On the basis of the utilization of active forms (cyclic thioimidates I, ketene-S, N-acetals II, and metalloenamines III) derived from the thioamide groups, synthetic approach to pharmacologically active heterocycles is described. The cyclic thioimidates I were used as important synthetic blocks for the synthesis of nitrogen heterocycles such as diazasteroids, β-lactams, pyrrolizidines, indolizidines, and quinolizidines. The ketene-S, N-acetals II are regarded as interesting enamines and used as synthetic intermediates for many kinds of nitogen- and oxygen heterocycles. Reaction of the metalloenamines III with electrophiles gave attractive building blocks, which were after elaboration, converted into potentially pharmacologically active heterocycles such as thiophenes and prolines.
Ciguatoxin (CTX), the principal toxin in ciguateric fish, produced a marked potentiation of contractile responses to agonists in the vas deferens. CTX markedly elevated the Na content of the vas deferens treated with ouabain. These effects of CTX were abolished by tetrodotoxin. These data suggest that CTX causes an increasing Na+ permeability across Na channels of smooth muscle cells, and this may play an important role in its mechanism of potentiation. We have shown for the first time that maitotoxin (MTX), the most potent marine toxin known from ciguateric fish, produces a Ca2+-dependent release of norepinephrine (NE) from a rat pheochromocytoma cell line, PC12 or adrenergic nerve terminals of the vas deferens and Ca2+-dependent contraction of smooth or cardiac muscle. These effects of MTX may be due to an increase in Ca2+ permeability which possibly occurred through Ca channels in muscle and nerve membranes. MTX has been widely used as a valuable tool, since Ca2+ plays an important role in the regulation of many cellular functions. We have isolated geographutoxin II (GTX II) from the venom extract of Conus geographus. Our pharmacological and electrophysiological results show that GTX II has the novel action of blocking skeletal muscle Na channels without effect on nerve Na channels. GTX II inhibited [3H] saxitoxin binding to Na channels of skeletal muscles but not of nerves. These results indicate that GTX II is the first to discriminate between the tetrodotoxin/saxitoxin receptor site on nerve and muscle Na channels. Anthopleurin-B (AP-B), a cardiotonic polypeptide isolated from Anthopleura xanthogramica, caused powerful excitatory and inhibitory actions in the ileum, taenia caeci and vas deferens. The AP-B-induced contractions of intestinal smooth muscles are due to the excitation of cholinergic nerves, while that of the vas deferens is caused by the NE release from adrenergic nerve endings. The AP-B-induced relaxation of the taenia caeci is due to the excitation of adrenergic nerves, while the relaxation of the ileum is mediated through non-adrenergic inhibitory mechanisms. Palytoxin (PTX) caused a first rapid contraction followed by the slow phasic contraction of the vas deferens. Our results reveal that the first component is the result of a direct action of PTX on smooth muscle site, whereas the second phase is the result of an indirect action mediated through the NE release from adrenergic nerve endings. Na+, K+-adenosine triphosphatase may be involved in the promotion of the first contraction of PTX. AP-B and PTX provide useful probes to study the neurotransmitter release.
Mukagolactone (I) and monachosoring A (II), B (III) and C (IV), previously isolated from Monachosorum arakii TAGAWA, were also found in Dennstaedtia scandens MOORE and three other Monachosorum species (M. henryi CHRIST, M. flagellare HAYATA and M. maximowiczii HAYATA). From the frond of M.flagellare, a dimeric dinorsesquiterpene, methyl monachosorin A (V), was newly isolated and the structure determined by spectroscopic and chemical methods. These experiments suggested a close affinity between D. scandens and the genus, Monachosorum, and further support the Holttum's view (1947), that Monachosorum was preferred to be included in the Dennstaedtioideae. However, the assignment of this genus as a member of Aspidioid was also phytochemically supported in the preceding paper. Therefore, Monachosorum is related on the one hand to Dennstaedtioideae (sensu Holttumi) and on the other Aspidioideae (sensu Holttumi). The phylogenical position of this genus is maintained by these chemical data and also botanical characters.
From the fronds of Macrothelypteris torresiana CHING var. calvata HOLTT. (=M. oligophlebia CHING), two new coumarins were isolated together with maltol, maltol 3-O-β-D-glucoside, kaempferol, rutin and kaempferol 3-O-β-rutinoside. The structures of the new compounds were established as 7-hydroxy-4-isopropyl-6-methylcoumarin (I) and 7-hydroxy-4-isopropyl-3-methoxy-6-methylcoumarin (II) by the chemical and spectroscopic methods.
In order to characterize the chemical change of the constituents of various Ginseng Radices which may occur during their processings, the chemical constituents of Ginseng Radix (white ginseng) and Ginseng Radix Rubra (red ginseng), which were prepared by processing the same Panax ginseng root, have been investigated in comparison with the constituents of the fresh root of Panax ginseng. It has been found that fresh ginseng root and red ginseng contain glycero-galactolipid (6) and steryl glucoside fatty acid ester (7) while white ginseng lacks 6 but contains 7 in less quantity. Gas chromatography-mass spectrometry reconstructed ion current (RIC) chromatography of the acetylene-alcohol constituents has confirmed that fresh ginseng root and white ginseng contain panaxynol (1) and panaxydol (2) while red ginseng contains, in addition to 1 and 2, heptadec-1-ene-4, 6-diyne-3, 9-diol (3) and panaxytriol (4). It has also been shown that aqueous hydrochloric acid treatment of 2 provides 4 and a new chlorine-containing acetylene 5. Comparison of total triterpene-oligosides by making use of a thin layer chromatography-chromatoscanner, has confirmed that 1) demalonylation of malonyl-ginsenosides in fresh ginseng root, 2) elimination of the glycosyl residue at C-20 of the aglycone moieties in ginsenosides, and 3) isomerization of the hydroxyl configuration at C-20 of the aglycones, may occur during the processing for preparing red ginseng and provide ginsenosides characteristic of red ginseng.
Supercritical fluid extraction was applied to the pigments of Lithospermum root and those of licorice root. Shikonin derivatives, the red pigments of Lithospermum root, were effectively extracted with supercritical carbon dioxide without using entrainer. Application of entrainer (ethanol or water) reduced efficiency in this extraction. The amounts of the substances which are immobile on TLC and regarded as oxidized products of shikonin derivatives, were significantly smaller than that obtained by the ordinary extraction with organic solvent (ether) when extracted with supercritical fluid without using entrainer, indicating an advantage of the latter extraction. Liquiritigenin of Sipei licorice (licorice root from the nor thwest region of China) and Tongpei licorice (licorice root from the northeast region of China), was extracted with supercritical carbon dioxide in the presence of the entrainer (5% ethanol). However, isoliquiritigenin possessing three phenolic hydroxyl groups was not extracted with supercritical fluid with or without entrainers (water and ethanol). Licochalcone A was extracted from Sinkiang licorice (licorice root from Sinkiang region of China), with carbon dioxide only, but the extraction of licochalcone B required addition of ethanol as entrainer.
Effect of oral administration of nineteen kinds of the Chinese medicines on the toxic side effect of cis-diamminedichloroplatinum (cisplatin ; cis-DDP) was examined by using ICR mice. Significant depression of the lethal toxicity and the renal toxicity (indicated by an increase in blood urea nitrogen value) of cis-DDP (45 μmol/kg ; s.c.) was observed in the mice treated with Ginseng and Tang-kuei Ten Combination, Coptis and Rhubarb Combination or Licorice Combination. In mice inoculated i.p. with Ehrlich ascites tumor cells, Ginseng and Tang-kuei Ten Combination, Coptis and Rhubarb Combination and Licorice Combination did not reduce the antitumor effect of cis-DDP. Daily consecutive oral administration of Ginseng and Tang-kuei Ten Combination at a dosage of 50 mg/kg/d completely inhibited the lethal toxicity of cis-DDP. This dosage of the medicine (50 mg/kg/d) is similar to that used in clinical treatment of adult patients. However, the effective doses of Coptis and Rhubarb Combination and Licorice Combination to reduce the toxicity of cis-DDP were about six times higher than those for clinical use. These results suggest that Ginseng and Tang-kuei Ten Combination is the most useful supporting drug for prevention of the toxic side effects of cis-DDP.
TJN-101 is one of the lignan components isolated from Schisandra fruits. Influences of resolvents, Tween 80 and sodium carboxymethyl cellulose (CMC-Na), on the antihepatotoxic action of TJN-101 were investigated in rats with acute liver injury caused by carbon tetrachloride (CCl4) 1 ml/kg, i.p., D-galactosamine 1.5 g/kg, i.p. or allyl alcohol 50 μl/kg, i.p. The characteristic histological changes, an increase in liver weight and marked elevation of plasma transaminase activities were observed after the injection of each hepatotoxic chemical. And resolvents showed a difference more or less on the changes of histological findings and plasma transaminase activities in every liver injury. 1. TJN-101, at 30-100 mg/kg, p.o. in each suspension, suppressed the elevation of plasma transaminase activities, prolongation of prothrombin time and histological changes such as necrosis and fatty deposition in CCl4-caused liver injury. 2. TJN-101 suppressed the elevation of plasma transaminase activities at 30-100 mg/kg, p.o. in each suspension and histologically the appearance of necrosis at 100 mg/kg in CMC-Na suspension in D-galactosamine-caused liver injury. 3. TJN-101, at 100 mg/kg, p.o. in each suspension, suppressed the elevation of plasma transaminase activities and histological changes such as necrosis and inflammatory cell infiltration in allyl alcohol-caused liver injury. 4. TJN-101, at 10-7-10-4 g/ml (in vitro), hardly gave any changes on serum transaminase activities in normal rats. From these results, it was confirmed that TJN-101 shows an antihepatotoxic action independently from resolvents and has directly no effects on transaminase activities in the blood.
A new spiro biflavonoid, genkwanol A (4) was isolated from the root of Daphne genkwa SIEB. et ZUCC. (Thymelaeaceae), as well as daphnodorin B (2), umbelliferone, daphnoretin, daphnin, syringin and yuenkwanin. The structure of 4 was established by chemical transformation of 4 into 2 with dil. HCl in MeOH, and spectroscopic means (circular dichroism, mass and nuclear magnetic resonance).