|
YAKUGAKU ZASSHI, 120(10), 817-824, 2000
YAKUGAKU ZASSHI, 120(10),825-837, 2000
One century has passed since fugu toxin was named tetrodotoxin (TTX) by Tahara. Chemical problems such as crystallization of tetrodotoxin and subsequent structure determination were solved by research groups headed by Tsuda, Hirata, Woodward, and Mosher. The International Symposium on the Chemistry of Natural Products in Kyoto (1964) was well known as symposium which the structure of TTX was internationally clarified. Since the first isolation of toxin from taricha torosa (imori) as natural source except for fugu fishes, distribution of toxin in nature has been widely investigated. And, it was proved that toxin is not produced by fugu fishes, but rather is formed by sea bacteria (30 sp.) such as Alteromonas sp, Vibrio sp, Shewanella. However, it seems to be difficult to explain the tetrodotoxin accumulation at high concentration in fugu by only toxin production by bacteria. TTX analogues were isolated from natural origins such as crabs, fish, annelids, and algae. Based on the structure of these toxin analogues, the biosynthesis of toxin and the structure-activity relationship (Na+ channel) were proposed by Yasumoto-Yamashita. The findings of wide distribution of toxin in nature may be attributed to development of highly sensitive detection method for toxin. The interesting proposal for the biosynthesis and the structure activity, and the detection method for toxin are outlined in this review.
Key words--TTX; tetrodotoxin; biosynthesis; bacteria; toxin analysis; Na+ channel
YAKUGAKU ZASSHI, 120(10),839-848, 2000
In the middle of 1950's, microbial transformation technology was introduced into the field of synthetic chemistry as a new methodology. There was a sudden interest in research on the problems of producing steroid hormones by microbial transformation. At that time, the first project entitled “The Study for Microbial Transformation of Steroids”, the “Tsuda Project”, was established in the Institute of Applied Microbiology (IAM), University of Tokyo, in the spring 1956, in which I took part. This paper summarizes a number of results of our microbial transformation reactions not only in the synthesis of steroidal compounds, but also more broadly for other organic compounds, such as pravastatin, etc. The results are divided into five categories: 1) Microbial transformation of steroids, 2) Correlation between isolation sources of Pseudomonas spp. and their transformation activities, 3) Fermentation Production of prednisolone by Bacillus pulvifaciens SANK 71760, 4) Microbial transformation of siccanin, and 5) Development and fermentation production of pravastatin. About 30 years later, almost at the end of my microbial transformation studies, I had the opportunity to find some microbial strains having superior hydroxylation ability of ML-236BNa to pravastatin. Fortunately, Streptomyces carbophilus SANK 62585 was finally selected as a potent microbial converter with the formation of a lesser amount of by-products. With the view of industrial production of pravastatin, many studies and improvements were made to the culturing conditions to obtain productivity available commercially.
Key words--microbial transformation reaction; steroid; siccanin; ML-236B; pravastatin
YAKUGAKU ZASSHI, 120(10),849-862, 2000
Licorice, the root of Glycyrrhiza spp. (Fabaceae), has been used since ancient Egyptian, Greek, and Roman times in the West and since the Former Han era (the 2nd--3rd century B.C.) in ancient China in the East. In traditional Chinese medicine, licorice is one of the most frequently used drugs. In Japan, the oldest specimen of licorice introduced from China in the middle of the 8th century still exists in Shosoin, the Imperial Storehouse, in Nara. Extracts of licorice were recommended as a remedy for gastric ulcer by Revers of the Netherlands in 1946, which was soon withdrawn owing to its side effects. Carbenoxolon sodium, glycyrrhetinic acid (GA) hemisuccinate Na, was prepared from licorice to treat peptic ulcer in the UK. In Japan for the past 60 years, a glycyrrhizin (GL) preparation under the name of Stronger Neo-Minophagen C (SNMC) has been used clinically as an antiallergic and antihepatitis agent. GL and GA sometimes induce edema, hypertension, and hypokalemia in patients treated with higher doses and long-term administration. The mecha nism of this side effect, pseudoaldosteronism, has been explained as due to the 11-hydroxy-steroid dehydrogenase inhibitory activity of GL and GA. The excess of endogenous cortisol produced combines with the renal mineral corticoid receptor, which promotes an aldosterone-like action. GL and GA reduce alanine transaminase (ALT) and aspartate transaminase (AST) values in the serum. This hepatoprotective effect has recently been explained as the inhibitory effects of GL and GA on immune-mediated cytotoxicity against hepatocytes and on nuclear factor (NF)-κB, which activates genes encoding inflammatory cytokines in the liver. To exclude the side effects and enhance the therapeutic activities, chemical modification of GL and GA has been performed. Deoxoglycyrrhetol (DG), homo- and heteroannular diene homologs of dihemiphthalates, showed a remarkable improvement in antiinflammatory, antiallergic, and antiulcer activities in animal experiments. Immunomodulating effects of GL, GA, and DG derivatives, which induce interferon-γ and some other cytokines, have been demonstrated in relation with their antiviral activities. Antiinflammatory, antitumorigenic, and antimalarial effects of licorice flavonoids have also been investigated.
Key words--licorice; glycyrrhizin; hepatoprotective effect; isoliquiritigenin; licochalcone A; deoxoglycyrrhetol
YAKUGAKU ZASSHI, 120(10),863-873, 2000
Campesterol (3) and dihydrobrassicasterol (4), typical C28-sterols in higher plants, are biosynthesized from a steroidal 24-ene precursor (desmosterol 1) via 24-methylenecholesterol (2) and 24-methyldesmosterol (5). A typical plant C29-sterol, sitosterol (6), is produced from 24-methylenecholesterol via isofucosterol (7) and 24-ethyldesmosterol (8). The biosynthetic mechanism, focussing stereochemical features, of these side-chain transformations has been stud ied in detail by feeding regio- and stereoselectively 13C- or 2H-labeled steroidal substrates to cell cultures of higher plants such as Oryza sativa, Catharanthus roseus and Morus alba. These studies allowed to correlate the matabolic origin of C-26 and C-27 of the intermediate sterols. It has been established that the 1st methylation leading to 24-methylenecholesterol from desmosterol involves a Re-face hydrogen migration from C-24 to C-25 based on unambiguous assignment of the isopropyl pro-R-Me and pro-S-Me of 24-methylenecholesterol. The 2nd methylation leading to isofucosterol was revealed to proceed in a trans-mechanism in which addition of the methyl group and elimination of the C-28 hydrogen occur on opposite faces of the original Δ24(28) plane. The double bond isomerization from Δ24(28) to Δ24(25) was found to proceed in a syn-SE2' mechanism with the pro-S-methyl group of isofucosterol becoming the (E)-methyl of 24-ethyldesmosterol. Finally, feeding studies of [E-Me-13C]- and [Z-Me-13C]-24-methyldesmosterols established that an anti-mode of hydrogen addition is operating in the conversion of 24-methyldesmosterol to campesterol and dihydrobrassicasterol. Similar studies established that 24-ethyldesmosterol is converted to sitosterol in an anti-mode of hydrogen addition. In addition, the mechanism of sterol side-chain formation in hairy roots of Ajuga reptans var. atropurpurea is briefly described.
Key words--sterol; biosynthesis; plant cell culture; stereochemistry; stable isotope
YAKUGAKU ZASSHI, 120(10),875-889, 2000
Microtubules (MT) are cylindrical polymers of the protein tubulin (TN) α, β-heterodimer, and are known to be the main component of spindles in mitotic apparatus of eucaryotic cells. MT are also involved in many other basic and essential cell functions. There are a number of natural and synthetic compounds that interfere with MT function to cause the mitotic arrest of eucaryotic cells. Such antimitotic agents show a broad biological activity, and can be used for medicinal and agrochemical purposes. On the other hand, they are important also as the biochemical tools for understanding the dynamics of MT network. Most of such antimitotic agents, with a few exceptions, bind to β-TN. Among them, colchicine (CLC), vinblastine and taxol have played major roles in practical uses as well as in biochemical studies of MT functions. They all bind to β-TN but their binding sites are different. We have worked on a variety of antimitotic agents that bind to either of colchicine-site, vinblastine-site and taxol-site, in discovery, structures, biological actions and/or interactions with TN. In this paper, the results of our studies on CLC-site ligands were summarized; (1) synthetic analogs of combretastatin A-4 (CBS A-4), isolated as a cytotoxic compound produced by a species of South African tree Combretum caffrum, (2) curacin A (CU-A), a cytotoxic metabolite of a marine cyanobacteria Lyngbya majuscula, and its related compounds. Interactions of these compounds with TN were studied and structure-activity relationships of these two classes of compounds were discussed.
Key words--microtubule, tubulin, inhibitor, combretastatin, curacin A
YAKUGAKU ZASSHI, 120(10),891-898, 2000
This article describes the works of one of Tsuda's students who owes their performance to him through the long-term, direct and indirect influence of the Tsuda school, especially supervised by him during his very last period as a Professor at the University of Tokyo. They consist of i) natural product chemistry, i.e. Siccanin and related congeners, ii) carbanion chemistry, i.e. iodomethylation (C1) and trans-iodopropenylation (C3) reactions using thiazoline derivatives and their synthetic application, and iii) β-lactam chemistry, i.e. 1,3-dipoler cycloaddition reaction of iminochloride of penicillin, new β-lactam ring synthesis, synthesis of carbapenem derivatives including microbial hydration and stereo-specific 1 β-methyl carbapenem synthesis.
Key words--siccanin; iodomethylationl trans-iodopropenylation; thiazoline derivative; β-lactam chemistry; 1β-methyl carbapenem synthesis
YAKUGAKU ZASSHI, 120(10),899-908, 2000
Copper (Cu) is an essential trace element and constitutes the active center of the redox Cu enzymes such as Cu, Zn-superoxide dismutase (Cu, Zn-SOD), ceruloplasmin and cytochrome c oxidase. Among hereditary diseases due to a defect in the metabolism of Cu, Menkes disease (caused by a Cu deficiency) and Wilson disease (caused by the excessive accumulation of Cu) have been shown to be caused by the mutation of genes encoding Cu-binding ATPase for the efflux of Cu, ATP7A and ATP7B, respectively. Following the identification of these causative genes, intracellular Cu transporters (Cu chaperones) specific for the Golgi apparatus, mitochondria and Cu, Zn-SOD were discovered, and these findings have facilitated the study of the underlying mechanisms of the biological regulation of Cu. Apart from these physiological and biochemical studies, toxicological studies have elucidated the underlying mechanisms of the occurrence of acute hepatitis caused by the accumulation of Cu accumulating in the liver of an animal model for Wilson disease, LEC rats. In these toxicological studies, two biological aspects of metallothionein (MT), i.e., antioxidant and prooxidant depending on the Cu/Zn ratio in Cu-containing MT have been proposed. The present article overviews the recent findings on the biological regulation of Cu and on the toxicological aspect of Cu. It is known that Cu forms a stable ternary complex with molybdenum and sulfur under reductive conditions in the body. On the basis of this observation, tetrathiomolybdate (TTM) has been applied to remove Cu from the liver of Long-Evans rats with a cinnamon-like coat color (LEC) rats. Precise mechanisms underlying the complex formation between Cu bound to MT and TTM were presented, and an appropriate protocol for the chelation therapy was also proposed together with the mechanisms underlying the occurrence of side-effects.
Key words--Wilson disease; copper; tetrathiomolybdate; LEC rat; hepatitis; metallothionein
YAKUGAKU ZASSHI, 120(10),909-921, 2000
The studies on both structure-activity relationship study and identification of the target enzyme of novel nonpeptide aminopeptidase inhibitors with cyclic imide skeleton are reviewed. Some N-phenylphthalimide or N-phenylhomophthalimide derivative showed potent protease inhibitory activity in an assay system using human acute lymphoblastic leukemia cells, Molt-4, with alanin-4-methylcoumaryl-7-amide (ala-AMC) as a substrate. Especially, 2-(2,6-diethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione (PIQ-22) (3) was found to be the most potent inhibitor and further it showed potent tumor-cell invasion inhibitory activity that is more effective than potent peptide aminopeptidase inhibitors such as bestatin (1) or actinonin (2). For the further investigation of this novel protease inhibitory activity, we have carried out the structural development of PIQ-22 (3) and it is assumed that tautomerism of imidobenzoylketone in cyclic imide structure may be related to the inhibitory activity. The requirement for the activity of electron donating groups such as NH2 or OH to the condensed phenyl ring in phthalimide inhibitors also supports this possibility. The target aminopeptidase of PIQ-22 was identified as puromycin-sensitive aminopeptidase (PSA), by N-terminal amino acid sequencing, and by comparison with chromatographic behavior and substrate-selectivity, and so on. Lineweaver-Burk plot showed that PSA is inhibited by PIQ-22 (3) in a noncompetitive manner while puromycin (83) and bestatin (1) inhibit PSA competitively.
Key words--puromycin-sensitive aminopeptidase; nonpeptide aminopeptidase inhibitor; N-phenylhomophthalimide; N-phenylphthalimide
YAKUGAKU ZASSHI, 120(10),923-934, 2000
The existence of the lupine alkaloids in leguminous plants mainly growing in Japan has been thoroughly ascertained, and 106 kinds of lupine alkaloids, including 51 kinds of novel lupine-type alkaloids, have been isolated and characterized from 28 species belonging to the 9 genera of leguminous plants (Table 1). Among them (e.g. Fig. 1-2), a number of unusual types of alkaloids (e.g. Fig. 2) may be regarded as possible metabolites of the lupine alkaloids that coexist in the same plant, such as (+)-kuraramine-type, (−)-mamanine-type (Fig. 3), (−)-tsukushinamine-type (Fig. 5) and (+)-hupeol-type (Fig. 7) alkaloids, or as products of alternative biosynthetic pathway, such as tashiromine-type and (−)-camoensidine-type alkaloids in the Maackia species. The biosynthetic pathways (Fig. 8) by enzymes (Fig. 9) and some of biological activities (e.g. Table 2) of the lupine alkaloids have also been presented. The leguminous plants that accumulate the common lupine alkaloids may be divided into three main groups: plants which produce the matrine, the cytisine/sparteine, and the lupinine-type alkaloids. In addition, the Maackia species and a few other species produce rare bases. Some of more detailed chemical properties of the lupine alkaloids that have been isolated and studied in our laboratory, including a newly proposed biosynthetic pathway, biotechnological studies, a summary of biological activities, and a discussion of chemotaxonomic aspects of the leguminous plants which accumulate lupine alkaloids, have been reviewed by authors in English papers shown in References 1, 55, 65, and also reviewed by one of the authors (I.M.) in a Japanese papers shown in Ref. 66, in which many aspects of the active research history on (+)-matrine and its relatively alkaloids since 1892 in Japan are described.
Key words--Leguminosae; lupine alkaloid; biosynthesis; molecular evolution; DNA; chemotaxonomy
YAKUGAKU ZASSHI, 120(10),935-949, 2000
Lactacystin was isolated from the culture broth of Streptomyces lactacystinaeus as an inducer of neurite outgrowth in Neuro 2a cells (a mouse neuroblastoma cell line). The structure of lactacystin, elucidated by spectroscopic analyses including NMR and X-ray crystallography, possesses a non-peptide skeleton consisting of two α-amino acids, N-acetylcysteine and a novel pyroglutamic acid derivative. Extensive studies on its mode of action revealed that lactacystin inhibits proteasome, a high molecular weight, multicatalytic protease complex responsible for most non-lysosomal intracellular protein degradation, by binding covalently to the active site N-terminal threonine residue in certain β-sub units of proteasome. Lactacystin and its cell-permeable β-lactone form, later designated omuralide by Prof. E. J. Corey, which are structurally different from the synthetic peptide aldehydes, are much more specific proteasome inhibitors. The demonstration of this lactacystin action gave decisive understanding of proteasome as a novel threonine protease. Since then, specific inhibitors have allowed researchers to simplify studies of proteasome functions, leading to many unexpected findings about the importance of the ubiquitin-proteasome pathway in various cellular processes, such as cell cycle, apoptosis, antigen presentation and the degradation of regulatory or membrane proteins. In this review, potential biomedical applications are also described.
Key words--lactacystin; proteasome; inhibitor; threonine protease; omuralide; microbial metabolite
YAKUGAKU ZASSHI, 120(10),951-958, 2000
This review article covers our research activities over 30 years in organofluorine chemistry. The followings are briefly summarized researches in this memorandum: (1) Trifluoromethylation of organic halides with trifluoromethyl copper complex and its application to trifluoromethylated nucleosides, (2) a systematic study on reactivity of aromatic trifluoromethyl compounds, (3) valence bond isomers of aromatic compounds stabilized by the trifluoromethyl groups, and (4) synthesis of fluorinated bioactive compounds which involve vitamin D3, arachidonic acid and its metabolites, and retinal.
Key words--trifluoromethyl; valence bond isomer; vitamin D; retinal; leukotriene B4
YAKUGAKU ZASSHI, 120(10),959-967, 2000
The leaves of a tropical plant, Mitragyna speciosa KORTH. (Rubiaceae), have been traditionally used as a substitute for opium. By phytochemical studies on the constituents of the plant growing in Thailand as well as in Malaysia, several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids including new natural products were isolated. The structures of these new compounds were elucidated by the modern spectroscopic methods and/or chiral-total syntheses. The chiral total synthesis of (−)-mitragynine, a major component of this plant, was achieved. Potent opioid agonistic properties of mitragynine, which acts on μ- and δ-opioid subtype receptors, and of mitragynine pseudoindoxyl, whose analgesic activity is more potent than that of morphine, were clarified in in vitro experiments. The essential structural features in mitragynine for revealing the analgesic activity were elucidated by pharmacological evaluation of the natural and synthetic mitragynine derivatives.
Key words--Mitragyna speciosa; indole alkaloid; mitragynine; chiral synthesis; analgesic activity; opioid
YAKUGAKU ZASSHI, 120(10),969-985, 2000
The aim of this paper is to understand why the molecule has its own structure (optimized geometry) which differs from the standard one (norm). Basic strategy to obtain the optimized geometry is to start from the norm. The emphases are 1) a theory predicting polarization exemplified by norbornene HOMO distortion and 2) when we apply any theory of 1), what framework should we use? The latter is very important due to the fact that the optimized geometries of cations and anions differ greatly from the norms. For polarization, we have elaborated “in-bond orbital method.”25) The method is based on the well-known correlation between separated atoms and united atom and able to represent polarization within minimum basis set only by the first-order perturbation theory. For cationic and anionic hydrocarbons, a new method consisting of an assumption and a few recipes is developed. Although the assumption that the framework distortion surpasses the orbital distortion (polarization) is based solely on organic chemist's intuition, this method correctly suggests the structure (framework) to which the in-bond orbital method should be applied. All of the optimized geometries used in this study are obtained by HF/6-31+G*.
Key words--in-bond orbital method; polarization; separated atoms-united atom; perturbation theory
YAKUGAKU ZASSHI, 120(10),987-995, 2000
Cancer is a common life-threatening disease. Prevention and therapy of the disease are the desire of everybody. This paper summarizes our attempt to the tough challenge. Chronologically we began the study of carcinogenesis, and then turned to the research of anticancer agents. Identification of food mutagens was extensively studied. Once they were identified, the mechanism of nucleic acid modifications by these mutagens had been studied. The modification study gave information on the nucleic acid modification by mitomycin and bleomycin.
The structure-activity relationship study of phorbol esters and teleocidines whose tumor promotion is epigenetic, was extensively studied. On the other hand, retinoic acid, a vitamin A metabolite, suppresses the epigenetic tumor promotion. This suggests that an epigenetically active compound rather than a cytotoxic anticancer agent can be used for tumor suppression. In the retinoid research, we found a number of characteristic new active substances which may be of therapeutic use: some of them are in the clinical trial stages in the field of dermatology and cancer. During the chemical study of retinoids, we encountered the retinoic acid receptor, coded by the retinoic acid receptor (RAR) gene which had just reported. Further retinoid research yielded retinoids antagonists, and then RXR(retinoic acid-X-receptor)-agonists and RXR-antagonists. These ligands have a big potential in the therapy of diabetes and obesity.
Key words--mutagen; teleocidin; retinoid; RXR ligand; Am80; HX600
YAKUGAKU ZASSHI, 120(10),997-1005, 2000
Nitrosamines are environmental carcinogens, and their relevance to human cancer is highly suspected. Dialkylnitrosamines require activation through metabolizing enzymes before they become ultimate electrophilic active species. This review summarizes two model systems for metabolic oxidation of dialkylnitrosamines. One system utilizes porphyrin and oxidant as a model for shunt pathway in the metabolizing pathway of cytochrome P450, and the other one utilizes Fenton reagent. Porphyrin and oxidant activated nitrosodialkylamines into direct acting mutagen by releasing aldehydes. During the process the alkylating activity was observed and alcohols are formed from the alkylation of water. Fenton reagent, consisting of iron salt and hydrogen peroxide supplemented with copper salt, activated dialkylnitrosamines into mutagens of a novel type containing an oxadiazine ring as their proposed structures. These works with model systems open a new aspect into the elucidation of the mechanism of xenobiotic metabolism.
Key words--N-Nitrosodialkylamine; cytochrome P450 model; metabolic activation; porphyrin and oxidant; Fenton reagent
YAKUGAKU ZASSHI, 120(10),1007-1016, 2000
Fullerene (C60, C70, etc.) is an effective photosensitizer and its utilization as a pharmacophore for photo-chemotherapy of tumors has received considerable attention. We developed a method to solubilize fullerenes into water with polyvinylpyrrolidone (PVP) as a detergent. By using thus prepared aqueous fullerene solutions, we have clarified a series of biological activities of fullerene under photoirradiation which include DNA-cleavage, hemolysis, mutagenicity, cancer-initiation, and cell-toxicity. A newly synthesized C60 derivative with an acridine moiety as a DNA-chelating function showed much more effective DNA-cleaving activity in the presence of NADH. Visible-light irradiation of PVP-solubilized C60 in water in the presence of NADH as a reductant and molecular oxygen resulted in the formation of O2·−, which was detected by the EPR spin-trapping method. Formation of O2·− was also evidenced by the direct observation of a characteristic signal of O2·− by the use of a low-temperature EPR technique at 77 K. On the other hand, no formation of 1 O2 was observed by the use of TEMP as a 1 O2 trapping agent. No near-IR luminescence of 1 O2 was also observed in the aqueous C60/PVP/O2 system. These results suggest that photoinduced bioactivities of the PVP-solubilized fullerene are caused not by 1O2, but by reduced oxygen species (O2·−, ·OH) which are generated by the electron-transfer reaction of C60·− with molecular oxygen.
Key words--fullerene; biological activity; active oxygen species; photosensitization; DNA-cleavage; hydroxyl radical
YAKUGAKU ZASSHI, 120(10),1017-1023, 2000
Monthly changes of the content-ratio between S-(−)- and R-(+)-hyoscyamine as well as those between S-(−)- and R-(+)-scopolamine in the leaves of Datura metelL. cultivated in the field, were quantitatively analyzed by the use of HPLC with a chiral adsorbent. It was found that S-(−)-isomer was predominant for hyoscyamine and the ratio of R-(+)-isomer gradually increased during the growth, whereas in the case of scopolamine, S-(−)-isomer was the sole one found throughout the cultivation period. The 1H-NMR study in the CD3OD solution has suggested that S-(−)-hyoscyamine (1) and S-(−)-scopolamine (2) take a “face-to-face” conformation between their tropane skeletons and the benzene rings of the tropic acid moieties. In the presence of an equimolar NaOD in the CD3OD solution, the racemization at C-2' of 1 and 2 proceeded more rapidly than the hydrolysis at the tropic acid ester bond, presumably due to the steric hindrance caused by their “face-to-face” conformations. In the D2O and H2O solutions, on the other hand, the racemization and the hydrolysis of 1 proceeded smoothly, while those of 2 did not occur. It has been supposed that these individual reaction manners are ascribable in considerable extent to the different basicity of N atom in each tropane skeleton of 1 and 2 and to stronger intramolecular hydrogen bond occurring between the carbonyl oxygen at C-1' and the hydroxyl group at C-3' in the tropic acid moiety of 1
Key words--optical purity; tropane alkaloid; hyoscyamine; scopolamine; racemization
YAKUGAKU ZASSHI, 120(10),1025-1033, 2000
Matrine and oxymatrine, major components of Sophora flavescens, were confirmed to have a protective effect on restraint and water immersion stress ulcer in mice. Oxymatrine inhibits the formation of some experimental gastric ulcer, pylorus ligation ulcer and indomethacin ulcer, which are considered to relate to acid secretion. Oxymatrine decreases acid secretion in Shay's rats and inhibits gastric motility induced by restraint and water immersion stress when administered intraduodenally. These results suggest that the protective effect of oxymatrine on stress ulcer is possibly due to a decrease of acid secretion and inhibition of gastric motility. In spite of its weak inhibition of gastric acid secretion, intravenous injection of matrine is rather effective for stress ulcer. Matrine exhibits the inhibition of writhing induced by acetic acid, prolongation of sleeping time induced by pentobarbital, hypothermia and inhibition of locomotor activity induced by methamphetamine. Matrine (i.v.) also inhibits gastric motility induced by restraint and water immersion stress. On the other hand, the administration of matrine exhibits clear contraction on the preparation of the fundus strip of rats at high concentration. The contractile response of the fundus strip to matrine is not inhibited by treatment with tetrodotoxin, and is not modified with atropine, while pretreatment of the fundus strip with antihistamine abolished or reduced the contractile response. It can therefore be assumed that the direct action of matrine on the stomach smooth muscle possibly contributes to the mechanism of the matrine induced inhibition of the spontaneous gastric motility and rise in the tone of stomach, and may play an important role in the protection of the restraint and water immersion stress ulcer formetion.
Key words--matrine; oxymatrine; stress ulcer
YAKUGAKU ZASSHI, 120(10),1035-1050, 2000
This review deals with total syntheses of biologically active natural products by the use of metal-mediated coupling reactions as key steps. First, we explored the coupling reactions mediated by samarium (II) diiodide (SmI2), which is a useful versatile one electron reducing reagent. The SmI2-mediated coupling reactions of N,N-dibenzyl-α-bromoamide and N,N-bis(p-methoxyphenyl)-α-bromoamide with carbonyl compounds gave the corresponding β-hydroxyamides, respectively. Then, oxidative treatment of compound 6c with ceric (IV) ammonium nitrate (CAN) gave d,l-myrmicacine (7b). Synthesis of pyrrolizidine alkaloid pyrrolam A (8), which causes damage to fertilized eggs at a low concentration, was accomplished via the SmI2-mediated cyclization between a bromoalkyl and ynamide group. Next, (±)-oxerine (15), a monoterpene alkaloid, was synthesized starting from 3-bromopyridine. The synthesis of (±)-oxerine (15) was also carried out via the SmI2-mediated intramolecular cyclization of γ-ethynyl bromide (40). Next, we focused on the palladium-catalyzed oxidation of alcohol and tried to expand it to the intermolecular cyclization. As a result, treatment of hydroxy-enamines and hydroxy-amines with a palladium catalyst gave the corresponding pyrroles and indoles in moderate to good yields. Finally, the syntheses of three pyrrolidine alkaloids were described. The chromium (II) chloride-mediated coupling reactions of (R)- and (S)-Garner aldehydes (56 and 57) with allyl bromides proceeded with moderate stereoselectivity to afford the corresponding homoallyl alcohols, which were converted to (2R, 3S)-2-hydroxymethyl-3-hydroxypyrrolidine (61), (2R, 3R, 4R)-3-hydroxy-4-methylproline (66), and the enantiomer (77) of (−)-bulgecinine (78).
Key words--total synthesis; metal-mediated reaction; samarium (II) diiodide; palladium catalyst; chromium (II) chloride
YAKUGAKU ZASSHI, 120(10),1051-1060, 2000
A high performance liquid chromatography (HPLC) method has been developed for the simultaneous determination of theophylline and its metabolites, with caffeine and its metabolites. The method is simple and applicable to planning the administration of theophylline. We used a column-switching system in combination with atmospheric pressure chemical ionization liquid chromatography-mass spectrometry (LC-APCI-MS) for the determination of theophylline and its metabolites in biological samples. In the mass spectrum, the molecular ions of these drugs and metabolites were clearly observed as base peaks. The method is sufficiently sensitive and accurate for the pharmacokinetic studies of these drugs.
Key words--HPLC; LC/MS; theophylline; caffeine; metabolite; column-switching system
YAKUGAKU ZASSHI, 120(10),1061-1073, 2000
Hypervalent iodine (III) reagents nowadays are used extensively in the field of organic chemistry. Especially, phenyliodine (III) diacetate (PIDA) or phenyliodine (III) bis(trifluoroacetate) (PIFA) have received much attention because of their reactivities similar to heavy metal reagents or anodic oxidation, low toxicity, ready availability and easy handling. In the continuous study of our oxidative phenolic coupling reactions using a hypervalent iodine (III) reagents, a versatile synthetic procedure for the galanthamine-type Amaryllidaceae alkaloids was accomplished. The first total synthesis of (±)-sanguinine and the total syntheses of (±)-galanthamine, (±)-narwedine, (±)-lycoramine, and (±)-norgalanthamine were also successfully carried out.
Key words--hypervalent iodine (III) reagent; phenolic coupling reactions; galanthamine-type Amaryllidaceae alkaloids; (±)-galanthamine; (±)-narwedine; (±)-sanguinine