Reza RASHIDI
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1066-1071
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1066
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    Aldehyde oxidase is a molybdenum-containing enzyme distributed throughout the animal kingdom. Although this enzyme is capable of metabolizing a wide range of aldehydes and N-heterocyclic compounds, there is no reported detailed study of physicochemical requirements of the enzyme-substrate interactions. The aim of this study, therefore, was to investigate quantitatively the relationships between the kinetic constants of aldehyde oxidase-catalyzed oxidation of some phthalazine and quinazoline derivatives (as substrates) and their structural parameters. Multiple regression and stepwise regression analyses showed that polarity of phthalazines (expressed as dipole moment μ, cohesive energy density δT and an indicator variable for hydrogen-bond acceptor ability of R1 substituent, HBA) had a negative effect on the enzyme activity (leading to the reduction of Vmax and increase of Km). Electron withdrawing substituents in the quinazoline series are favorable for interaction with the enzyme. This finding and also the relationships of 1/Km of phthalazines with the energy of the lowest unoccupied molecular orbital and log Vmax/log Km of phthalazines with degree of bonding of the two nitrogen atoms in the molecules are consistent with the mechanism of action. The reaction involves a nucleophilic attack on an electron-deficient sp2-hybridized carbon atom and formation of an epoxide intermediate following the disruption of the aromatic structure.
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  • Sesquiterpenoid Derivatives from Ferula ferulioides. V
    Kimio ISAKA, Akito NAGATSU, Purev ONDOGNII, Oyun ZEVGEEGIIN, Purevsure ...
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1072-1076
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1072
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    Nine novel prenyl-dihydrofurocoumarin-type sesquiterpenoid derivatives, 2, 3-dihydro-7-hydroxy-2R*, 3R*-dimethyl-2-[4, 8-dimethyl-3(E), 7-nonadienyl]-furo[3, 2-c]coumarin, 2, 3-dihydro-7-hydroxy-2S*, 3R*-dimethyl-2-[4, 8-dimethyl-3(E), 7-nonadien-6-onyl]-furo[3, 2-c]coumarin, 2, 3-dihydro-7-hydroxy-2S*, 3R*-dimethyl-2-[4-methyl-5-(4-methyl-2-furyl)-3(E)-pentenyl]-furo[3, 2-c]coumarin, 2, 3-dihydro-7-hydroxy-2R*, 3R*-dimethyl-2-[4-methyl-5-(4-methyl-2-furyl)-3(E)-pentenyl]-furo[3, 2-c]coumarin, 2, 3-dihydro-7-methoxy-2S*, 3R*-dimethyl-2-[4, 8-dimethyl-3(E), 7-nonadienyl]-furo[3, 2-c]coumarin, 2, 3-dihydro-7-methoxy-2R*, 3R*-dimethyl-2-[4, 8-dimethyl-3(E), 7-nonadienyl]-furo[3, 2-c]coumarin, 2, 3-dihydro-7-methoxy-2S*, 3R*-dimethyl-2-[4, 8-dimethyl-3(E), 7-nonadien-6-onyl]-furo-[3, 2-c]coumarin, and 2, 3-dihydro-7-methoxy-2S*, 3R*-dimethyl-2-[4-methyl-5-(4-methyl-2-furyl)-3(E)-pentenyl]-furo[3, 2-c]coumarin, were isolated from the roots of Ferula ferulioides. The structures were established by comprehensive spectral analysis. The biosynthetic pathway leading to these prenyl-furocoumarin-type sesquiterpenoids is proposed based on their structures.
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  • Synthesis and Cytotoxic Activity of Benzophenanthrolinone Analogues of Acronycine
    Jean-Bernard BONGUI, Abdelhakim ELOMRI, Elisabeth SEGUIN, Francois TIL ...
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1077-1080
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1077
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    Condensation of either 2-bromobenzoic acid (4) or 2-chloro-3-nitrobenzoic acid (5) with suitable aminoquinolines 6-8 afforded phenylquinolylamines 9-13. Acid mediated cyclization gave the corresponding 12H-benzo[b][1, 7]phenanthrolin-7-ones 14 and 15, and 12H-benzo[b][1, 10]phenanthrolin-7-ones 16-18. Compounds 14, 16, and 17 were subsequently N-methylated to 6-demethoxyacronycine and acronycine analogues 19-21, whereas reduction of the aromatic nitro group of 18 gave the amino derivative 22. Unsubstituted 12H-benzo[b][1, 10]phenanthrolin-7-ones 16, 17, 20, and 21 were devoid of significant cytotoxic activity, whereas 18 and 22, bearing a nitrogen substituent at position 11, were significantly active. Unsubstituted 12H-benzo[b][1, 7]phenanthrolin-7-ones 14 and 19, which include a pyridine nitrogen in the same 4-position as the pyran oxygen of acronycine exhibited cytotoxic activities within the same range of magnitude as acronycine itself.
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  • New Progesterone Esters as 5α-Reductase Inhibitors
    Marisa CABEZA, Ivonne HEUZE, Eugene BRATOEFF, Eugenia MURILLO, Elena R ...
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1081-1084
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1081
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    The pharmacological activity of four new progesterone derivatives: 4-bromo-17α-(p-fluorobenzoyloxy)-4-pregnene-3, 20-dione (7), 4-bromo-17α-(p-bromobenzoyloxy)-4-pregnene-3, 20-dione (8), 4-bromo-17α-(p-chlorobenzoyloxy)-pregnene-3, 20-dione (9) and 4-bromo-17α-(p-toluoyloxy)-4-pregnene-3, 20-dione (10) was determined. These compounds were evaluated as 5α-reductase inhibitors on gonadectomized hamster seminal vesicles and flank organs. The pharmacological data of this study indicate that compounds 7 and 9 having at C-17 p-fluorobenzoyloxy and p-chlorobenzoyloxy ester functions respectively showed the highest antiandrogenic effect as measured by the reduction of the weight of the seminal vesicles. In the flank organ model, the same compounds 7 and 9 exhibited a smaller diameter, 1.8 and 1.0 mm, respectively, than the commercially available finasteride 3 (2.3 mm), thus indicating a higher inhibitory effect on 5α-reductase enzyme. Steroid 7 showed a higher inhibitory activity on the conversion of T to DHT (Fig. 3) than the presently used finasteride, thus indicating a higher antiandrogenic effect. The nonsubstituted benzoyloxy ester (compound 15) showed a lower antiandrogenic activity as measured in the seminal vesicles model than the p-substituted benzoyloxy compounds.
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  • Seven New Bifuranocoumarins, Dahuribirin A-G, from Japanese Bai Zhi
    Nian-He WANG, Koichiro YOSHIZAKI, Kimiye BABA
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1085-1088
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1085
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    Five new spirobifuranocoumarins, dahuribirins A-E (1-5) and two new bifuranocoumarins, dahuribirins F and G (6 and 7) were isolated from Japanese Bai Zhi (the root of Angelica dahurica BENTH. et HOOK. var. dahurica BENTH. et HOOK.) and their structures were established by chemical and spectral means.
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  • Evaluation of the Trifluoromethanosulfonic Acid/Trifluoroacetic Acid/Thioanisole Cleavage Procedure for Application in Solid-Phase Peptide Synthesis
    Guita N. JUBILUT, Eduardo M. CILLI, Mineko TOMINAGA, Antonio MIRANDA, ...
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1089-1092
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1089
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    As an extension of our investigation of peptidyl-resin linkage stability towards different cleavage procedures used in the solid-phase peptide synthesis (SPPS) technique, the present paper evaluated the trifluoromethanesulfonic acid (TFMSA)/trifluoroacetic acid (TFA)/thioanisole method, varying the type of resin (benzhydrylamine-resin, BHAR; methylbenzhydrylamine-resin, MBHAR and 4-(oxymethyl)-phenylacetamidomethyl-resin, PAMR) and peptide resin-bound residue (Gly and Phe). The vasoactive angiotensin II (AII, DRVYIHPF) and its [Gly8]-AII analogue linked to those resins used routinely in tert-butyloxycarbonyl (Boc)-SPPS chemistry were submitted comparatively to a time course study towards TFMSA/TFA cleavage. At 0 °C, [Gly8]-AII was completely removed from all resins in less than 6 h, but the hydrophobic Phe8 moiety-containing AII sequence was only partially cleaved (not more than 15%) from BHAR or MBHAR in this period. At 25 °C, [Gly8]-AII cleavage time decreased to less than 2 h irrespective of the solid support, and quantitative removal of AII from PAMR and MBHAR occurred in less than 3 h. However, about 10-15 h seemed to be necessary for cleavage of AII from BHAR, and in this extended cleavage reaction a significant increase in peptide degradation rate was observed. Regardless of the cleavage temperature used, the decreasing order of acid stability measured for resins was BHAR>MBHAR>PAMR. Collectively, these findings demonstrated the feasibility of applying TFMSA/TFA solution as a substitute for anhydrous HF at the cleavage step in Boc-SPPS methodology. Care should be taken however, as the cleavage efficacy depends on multiple factors including the resin, peptide sequence, the time and temperature of reaction.
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  • Myrsinionosides A-E: Megastigmane Glycosides from the Leaves of Myrsine seguinii LEV.
    Hideaki OTSUKA, Xi-Ning ZHONG, Eiji HIRATA, Takakazu SHINZATO, Yoshio ...
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1093-1097
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1093
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    Eight megastigmane glycosides were isolated from the leaves of Myrsine seguinii collected in Okinawa. Three of them were found to be known compounds, i.e., ampelopsisionoside, alangionoside J, and linarionoside A. The structures of the new megastigmane glycosides were elucidated from the spectroscopic data and their absolute stereochemistries were determined in detail using a modified Mosher’s method.
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  • Homocyclotirucallane and Two Dihydrophenanthrenes from Spiranthes sinensis
    Yun-Lian LIN, Wan-Yi WANG, Yueh-Hsiung KUO, Yi-Hung LIU
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1098-1101
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1098
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    A novel homocyclotirucallane, sinetirucallol (1), and two additional new dihydrophenanthrenes, sinensols G (2) and H (3), were isolated from the aerial parts of Spiranthes sinensis (PERS.) AMES. Their structures were determined by various spectral analyses, including MS and two-dimensional nuclear magnetic resonance techniques. The structure of compound 1 was further confirmed by single-crystal X-ray analysis. The absolute configuration of 1 was determined by modified Mosher’s method.
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  • Optically Active Antifungal Azoles. XII. Synthesis and Antifungal Activity of the Water-Soluble Prodrugs of 1-[(1R, 2R)-2-(2, 4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1, 2, 4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone
    Takashi ICHIKAWA, Tomoyuki KITAZAKI, Yoshihiro MATSUSHITA, Masami YAMA ...
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1102-1109
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1102
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    1-[(1R, 2R)-2-(2, 4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1, 2, 4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (1: TAK-456) was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, the quaternary triazolium salts 2 were designed as water-soluble prodrugs. Among the prodrugs prepared, 4-acetoxymethyl-1-[(2R, 3R)-2-(2, 4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1-terazolyl)phenyl]-1-imidazolidinyl]butyl]-1H-1, 2, 4-triazolium chloride (2a: TAK-457) was selected as an injectable candidate for clinical trials based on the results of evaluations on solubility, stability, hemolytic effect and in vivo antifungal activities.
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  • Optically Active Antifungal Azoles. XIII. Synthesis of Stereoisomers and Metabolites of 1-[(1R, 2R)-2-(2, 4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1, 2, 4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456)
    Takashi ICHIKAWA, Masami YAMADA, Masashi YAMAGUCHI, Tomoyuki KITAZAKI, ...
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1110-1119
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1110
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    1-[(1R, 2R)-2-(2, 4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1, 2, 4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone [(1R, 2R)-1: TAK-456] is a new antifungal agent selected as a candidate for clinical trials. The three stereoisomers [(1S, 2R)-, (1S, 2S)- and (1R, 2S)-1] of this compound were prepared as authentic samples to determine the enantiomeric and diastereomeric purity of TAK-456 as well as to compare their in vitro antifungal activity. Pharmacokinetic studies of TAK-456 using rats identified the existence of metabolites in the liver homogenate. The structures of the major metabolites were assigned as 4-hydroxy-2-imidazolidinone (3) and/or 5-hydroxy-2-imidazolidinone (4), based on HPLC and LC/MS/MS analyses. These hydroxylated compounds, 3 and 4, were prepared by reduction of the corresponding imidazolidinediones, 11 and 12, and confirmed to be identical to the metabolites by HPLC. In vitro antifungal activities of the three stereoisomers and the synthesized metabolites were considerably weaker than TAK-456.
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  • Studies on Macrolide Antibiotics I. Synthesis and Antibacterial Activity of Erythromycni A 9-O-Substituted Oxime Ether Derivatives against Mycobacterium avium Complex
    Akemi NISHIMOTO, Ken NARITA, Shinobu OHMOTO, Yoshie TAKAHASHI, Satoshi ...
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1120-1127
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1120
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    A series of erythromycin A 9-O-substituted oxime ether derivatives have been synthesized and evaluated for antibacterial activity against Mycobacterium avium complex (MAC) and Staphylococcus aureus. These compounds possessed stronger in vitro activity against MAC including macrolide-resistant strains than clarithromycin (2), although in vitro antibacterial activities of these compounds were less than that of 2 against Staphylococcus aureus. Our studies found that several factors contribute to the antibacterial activity against MAC. The length and spatial orientation of the substituent at 9-position were found to significantly influenced the anti-MAC activity, especially against macrolide-resistant strains. Of all the compounds prepared, erythromycin A 9-[O-(4-phenylbutyl)oxime] (12q) and erythromycin A 9-[O-(3-phenoxypropyl)oxime] (12t) possessed 16 times stronger antibacterial activity than 2 against clarithromycin-resistant strains. Surprisingly, the minimum inhibitory concentrations (MICs) of 12q and 12t against the resistant strains were almost same as those against the susceptible strains. These results suggest that the erythromycin A 9-O-substituted oxime ether derivatives would be promising macrolide antibiotics.
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  • Application of Combined Reagent Solution to the Oxidative Refolding of Recombinant Human Interleukin 6
    Takushi HARADA, Eiji KURIMOTO, Yuji MORIYAMA, Daisuke EJIMA, Tomoya SA ...
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1128-1131
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1128
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    Human interleukin 6 (hIL-6), which is a cytokine involved in diverse biological activities, consists of a four-helix bundle with two disulfide bonds. For the clinical use of hIL-6 in cancer therapy, designing of commercial-scale production systems of recombinant hIL-6 (rhIL-6) expressed by E. coli has been attempted. Since rhIL-6 has been produced as inclusion bodies in the expression systems reported to date, establishment of a strategy to achieve a high yield of refolding of this recombinant protein is quite desirable. It has been reported that oxidation of rhIL-6 under a completely denaturing condition suppresses aggregation during the refolding process [Ejima et al., Biotechnol. Bioeng., 62, 301-310 (1999)]. In this protocol, however, small but significant amounts of unidentified by-products unavoidably arose, which might be problematic in the therapeutic use of rhIL-6. In the present study, detailed characterization of the individual by-products has been performed on inspection of peptide maps, and the by-products found to originate from improperly formed disulfide bonds, most of which are disulfide-linked dimers. In order to minimize these by-products, combined solutions of urea and LiCl were used for oxidative refolding of rhIL-6. It was demonstrated that combined use of 1-2 M urea and 1-3 M LiCl effectively suppresses the formation of the by-products as well as aggregates. We propose that the use of the combined reagents can be an alternative method for refolding of rhIL-6 for clinical purposes.
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  • Intramolecular Capture of Pummerer Reaction Intermediates by an Aromatic Nucleophile: Selective Construction of 1, 4-Benzothiazine and Indole Ring Systems
    Yoshie HORIGUCHI, Akihiro SONOBE, Toshiaki SAITOH, Jun TODA, Takehiro ...
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1132-1137
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1132
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    The simple alkyl sulfoxide 6 carrying two aromatic nucleophiles, when treated with trifluoroacetic anhydride at room temperature (Pummerer reaction conditions), underwent an intramolecular aromatic sulfenylation of the 6-exo-tet process in an exclusive manner to yield two regioisomeric 1, 4-benzothiazine derivatives, 8 and 9. On the other hand, a similar reaction of the α-acyl sulfoxide 7, possessing identical aromatic nucleophiles, caused an intramolecular aromatic alkylation of the 5-exo-trig process to produce the 3-oxo-indole derivative 14 in a quantitative yield. These results demonstrate that the construction of 1, 4-benzothiazine and indole ring systems can be achieved in a selective manner by proper choice of the sulfoxide side chain.
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  • Solution-Phase Automated Synthesis of Tripeptide Derivatives
    Noritaka KURODA, Taeko HATTORI, Chieko KITADA, Tohru SUGAWARA
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1138-1146
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1138
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    An improved general method for automated synthesis of tripeptides was developed, in which methanesulfonic acid (MSA) was used in place of trifluoroacetic acid (TFA), thus making it possible to avoid, 1) corrosion of the apparatus by strong acid vapor, 2) formation of emulsions, and 3) use of the restricted solvent, dichloromethane. As an application of the automated synthesis apparatus, 216 fragment tripeptide derivatives were synthesized systematically using the MSA method, in excellent yield and with increased efficiency.
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  • Application of an Automated Synthesis Suite to Parallel Solution-Phase Peptide Synthesis
    Noritaka KURODA, Taeko HATTORI, Yoko FUJIOKA, David G. CORK, Chieko KI ...
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1147-1154
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1147
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    An in-house developed automated synthesis suite was used to prepare a library of 72 tetrapeptide derivatives, the starting materials for pharmaceutically attractive pentapeptides, employing a convergent strategy. An initial set of 18 dipeptides were synthesized on a large-scale (100-1000 g) using automated synthesis workstations, and then 72 tetrapeptides were synthesized on a medium scale (5-10 g) using an automated system. Each di- or tetrapeptide was prepared in a single operating cycle using a modified methanesulfonic acid method, then a sub-library of 56 pentapeptides were synthesized in parallel, on a small-scale (100 mg-1 g) using a robotic workstation.
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  • Effects of Double-Chained Cationic Surfactants n-Dimethyldialkylammoniums on Skin Permeation of Benzoic Acid through Excised Guinea Pig Dorsal Skin: Comparison of Their Enhancement Effects with Hemolytic Effects on Erythrocytes
    Shuji KITAGAWA, Masatoshi KASAMAKI, Fuyuko HIYAMA
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1155-1158
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1155
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    We examined the effects of the double-chained cationic surfactants dimethyldialkylammoniums (CH3)2N+(CnH2n+1)2 on the permeation of benzoic acid through excised guinea pig dorsal skin. Among five dimethyldialkylammoniums tested (n=10-18), dimethyldidecylammonium (n=10) had dose-dependent enhancement effects at concentrations of more than 20 μM. Compared with the marked enhancement effects of dimethyldialkylammoniums with relatively shorter alkyl chains, those of long-chain dimethyldiakylammoniums (n=16, 18) were much less. We compared the enhancement effects of these cationic surfactants on skin permeation with their hemolytic effects on guinea pig erythrocytes. Their enhancement effects corresponded to their hemolytic activity. The findings suggest that dimethyldialkylammoniums with relatively shorter alkyl chains, which form either vesicles with looser molecular packing or micelles and appear to be present as surfactant monomers in higher ratios than those with longer alkyl chains, favor the interaction with skin. Their enhancement mechanism is possibly similar to that of single-chained cationic surfactants.
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  • The Chemistry of Indoles. CVII. A Novel Synthesis of 3, 4, 5, 6-Tetrahydro-7-hydroxy-1H-azepino[5, 4, 3-cd]indoles and a New Finding on Pictet-Spengler Reaction
    Masanori SOMEI, Sakiko TERANISHI, Koji YAMADA, Fumio YAMADA
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1159-1165
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1159
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    Serotonins were found to produce 3, 4, 5, 6-tetrahydro-7-hydroxy-1H-azepino[5, 4, 3-cd]indoles by simple heating with amines under an oxygen atmosphere. Serotonins also reacted with various aldehydes to provide 3, 4, 5, 6-tetrahydro-7-hydroxy-1H-azepino[5, 4, 3-cd]indoles rather than β-carbolines under basic conditions. In these novel reactions, the presence of the 5-hydroxy group on the indole nucleus was suggested to be essential. Possible mechanisms are discussed.
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  • A Novel 1: 1 Complex of Potassium Mikanin-3-O-sulfate with Methanol
    Ren-Wang JIANG, Zhen-Dan HE, Paul Pui-Hay BUT, Yiu-Man CHAN, Shuang-Ch ...
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1166-1169
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1166
    JOURNAL FREE ACCESS
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    Mikanin-3-O-sulfate (1), in the form of its potassium salt, together with mikanin (2) and alpinetin (3) were isolated from Mikania micrantha. The crystal structures of K(1)·CH3OH, 2 and 3·H2O were established by X-ray crystallography. The potassium ions in K(1)·CH3OH are bridged by O5, O7 and O8 to form a chain of face-sharing KO8 coordination polyhedra, from which the aglycon units are outstretched to form a polymeric molecular column. Adjacent molecular columns are linked by π-π stacking between parallel, intercalating aglycon units to form layers matching the (101) family of planes, which are further interconnected into a three-dimensional supramolecular assembly. Sulfation at 3-OH induced better co-planarity and conjugation of the rings.
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  • Analysis of Terpenelactones in Ginkgo biloba by High Performance Liquid Chromatography and Evaporative Light Scattering Detection
    Markus GANZERA, Jianping ZHAO, Ikhlas A. KHAN
    Article type: scientific monograph
    2001 Volume 49 Issue 9 Pages 1170-1173
    Published: 2001
    Released on J-STAGE: May 31, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1170
    JOURNAL FREE ACCESS
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    A reversed phase HPLC method permitting the determination of 5 terpenelactones in Ginkgo biloba, without the need of any sample preparation is presented in this paper. The compounds were successfully separated within 25 min by using a C-12 column, an evaporative light scattering (ELS) detector and a mobile phase comprising of ammonium acetate buffer, methanol and isobutanol. All terpenelactones were detectable at concentrations as low as 20.3 μg/ml. The analysis of G. biloba market products showed remarkable variations in the lactone content, and more than 2 fold differences in the suggested daily doses of the total lactones, from 8.84 mg to 18.28 mg, respectively.
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