AIDS dementia: synthesis and properties of a derivative of 3'-azido-3'-deoxythymidine (AZT) that may become 'locked' in the central nervous system.

In an attempt to provide a derivative of 3'-azido-3'-deoxythymidine (AZT) which might be sequestered in the central nervous system and release AZT, the dihydropyridine ester 5'-(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)-3'-deoxythymidine, was synthesized in a three step sequence. This material showed potent anti-HIV-1 activity in MT-4 cells most probably by hydrolysis to the parent nucleoside, AZT. This dihydropyridine derivative of AZT could be easily oxidized to a positively charged pyridinium derivative of AZT in rat brain cytosol. In turn the pyridinium form could be hydrolyzed, non-enzymatically, to AZT.

Synthesis and pharmacokinetics of a dihydropyridine chemical delivery system for the antiimmunodeficiency virus agent dideoxycytidine.

In order to explore the possibility that a dihydropyridine/pyridinium redox chemical delivery system might enhance significantly the brain uptake of the anti-HIV agent dideoxycytidine (DDC), we prepared a DDC derivative which bore the 1,4-dihydro-1-methyl-3-pyridylcarbonyl moiety at both the cytidine exocyclic amino moiety and the sugar 5'-hydroxyl function; namely, 5',4N-bis-[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl]-2',3'- dideoxycytidine (2). In cell-free extracts of rat brain tissue, compound 2 was readily converted to free DDC by stepwise oxidation and hydrolysis of the dihydropyridyl groups. Time-dependent plasma and brain concentrations of DDC and 2 were determined following iv administration of 2 (49.3 mg/kg) to rats. Compound 2 could be detected in brain, reaching peak concentrations of 7.7 +/- 2.9 nmol/g at 15 min. Low levels of DDC also were detected with a peak concentration of 1.4 +/- 0.5 nmol/g at 240 min after injection. The brain/plasma concentration integral of compound 2 was 0.95 whereas that for DDC in brain as a ratio of combined DDC and compound 2 levels in plasma was 0.24. Despite this, brain concentrations remained low and not significantly different from those achieved following administration of DDC alone.

Triterpenoidal saponins from Dumasia truncata.

Extraction of the aerial parts of Dumasia truncata Sieb et Zucc. afforded two new triterpenoidal saponins, together with four known ones. The structures of the new compounds were elucidated by spectral analysis as 3-O-alpha-L-rhamnopyranosyl-(1-->3)-beta-D-glucuronopyranosy-28-O- beta-D- glucopyransoyl hederagenin and 3-O-beta-D-xylopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl (1-->3)]-beta-D-glucuronopyranosyl oleanic acid.

Triterpenoidal saponins from Baptisia australis.

Extraction of the roots of Baptisia australis afforded a new triterpenoid saponin, baptisiasaponin I together with kaikasaponin III. The structure of baptisiasaponin I was elucidated as 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-xylopyranosyl- (1-->2)-beta-D-glucuronopyranosyl sophoradiol on the basis of its spectral data and chemical degradation.

Antinociceptive substances from Incarvillea delavayi.

Antinociceptive activities of an Incarvillea delavayi extract, as well as its constituents, 8-epideoxyloganic acid and delavayine A, were evaluated in the acetic acid induced writhing test in mice. An oral administration of the delavayi extract weakly decreased the number of writhings and stretchings in this test, in a dose-dependent manner. Furthermore, orally administered 8-epideoxyloganic acid showed weak antinociceptive activity, whereas administration by subcutaneous injection did not. However, subcutaneous injection of delavayine A, a novel monoterpene alkaloid, showed a more significant level of antinociceptive activity.

Triterpenes from Mucuna birdwoodiana.

Methanolic extracts of the stalks of Mucuna birdwoodiana on acid hydrolysis and subsequent methylation with diazomethane provided four triterpene sapogenols. On the other hand, investigation of glycosides after methylation of the same extract led to the isolation of four triterpene glycosides. On the basis of chemical and spectral evidence, their structures were characterized as methyl asiatate, methyl maslinate, two new sapogenols, methyl 1 beta,2 alpha,3 beta,23-tetrahydroxyolean-12-en 28-oate (mucunagenin a), its urs-12-en isomer (mucunagenin b), 3-O-(6-O-methyl-beta-D-glucuronopyranosyl) methyl asiatate 3-O-[alpha-L-arabinopyranosyl(1----2)]-6-O-methyl-beta-D-glucur onopyranosyl methyl maslinate, 3-O-[alpha-L-arabinopyranosyl(1----2)]-6-O-methyl-beta-D-glucur onopyranosyl methyl asiatate and 3-O-(6-O-methyl-beta-D-glucuronopyranosyl) asiatic acid 28-O-beta-D-glucopyranoside.

Pharmacological studies on Puerariae flos III: protective effects of kakkalide on ethanol-induced lethality and acute hepatic injury in mice.

Kakkalide, one of the major isoflavonoid components of Puerariae flos, has been investigated for its effect on ethanol-induced intoxication and on hepatic injury, including hyperglycaemia, in mice. Kakkalide reduced mortality associated with administration of ethanol. At doses of 100 and 200 mg kg-1 the effect of kakkalide was significant. The same dose of kakkalide prevented increased serum glutamic oxaloacetic transaminase and glutamic pyruvic transaminase activity. At a dose of 200 mg kg-1 it also counteracted ethanol-induced elevation of glucose levels. These results suggest that kakkalide might be useful for counteracting the effects of alcohol and might be effective for treating hepatic injury.

Pharmacological studies on Puerariae Flos. IV: Effects of Pueraria thomsonii dried flower extracts on blood ethanol and acetaldehyde levels in humans.

We investigated the effects of extracts from the dried flower of Pueraria thomsonii on blood ethanol and acetaldehyde levels in humans consuming alcoholic beverages. The extracts of Pueraria thomsonii had no influence on blood ethanol and acetaldehyde concentration in humans. However, the extracts increased the elimination rate constant of blood acetaldehyde, although they had no effect on the elimination of blood ethanol in humans. These results suggest that Pueraria thomsonii promotes the elimination of blood acetaldehyde in humans. The present study clinically suggests that a modest stimulatory effect of Pueraria thomsonii on the elimination of blood acetaldehyde may passively mitigate acetaldehyde toxicity, such as flushing, palpitation, headache, etc., associated with excessive alcohol intake.

[Pharmacological studies on puerariae flos. II. The effects of puerariae flos on alcohol-induced unusual metabolism and experimental liver injury in mice].

The present study was designed to examine the effects of methanolic extract (PE-ME), isoflavonoid fraction (PF-IF), triterpenoid saponin fraction (PF-SP) and N-acyl-N1-glucosyl-tryptophan (PF-P) isolated from puerariae flos on alcohol-induced unusual metabolism (as for glucose (BG), triglyceride (TG), and urea nitrogen (BUN) level in blood) and experimental liver injury (model: CCl4- and high fatty food induced) in mice. These alcohol-induced increasing responses were inhibited by the extracted and refined substances from puerariae flos. In short, PF-ME (4500 mg/kg) and PF-P (400 mg/kg) inhibited an increase in BG level induced by alcohol, whereas PF-IF (1000 mg/kg) and PF-SP (1000 mg/kg) did not. Similary, PF-ME and PF-SP inhibited an increase in TG induced by alcohol, whereas PF-IF did not. In addition, PF-IF and PF-SP inhibited increasing BUN level. Still more, PF-IF and PF-SP significantly inhibited an increase in gulutamate oxalacetate transaminase or gulutamate pyruvate transaminase level induced by high-fatty food and CCl4 in control animals. Especially PF-IF (250 mg/kg) administration showed a remarkable effect (inhibition: 76.3%) in control animals. These results suggested that puerariae flos or its combination drugs may be a useful drug as a traditional medicinal system for counteraction to drinking.

[Pharmacological studies on puerariae flos. I. The effects of puerariae flos on alcoholic metabolism and spontaneous movement in mice].

In the general rule, Puerariae Flos or it's combination drugs are used in traditional medicinal system for counteraction to drinking among Japanese and Chinese therapy. One of such drugs is Kakkakaiseito. Here we report the results of investigation on some pharmacological actions including alcoholic metabolism. The experiments were carried out to confirm its actual effect on alcohol, acetaldehyde and ketone body metabolism in the blood and the alteration of behaviour pattern of mice. Drugs used in this study were methanolic extract (PF-ME), isoflavonoid fraction (PF-IF) and triterpenoid saponin fraction (PF-SP) isolated from Puerariae Flos. Each drug was orally administrated to mice. These results were shown as follows: the concentrations of blood alcohol and acetaldehyde decreased more after the treatment with PF-IF (800 mg/kg) than those of the control group. This fact was evidenced remarkable effects with area under the blood concentration-time curve, mean residence time, and variance residence time and values on the moment analysis. However, a reduction effect was not recognized by the treatment with PF-SP (1000 mg/kg). Moreover, PF-ME and PF-IF suppressed the increment of spontaneous movement induced by alcohol administration, whereas PF-SP did not prevent the decrease in the increment caused by alcohol administration. These results support the basis that Puerariae Flos or its combination drugs is used in a traditional medicinal system for counteraction to drinking. However, further investigation is necessary.

[Phytoestrogens].

Epidemiological studies revealed that foodstuffs, in particular, soy foods containing isoflavonoid phytoestrogens may reduce the risk of some hormone-dependent disease such as not only postmenopausal symptoms but also certain(breast, prostate and colon) cancers and cardiovascular disease. This review introduces the metabolism of soybean isoflavonoids by human intestinal bacteria and the binding and gene-expression activity of the metabolites towards the human estrogen receptor(hER) alpha and beta. The dietary isoflavones(daidzin and genistin) in soybean were metabolized to equol and dihydrogenistein via daidzein and genistein, respectively. The metabolites bind more strongly to hER beta than hER alpha. The binding affinity of genistein is comparable that of 17 beta-estradiol. Equol induces transcription most strongly both with hER beta and hER alpha.

A novel macrocyclic spermine alkaloid from Incarvillea sinensis.

A novel macrocyclic spermine alkaloid incasine C' (1), along with a known compound incasine C (2), were isolated from the whole plants of Incarvillea sinensis, and their structures were elucidated on the basis of chemical and spectroscopic evidence.

Triterpene glycosides from the bark of Robinia pseudo-acacia L. I.

From the bark of Robinia pseudo-acacia L., five new triterpene glycosides, robiniosides A-D (3, 5-7) and compound III (4), were isolated and their structures were elucidated as 3-O-alpha-L-rhamnopyranosyl(1-->2)-beta-D-glucopyranosyl(1-->2)-beta-D- glucuronopyranosyl 3 beta,22 beta-dihydroxyolean-12-en-29-oic acid (3), 3-O-alpha-L-rhamnopyranosyl(1-->2)-beta-D-galactopyranosyl(1-->2)-beta-D -glucuronopyranosyl 3 beta,22 beta,24-trihydroxyolean-12-en-29-oic acid (4), whose sapogenol was unambiguously characterized and designated as oxytrogenin, 3-O-alpha-L-rhamnopyranosyl(1-->2)-beta-D-glucopyranosyl(1-->2)-beta-D glucuronopyranosyl oxytrogen (5), 3-O-alpha-L-rhamnopyranosyl(1-->2)-beta-D galactopyranosyl(1-->2)-beta-D-glucuronopyranosyl oxytrogenin 22-O-alpha-L-rhamnopyranoside (6), 3-O-alpha-L- rhamnopyranosyl(1-->2)-beta-D-glucopyranosyl(1-->2)-beta-D-glucuronop yranosyl oxytrogenin 22-O-alpha-L-rhamnopyranoside (7), respectively, together with two known triterpene glycosides, kaikasaponin III (1) and 3-O-alpha-L-rhamnopyranosyl(1-->2)-beta-D-galactopyranosyl(1-->2)-beta-D - glucuronopyranosyl 3 beta,22 beta-dihydroxyolean-12-en-29-oic acid (2).

An arrhythmic-inducing glycoside from Albizzia julibrissin Durazz, IV.

Three pyridoxine derivatives have been isolated from the fresh stem bark of Albizzia julibrissin DURAZZ.. One of them, named julibrin II, was found to exhibit arrhythmic-inducing action. However, neither the others having the same aglycone nor some glycosides having the same sugar unit showed the action.

Triterpene glycosides from the bark of Robinia pseudo-acacia L. II.

From the bark of Robinia pseudo-acacia L., six new triterpene glycosides, Robiniosides E--J, were isolated and their structures were elucidated as abrisapogenol B 3-O-alpha-L-rhamnopyranosyl(1-->2)-beta-D-galactopyranosyl(1-->2)-beta-D - glucuronopyranoside (1), abrisapogenol B 3-O-alpha-L-rhamnopyranosyl(1-->2)-beta-D- glucopyranosyl(1-->2)-beta-D-glucuronopyranoside (2), 3-O-alpha-L-rhamnopyranosyl(1-->2)-beta-D-galactopyranosyl(1-->2)-beta-D - glucuronopyranosyl abrisapogenol B 22-O-alpha-L-rhamnopyranoside (3), 3-O-alpha-L-rhamnopyranosyl(1-->2)-beta-D- glucopyranosyl(1-->2)-beta-D-glucuronopyranosyl abrisapogenol B 22-O-alpha-L-rhamnopyranoside (4), 3-O-alpha-L- rhamnopyranosyl(1-->2)-beta-D-galactopyranosyl(1-->2)-beta-D-glucuron opyranosyl abrisapogenol E 30-O-beta-D-apiofuranosyl(1-->6)-beta-D-glucopyranoside (5) and 3-O-alpha-L-rhamnopyranosyl(1-->2)-beta-D-glucopyranosyl(1-->2)-beta-D- glucuronopyranosyl abrisapogenol E 30-O-beta-D-apiofuranosyl(1-->6)-beta-D-glucopyranoside (6), respectively.

Two new triterpenoidal glycosides from Medicago polymorpha L.

Two new triterpenoid glycosides called medicago-saponins P1 (1) and P2 (2) were isolated together with five known glycosides from the aerial parts of Medicago polymorpha L. (Leguminosae). The structures of 1 and 2 were determined to be 3-O-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranosyl caulophyllogenin 28-O-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranoside and the desglucoside of 1.

Two novel actinidine-type monoterpene alkaloids from Incarvillea delavayi.

Two new actinidine-type monoterpene alkaloids, delavayines B (1) and C (2), were isolated from the MeOH extract of the aerial parts of Incarvillea delavayi, a close species of which, I. sinensis, is used as an analgesic for rheumatic pain in China, and the structures have been elucidated on the basis of spectroscopic evidence.

Oleanene-type triterpene glycosides from puerariae radix. IV. Six new saponins from Pueraria lobata.

From Puerariae Radix, the root of Pueraria lobata (Leguminosae), six new oleanene-type triterpene glycosides, called kudzusaponins A1 (1), A2 (2), Ar (3), SA4 (5), and SB1 (6) were isolated together with kudzusaponin A3 (7), soyasaponins SA3 (8), and I (9). The structures of 1-6 were determined to be 3-O-alpha-L-rhamnopyranosyl- (1-->2)-beta-D-arabinopyranosyl-(1-->2)beta-D-glucuronopyranosy l kudzusapogenol A 22-O-beta-D-xylopyranoside, 3-O-beta- D-galactopyranosyl-(1-->2)-beta-D-glucuronopyranosyl kudzusapogenol A, 3-O-beta-D-glucopyranosyl-(1-->2)-beta-D-glucuronopyranosyl kudzusapogenol A, 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranosyl-(1-->2)-beta- D-glucoronopyranosyl kudzusapogenol A, 3-O-beta-D-glucuronopyranosyl[(1-->2)-beta-D-glucuronopyranosyl soyasapogenol A22-O-alpha-L-arabinopyranoside,and 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-galactopyranosyl- (1-->2)-beta- D-glucuronopyranosyl (beta-fabatriosyl) soyasapogenol B 22-O-alpha-L-arabinopyranoside, respectively.

DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity of flavonoids obtained from some medicinal plants.

A reactive oxygen species has been implicated in a range of human pathological diseases such as atherosclerosis and certain cancers. Flavonoids are reported to exhibit various biological activities, including antioxidative and free radical scavenging activities. Several flavonoids obtained from barley leaves, soybean and some medicinal plants, Silybum marianum, Sophorae Flos, Cinnamon, Ephedrae Herba and Scutellariae Radix, were tested for their DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity. The structure-activity relationships suggested that not only the numbers of hydroxy group but also the position of hydroxy group might be important for mediating potent activity.