Immunoregulatory circuits and potential treatment of connective tissue diseases

Thirteen new (1-13) and seven known (14-20) steroid glycosides were isolated from Henricia downeyae, collected from the offshore waters of the northern Gulf of Mexico. Ethanolic extracts of these starfish caused growth inhibition in bacteria and fungi, potent antifouling activity against barnacle and bryozoan larvae, and feeding deterrent activity against a marine fish. The known compounds are typical glycosides found in several species of the family Echinasteridae, i.e., Echinaster sp. and Henricia laeviuscola. One of the new compounds belongs to this group, whereas the remaining 12 new compounds represent a novel series of steroid glycosides which have aglycons with structural similarities to the "asterosaponins". They possess a delta 9(11) 3 beta, 6 alpha-dihydroxysteroidal aglycon with 23-oxo or 22,23-epoxy functionalities and often a 20-hydroxyl group in the side chain. The sulfate is located at C-6 and the saccharide moiety at C-3, in contrast with the asterosaponins which have the sulfate at C-3 and the oligosaccaride moiety at C-6. All the new compounds contain a glucuronic acid unit, which is uncommon among steroid glycosides from echinoderms. The structures of the new compounds, isolated in amounts ranging from 3.4 to 0.9 mg, were determined by interpretation of their spectral data and by comparison with spectral data of known compounds.     

Pregnane glycosides, gymnepregosides A-F from the roots of Gymnema alternifolium

The structural elucidation of six new related polyoxypregnane glycosides, gymnepregosides A (1), B (2), C (3), D (4), E (5) and F (6), together with two known compounds, from the roots of Gymnema alternifolium (Asclepiadaceae) was achieved through on a detailed study of 1H- and 13C-NMR spectral data and chemical means. The results obtained for new compounds, 1-6, show that they are (20S)-pregn-6-ene-3 beta,5 alpha,8 beta,12 beta,14 beta,17 beta,20-heptaol or sarcostin 3-O-glycosides, and all the sugars at C-3 are beta(1-->4)-linked. Some of them possessed benzoyl, cinnamoyl and tigloyl residues as the ester linkages located at C-12 and/or C-20 of the aglycon.     

Steroids as Sewage Specific Indicators in New York Bight sediments

Sediments of the New York Bight were examined for steroidal compounds and found to contain relatively large amounts of coprostanol and 24 beta-ethyl coprostanol. These steroids were found to be derived from sewage, and it is suggested that they be used as sewage tracers in marine sediments.     

Relative binding affinity of androstane and C-19-nor-androstane-steroids for the estradiol-receptor in human myometrial and mammary cancer tissue

The relative binding affinity of several androstane- and C-19-nor-androstane-compounds for the estradiol (E2)-receptor in human myometrial and mammary cancer tissue was studied. High speed cytosol was incubated with tritiated E2 alone as well as in the presence of increasing amounts of the compound to be tested. The highest affinity is found for steroids with two hydroxyl-groups at C-3 and C-17 in the beta-position and a double bond at C-4-5 or C-5-6. Saturation of the A-ring decreases the affinity: 5alpha-compounds have less affinity, 5-beta-compounds have less affinity; 5beta-compounds hardly any affinity. The presence of a hydroxyl-group in the 3alpha, 11beta or 16beta-position decreases the affinity, as dose a 3-oxo or 17-oxo-group. Removal of the C-19-methyl-group facilitates the binding. This data led to the concept that flatness of the A-ring in respect to the B-ring of the steroid molecule is a principal requirement for binding to the E2-receptor. The rank order of RBA is identical in myometrium and in mammary cancer tissue, indicating that estrogen-receptors are at least highly similar in both target tissues.     

Steroidal glycosides from Allium albopilosum and A. ostrowskianum

Chemical studies of the bulbs of Allium albopilosum and A. ostrowskianum have led to the isolation of two new steroidal saponins and four new cholestane glycosides together with several known compounds. The structures of the new compounds were established by the spectroscopic data, hydrolysis and chemical correlations as (25 R and S)-5 alpha-spirostane-2 alpha,3 beta,6 beta-triol 3-O-(O-beta-D-glucopyranosyl-(1-->2)-O-[3-O-acetyl-beta-D-xylopyranosyl- (1-->3)]-O-beta-D-glucopyranosyl-(1-->4)-beta-D-galactopyranoside), (25R)-2-O-[(S)-3-hydroxy-3-methylglutaroyl]-5 alpha-spirostane-2 alpha, 3 beta, 6 beta-triol 3-O-(O-beta-D-glucopyranosyl-(1-->2)-O-[beta-D-xylopyranosyl-(1-->3)]-O- beta-D-glucopyranosyl-(1-->4)-beta-D-galactopyranoside), (22S)-cholest-5-ene-1 beta,3 beta,16 beta,22-tetraol 1-O-alpha-L-rhamnopyranoside 16-O-(O-alpha-L-rhamnopyranosyl-(1-->3)-beta-D-glucopyranoside), 1 beta,3 beta,16 beta-trihydroxycholest-5-en-22-one 1-O-alpha-L-rhamnopyranoside 16-O-(O-alpha-L-rhamnopyranosyl-(1-->3)-beta-D-glucopyranoside), 1 beta,3 beta,16 beta-trihydroxy-5 alpha-cholestan-22-one 1-O-alpha-L-rhamnopyranoside 16-O-(O-alpha-L-rhamnopyranosyl-(1-->3)-beta-D-glucopyranoside) and (22S)-cholest-5-ene-1 beta,3 beta,16 beta,22-tetraol 16-O-(O-beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranoside).     

Transport of tissue inhibitor of metalloproteinases-1 through cartilage: contributions of fluid flow and electrical migration

Besides the known iridoids 6-O-alpha-L-rhamnopyranosylcatalpol (1), 6-O-(3"-O-trans-feruloyl)-alpha-L-rhamnopyranosylcatalpol (14), 6-O-(2"-O-acetyl-3", 4"-O-di-trans-cinnamoyl)-alpha-L-rhamnopyranosylcatalpol (15) and the known phenylpropanoid glycosides verbascoside (acteoside) and martynoside, 12 new acylated iridoid glycosides named gmelinosides A-L (2-13) have been isolated from the leaves of Gmelina arborea. These compounds were structurally characterized using a variety of spectral methods.     

Synthesis of androst-5-en-7-ones and androsta-3,5-dien-7-ones and their related 7-deoxy analogs as conformational and catalytic probes for the active site of aromatase

A series of androst-5-en-7-ones and androsta-3,5-dien-7-ones and their 7-deoxy derivatives, respectively, were synthesized and tested for their abilities to inhibit aromatase in human placental microsomes. All the steroids inhibited the enzyme in a competitive manner with Ki's ranging from 0.058 to 45 microM. The inhibitory activities of 17-oxo compounds were much more potent than those of the corresponding 17 beta-alcohols in each series. Steroids having an oxygen function (hydroxy or carbonyl) at C-19 were less potent inhibitors than the corresponding parent compounds having a 19-methyl group. 3,5-Dien-7-one 24 and its 19-hydroxy and 19-oxo derivatives (12 and 13) as well as 19-oxo-5-en-7-one 3 caused a time-dependent inactivation of aromatase only in the presence of NADPH in which the kinact values of 19-als 3 and 13 (0.143 and 0.189 min-1, respectively) were larger than those of the corresponding 19-methyl (23 and 24) and 19-hydroxy (1 and 12) steroids, respectively. 19-Nor-5-en-7-one 4 but not its 3,5-diene derivative 14 also inactivated the enzyme in a time-dependent manner. In contrast, 7-deoxy steroids 21 and 27, having a 19-methyl group, did not cause it. The inactivations were prevented by the substrate androstenedione, and no significant effects of L-cysteine on the inactivations were observed in each case. The results suggest that oxygenation at C-19 would be at least in part involved in the inactivations caused by the inhibitors 23 and 24. The conjugated enone structures should play a critical role in the inactivation sequences.     

New diterpenoids, isodoternifolins A and B, from Isodon ternifolius

Two new diterpenoids, named isodoternifolin A and B, together with seven known compounds were isolated from the ethanol extract of dried stems and leaves of Isodon ternifolius (D. Don) Kudo. Their structures were determined as 7 beta-hydroxy-6 beta, 11 alpha, 15 beta-triacetoxy-7 alpha, 20-epoxyentkaur-16-ene (1) and 6 beta, 7 beta, 15 beta-trihydroxy-11 alpha-acetoxy-7 alpha, 20-epoxy-entkaur-16-ene (2) by chemical and spectral evidence.     

Four new bioactive polybrominated diphenyl ethers of the sponge Dysidea herbacea from West Sumatra, Indonesia

The marine sponge Dysidea herbacea collected from Indonesia yielded four new polybrominated diphenyl ether congeners 2-5 and the known derivatives 1, 6, and 7. The structures of the new compounds were unambiguously established on the basis of NMR spectroscopic (1H, 13C, COSY, 1H-detected direct and long-range 13C-1H correlations) and mass spectrometric (EIMS) data. All of the compounds were active against the Gram-positive bacteria Bacillus subtilis and the phytopathogenic fungus Cladosporium cucumerinum. The isolated polybrominated compounds were also active in the brine shrimp lethality test. In the latter bioassay, compounds 1 and 6 were the most active with LC50's of 0.96 [SE +/- 0.19] and 0.94 [SE +/- 0.70] microg/mL, respectively.     

Steroidal glycosides of the 14,15-seco-18-nor-pregnane series from Cynanchum ascyrifolium

Three new steroidal glycosides named cynascyrosides A-C were isolated from the roots of Cynanchum ascyrifolium. The structures of these compounds were determined on the basis of spectroscopic and chemical evidence as cynajapogenin A 3-O-alpha-D-oleandropyranosyl-(1-->4)-beta-L-cymaropyranosyl -(1-->4)-beta-D- digitoxopyranoside; cynajapogenin A 3-O-beta-D-glucopyranosyl-(1-->4)-alpha-L-cymaropyranosyl- (1-->4)-beta-L-cymaropyranosyl-(1-->4)-beta-L-cymaropyranoside+ ++; cynajapogenin A 3-O-beta-D-glucopyranosyl-(1-->4)-alpha-L-cymaropyranosyl- (1-->4)-beta-D-digitoxopyranosyl-(1-->4)-beta-L-cymaropyranosid e.     

Three acylated saponins and a related compound from Pithecellobium dulce

Four new oleanane-type triterpene glycosides, pithedulosides H-K (1-4), were isolated from the seeds of Pithecellobium dulce. Their structures were established by extensive NMR experiments and chemical methods. Compounds 1-3 comprised acacic acid as the aglycon and either monoterpene carboxylic acid and its xyloside or monoterpene carboxylic acid as the acyl moiety at C-21. The oligosaccharide moieties linked to C-3 and C-28 were determined as alpha-L-arabinopyranosyl-(1-->2)-alpha-L-arabinopyranosyl-(1 -->6)- [beta-D-glucopyranosyl-(1-->2)]-beta-D-glucopyranosyl and alpha-L-arabinofuranosyl-(1-->4)-[beta-D-glucopyranosyl-(1-->3)]-alpha- rhamnopyranosyl-(1-->2)-beta-D-glucopyranosyl ester, respectively. Compound 4 was established as an echinocystic acid 3-O-glycoside having the same sugar sequences as 1-3. Also obtained in this investigation was the known compound 5, which was identified as echinocystic acid 3-O-beta-D-xylopyranosyl- (1-->2)-alpha-L-arabinopyranosyl-(1-->6)-[beta-D-glucopyranosyl-(1 -->2)]- beta-D-glucopyranoside.     

A reproducible model of middle cerebral artery occlusion in mice: hemodynamic, biochemical, and magnetic resonance imaging

Structural comparisons of meropenem (1), desmethyl meropenem (2) and the penem analogue (3) which contain the same side chains at both C-2 and C-6 were performed using 1H NMR measurements together with 3-21G* level of ab initio MO and molecular mechanics calculations. The ab initio MO calculations reproduced the skeletons of these strained beta-lactam rings in good agreement with the crystallographic data. 1H NMR measurements in aqueous solution together with molecular modeling studies indicated that there were conformational differences of the C-2 and C-6 side chains in this series of compounds. These observations suggested that the conformational differences could affect their biological activities.     

Two novel oleanolic acid saponins having a sialyl Lewis X mimetic structure from Achyranthes fauriei root

Two novel triterpene glycosides, achyranthosides E and F, were isolated as methyl esters from the root of Achyranthes fauriei, an antiinflammatory medicinal plant. Their structures were characterized as oleanolic acid glucuronides having unique substituents composed of C6H9O5 and C9H15O7, respectively, at the C-3 position of glucuronic acid. These compounds are active components which can inhibit the excess recruiting of neutrophiles to injured tissues 1,000 times more potently than sialyl Lewis X.     

Stimulation of the gerbil's gustatory receptors by monosaccharides

The gustatory responses of the Mongolian gerbil were tested with a large number of monosaccharides. Electrophysiological methods were used to record from the chorda tympani nerve. Methyl glycosides which have structural features in common with sucrose are the most effective monosaccharides for eliciting a neural response. Among the monosaccharides tested, efficacy appears to be highest in D-pyranosides having equatorial substituents at the C-2 and C-4 positions and axial substituents at the C-1 position. A C-5 hydroxymethyl group is not required. Similarities in the structural requirements for taste response in the fly and gerbil are discussed.     

Cycloartane triterpene glycosides from the roots of Astragalus brachypterus and Astragalus microcephalus

Three new cycloartane-type triterpene glycosides, brachyosides A (1), B (3), and C (2), from the roots of Astragalus brachypterus and one new glycoside, cyclocephaloside II (4), from the roots of Astragalusmicrocephalus have been isolated together with five known saponins, astragalosides I, II, and IV, cyclocanthoside E, and cycloastragenol. The structures of the new compounds were established as 3-O-[beta-D-xylopyranosyl(1-->3)-beta-D-xylopyranosyl-6-O-beta-D-gluc opyranosyl-3beta,6alpha,16beta,24(S),25-pentahydrox ycycloartane (1), 3-O-beta-D-xylopyranosyl-6-O-beta-D-glucopyranosyl-24-O-beta-D-glucop yranosyl-3beta,6alpha,16beta,24(S),25-pentahydroxyc ycloartane (2), 20(R),24(S)-epoxy-6-O-beta-D-glucopyranosyl-3beta,6alpha,16beta , 25-tetrahydroxycycloartane (3), and 20(R), 24(S)-epoxy-3-O-(4'-O-acetyl)-beta-D-xylopyranosyl-6-O-beta-D-glucopy ranosyl-3beta,6alpha,16beta,25-tetrahydroxycycloart ane (4). For the structure elucidations, 1D- and 2D-NMR experiments and FABMS were used.     

Trans-fused iridoid glycosides from Penstemon mucronatus

Two new trans-fused iridoid glycosides (5 alpha H)-6 alpha-8-epidihydrocornin and (5 alpha H)-6 alpha-8-hydroxy-8-epiloganin, were isolated from Penstemon mucronatus, along with cornin, penstemoside and three hastatosides. The trans-fused iridoids are only the second and third known among over 900 described cis-fused iridoid glycosides. Two pairs of iridoids, identical except for the stereochemistry at C-8, were found. Structures were determined by spectroscopic methods.     

Xanthones from the twigs of Mammea siamensis

1,2-Dimethoxy-5-hydroxyxanthone, a new xanthone, was isolated from the twigs of Mammea siamensis, in addition to six known xanthones (5-hydroxy-1-methoxy-, 1,3-dimethoxy-5-hydroxy-, 2,5-dihydroxy-1-methoxy-, 1,7-dihydroxy-, 1,3,7-trihydroxy- and 3,5-dihydroxy-1-methoxyxanthone). Structures for these compounds were deduced from their spectral data.     

Chemical constituents of original plants of Cimicifugae rhizoma in Chinese medicine

Cimicifugae Rhizoma have been used as an anti-inflammatory, analgesic and antipyretic remedy in the traditional Chinese medicines. Many 9,19-cyclolanostane glycosides have been isolated from Cimicifuga and related genera. Two biogenetically key compounds, acetylshengmanol xyloside and cimicifugoside H-1, were isolated and their chemical structures were elucidated by our group. The former compound seems to be the parent component of the other glycosides such as cimigenol xyloside from C. dahurica, C. iaponica and C. acerina. The latter glycoside, cimicifugoside H-1 was isolated together with cimicifugosides H-2-H-6 from commercial Cimicifugae Rhizoma. They are novel glycosides having a hydroxyl group ay C-11, and cimicifugosides H-3, H-4 and H-6 were trinor-triterpenol glycosides. Cimicifugoside H-1 changed into H-2, H-3 and H-4 under acidic or alkaline conditions. In this review, the structure elucidation of the above glycosides and their chemical transformation into other Cimicifuga glycosides are described.     

Studies on the constituents of the leaves of Phellodendron japonicum Maxim

From the leaves of Phellodendron japonicum Maxim. (Rutaceae), six new flavonoid glycosides (I-VI) were isolated, together with eight known compounds. The structures of I-VI were shown to be 8-prenyl-3,4',5-trihydroxy-flavone 7-O-beta-D-(6-O-malonyl) glucopyranoside, (2R,3R)-8-prenyl-3,4',5-trihydroxyflavanone 7-O-beta-D-(6-O-malonyl) glucopyranoside, 8-[(S)-2,3-dihydroxy-3-methylbutyl]-3,4',5-trihydroxyflavone 7-O-beta-D-glucopyranoside, 8-[(R)-2,3-dihydroxy-3-methylbutyl]-3,4',5-trihydroxyflavone 7-O-beta-D-glucopyranoside (2R,3R)-8-[(S)-2,3-dihydroxy-3-methylbutyl]-3,4',5-trihydroxyflavanon e 7-O-beta-D-glucopyranoside and (2R,3R)-8-[(R)-2,3-dihydroxy-3-methylbutyl]-3,4',5-trihydroxyflavanon e 7-O-beta-D-glucopyranoside, respectively, on the basis of the chemical and spectral data.     

Conversion of a C-20-deoxy-C21, steroid, 5-pregnen-3beta-ol, into testosterone by rat testicular microsomes

5-[7ALPHA-3H] Pregnen-3beta-ol, a C-20-deoxy analog of pregnenolone, was synthesized and tested as a substrate for the enzyme system occurring in testes that cleaves the side chain of C21 steroids between C-17 and C-20. This C-20-deoxy C21 steroid was incubated with a microsomal preparation obtained from rat testis and was converted into testosterone in 5% yield. Another C-20-deoxy analog of pregnenolone, 5,20-pregnadien-3beta-ol, was not converted into testosterone by this enzyme system. The significance of this finding for the natural processes by which pregnenolone is converted by the same subcellular fraction into the male sex hormone is examined in the light of the hypothesis that intermediates involved in steroidogenesis are transient, reactive complexes of the appropriate reactants (steroids, oxygen, etc.) with specific enzymes.