The ultimate synthesis is defined as an ideal one step synthesis satisfying the first to the third element of our synthetic philosophy as shown in Fig. 1. The fourth element is a necessary process for accessing to the ultimate synthesis. One pot synthesis is the second best. In our continuing studies directed toward the ultimate synthesis for ergot alkaloids, simple and practical methods for the preparation of various 4-substituted indoles were elaborated starting from indole-3-carboxaldehyde (1). A common synthetic method, shown in Chart 4, was also elaborated and total syntheses of (±)-6, 7-secoagroclavine, (±)-isochanoclavine-I and II, (±)-norchanoclavine-I, (±)-chanoclavine-I and II, (±)-isochanoclavine-I and II, (±)-agroclavine, (±)-agroclavine-I, and (±)-aurantioclavine were achieved by changing only olefin component at the second step with the same common procedures for other steps. Basic concept of thallation-palladation reaction (in the broad sense) is illustrated and in the process of its generalization, thallation-palladation (in the narrow sense), boronation-thallation, and tin-thall reactions were discovered as desired new cross coupling reactions which work directly at the 4-position of the indole nucleus. By employing tin-thall reaction, 4-(3-pyridyl)indole-3-carboxaldehyde (104) and methyl 5-(3-formylindol-4-yl)nicotinate (120) become readily available in one pot operation from 1.

View full abstract

Four biosynthetic intermediates for non-tryptophan moieties of indole alkaloids, 10-oxogeraniol (27a), 10-hydroxygeranial (27b), 10-oxogeranial (28) and iridodial (3), were isolated from the incubation system of 10-hydroxygeraniol (16) and crude enzyme extracts from Rauwolfia serpentina cell suspension cultures. This finding enabled us to establish the mechanism of iridane skeleton formation from 16 in the biosynthesis of indole alkaloids. Furthermore, a novel type of monoterpene cyclase catalyzing the iridodial (3) formation from 28 in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) was partially purified and characterized. Systematic research has not yet been performed on the biosynthesis of iridolactones. However, feeding experiments of several ³H-labelled putative precursors to Nepeta cataria and Patrinia gibbosa suggested that some of iridolactones in these plants are biosynthesized via somewhat different route from those for the usual iridoids.

View full abstract

Since 1970's we have been investigating marine natural products in search of new bioactive substances. We started chemical studies of saponins characteristically produced by echinoderms such as sea cucumber and starfish, and found that some saponins from sea cucumbers showed significant antifungal activities. Afterwards, our studies have been extended to other marine organisms, and in recent years, our investigations have been focused to survey bioactive constituents from marine sponges and octocorallian corals inhabiting in the Okinawan coral reefs. This article reviews our recent studies on these marine natural products.

View full abstract

From the fronds of Pyrrosia linearfolia (HOOK.) CHING, two new flavanone glycosides, named pyrroside A and B, were isolated. Their structures were determined as 7-O-[β-D-apio-D-furanosyl-(1→6)-β-D-glucopyranosyl]-2R-eriodictyol and 7-O-[β-D-apio-D-furanosyl-(1→6)-β-D-glucopyranosyl]-2R-naringenin, respectively, on the basis of spectral data and chemical reactions. Their yields from the dried fronds were amounted to be 2.5%.

View full abstract

From the Mexican fern, Dennstaedtia distenta MOORE, two new pterosin-type dinorsesquiterpene dimers, I and II(distentoside), were isolated. The structures of I and II were elucidated as 14'-O-methyl monachosorin B and 14'-O-β-D-glucopyranosyl monachosorin B, respectively, by using the spectroscopic and chemical methods. Though American and Asian Dennstaedtia ferns are differentiated by cytology, these chemical data support the close relationship between them.

View full abstract

Fifty-four species of extracts of Chinese herbal medicinal prescription were tested for the inhibitory activity of adenosine 3', 5'-cyclic monophosphate (cAMP) phosphodiesterase."Hange-shashin-to"was especially studied among these prescriptions. The inhibitory activity for this enzyme depended chiefly on Scutellaria root and Glycyrrhiza in this prescription. Ginseng acted as a synergistic component for Scutellaria root and on the other hand, Jujube acted as a mitigatory component for Scutellaria root in cAMP phosphodiesterase inhibition test.

View full abstract

From the mature plants of Artemisia montana ("ezoyomogi" in Japanese), three new sesquiterpene lactones, ezoartemin (I), ezomontanin (II) and 11, 13-dihydroezomontanin (III) were isolated together with the two known sesquiterpene lactones, yomogiartemin and yamayomoginin. The structure of I, II and III were elucidated mainly by high field ¹H-nuclear magnetic resonance spectroscopy.

View full abstract

2-Chloroquinoxaline (I) reacted with NaI, sodium benzenesulfinate, sodium p-toluenesulfinate or KSCN to afford 2-iodoquinoxaline (V), 2-phenylsulfonylquinoxaline (IX), 2-(4-methylphenyl)sulfonylquinoxaline (X) or 2-quinoxalinyl thiocyanate (XVII) in good yield, respectively. Cyano and nitro groups were interduced into 2-position of quinoxaline in low yield by using of KCN and AgNO₂.

View full abstract

Water-soluble, substrate-analogous chymotrypsin inhibitors were synthesized to study the role of chymotrypsin and chymotrypsin-like enzymes in vivo. It was previously reported that the phenyl esters of carboxylic acids containing condensed ring such as tetralin, naphthalene, indole etc. showed potent inhibitory activity against chymotrypsin. In this report, the influence of several substituents on the benzene nucleus of phenyl component upon the inhibitory activity against enzymes was investigated. The esters derived from the phenol containing basic substituents in the 4 position (basic esters) exhibited potent inhibition against chymotrypsin, e.g. the IC₅₀ value of 4-amidinophenyl tetralin-1-carboxylate was 5×10^-7 M. But the activity of the ester obtained from the phenol containing neutral substituent in the 4 position (neutral ester) was weaker than that of the basic esters. The IC₅₀ value of the neutral ester of the corresponding acyl component, 4-(N, N-dimethylcarbamoylmethoxycarbonylmethyl)phenyl tetralin-1-carboxylate was 7×10^-6 M. And the acidic ester with carboxyl group on the benzene nucleus inhibited most weakly of the three, whose IC₅₀ value was 6×10^-5 M. With respect to the influence of these substituents, a similar tendency was observed in other esters derived from benzoic acid, 1-naphthylacetic acid, 3-indolylacetic acid etc. As for the influence of the acyl components on the inhibitory activity against chymotrypsin, the relative order was as follows : 5-methoxy-2-methyl-3-indolylacetyl≥1-naphthylacetyl≥tetralin-1-carbonyl>3-indolylacetyl>benzoyl. 4-(4-Guanidinobenzoyloxy)phenyl esters and 4-amidinophenyl esters inhibited not only chymotrypsin but also trypsin. On the other hand, the others such as 4-(4-isopropylpiperazinocarbonyl)phenyl esters inhibited chymotrypsin specifically.

View full abstract

The methanol (MeOH) extracts from 36 crude drugs or medicinal plants were investigated for their effects on [³H]spiperone-binding to membrane preparation from rat brain. The MeOH extracts of Amsonia elliptica or Corydalis Tubur or Evodia Fructus showed a strong inhibitory effect of [³H]spiperone-binding to D-2 receptors of membrane fraction from rat brain. The activity of MeOH extracts of these drugs transferred to the alkaloid fraction, while main alkaloids of each medicinal plant or crude drug, for example, β-yohimbine, corydaline, evodiamine, synephrine, could not show high actibity, respectively. Thus, these results suggest that inhibition by these medicinal plants may be due to another components in the alkaloid fraction.

View full abstract

A high sensitive method for the determination of isofloxythepin (IFT) in biological fluids by high-performance liquid chromatography (HPLC) with fluorometric detection is described. When IFT was treated with 1-anthroyl (AN) nitrile in the presence of triethylamine at 70°C, the condensation reaction occurred and was completed in 60 min, yielding the AN derivative (IFT-AN). The chromatographic separation of IFT-AN was achieved on YMC-PACK A-302-ODS with 0.2% ammonium bicarbonate-methanol-acetonitrile(1 : 4 : 9) as a mobile phase. A calibration curve was constructed by plotting the ratio of the peak height of IFT to that of internal standard against the amount of IFT, a linear response being observed in the range 0.15-12.89 ng. Clean-up of IFT in the plasma and urine of the dog was efficiently attained by extracting with n-hexane under basic conditions and derivatized with AN nitrile. The resulting product was extracted with hexane-benzene in the presence of acetonitrile under acidic conditions and subjected to HPLC. The quantitation limit of IFT in the canine plasma was estimated to be 0.6 ng/ml. The recovery rates of standard sample added to the canine plasma and urine were found to be 93.9 and 95.9%, respectively.

View full abstract

Highly oxygenated natural sesquiterpene lactones, ezomontanin (I) and 11, 13-dihydro derivative (II) of I having both 1, 4-β-endoperoxide showed potent cytotoxicities against mouse leukemia L-1210/v/c and human carninoma KB cells in vitro. Yomogiartemin (III) having α-methylene-γ-lactone also showed similar activity to I and II. 11, 13-Dihydro derivative (IV) of III showed no cytotoxicities.

View full abstract