Three isoflavanones with cannabinoid-like moieties from Desmodium canum.

Three further derivatives of 5,7,2',4'-tetrahydroxy-6-methyl isoflavanone have been isolated from the root extract of Desmodium canum and assigned the structures 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(1a,2,3,3a,8b,8c-hexahydro-6-hydroxy-1,1,3a-trimethyl-1H-4-oxabenzo[f]cyclobut[c,d]inden-7-yl)-4H-1-benzopyran-4-one (1) 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(6a,7,8,10a-tetrahydro-3-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-2-yl)-4H-1-benzopyran-4-one (2) 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(3-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-2-yl) 4H-1-benzopyran-4-one (3). The three compounds and the previously isolated chromene 4 all derive from the geranylated precursor 5 by a series of cannabinoid-like oxidative rearrangements.

Synthesis and stereochemical characterization of diastereomeric nucleoside-phosphorothioselenoates by NMR methods.

Synthesis and stereochemical characterization of enantiomerically pure nucleoside-phosphorothioselenoates are reported. The effects of solvent and temperature on the vicinal carbon-phosphorus couplings are described and the results are interpreted in terms of conformational changes influenced by stacking interactions between the bases and the phenyl rings.

Conformational search of antisense nucleotides.

A preliminary MMFF implementation of selenium atom parameters necessary to model the nucleoside 1 is reported. X-ray structures of two compounds 1 and 2 have been used as references. Ab initio methods have been adopted for checking torsional energy profile and charge distribution. Monte Carlo calculations and energy minimization in solvation complete the conformational search.

Conformational properties of diastereomeric 5'-O-DMT-2'deoxythymidine 3'-O-(S-methyl-methanephosphonothiolate)s and -(se-methyl-methanephosphonoselenolate)s in solution as studied by NMR methods

Stereochemical characterization of diastereomerically pure 5'-O-DMT-2'deoxythymidine 3'-O-(S-methyl-methanephosphonothiolate)s and -(Se-methyl-methane-phosphono-selenolate)s by NMR methods are reported. (1)H-(1)H, (1)H-(31)P, and (13)C-(31)P coupling constants and nuclear overhauser enhancement (NOE) connectivities from transverse cross-relaxation experiments in rotating frame (T-ROESY) were measured to correlate the conformational properties of the isomers with the absolute configurations at the phosphorus obtained from X-ray studies of the relatives of S(p) configured isomers. Conformational differences between the stereoisomers were found to be restricted to the different orientation of the C3'-O3'-P bond. The NMR data reflected the preferred epsilon(-) conformation for the S(p) isomers, while in the R(p) isomers the conformational equilibrium was shifted toward the epsilon(t) domain. These results also indicated that for 5'-protected mononucleotides the absolute configuration at the phosphorus atom can be inferred from the NOE experiments and the trends observed in vicinal carbon-phosphorus coupling constants. Copyright 2000 Wiley-Liss, Inc.

Synthesis and NMR characterization of diastereomeric CPSMeG derivatives.

Synthesis and stereochemical characterization of enantiomerically pure CPSMeG derivatives by NMR methods are reported. The effect of 5'-dimethoxytrityl on the conformational properties is described. It was found that in P-diastereomers the conformational differences about the C3'-O3' bond, as discernible from the delta J values, are enhanced by the presence of this protecting group.

An economic synthesis of 1,2,3,4-tetra-O-acetyl-5-thio-D-xylopyranose and its transformation into 4-substituted-phenyl 1,5-dithio-D- xylopyranosides possessing antithrombotic activity.

D-Xylose was converted via 1,2-O-isopropylidene-alpha-D-xylofuranose (4) into 3-O-benzoyl-5-S-benzoyl-1,2-O-isopropylidene-alpha-D-xylofuranose which, after methanolysis, acetylation and subsequent acetolysis afforded 1,2,3,4-tetra-O-acetyl-5-thio-alpha-D-xylopyranose (14) in an overall yield of 36%. Reaction of 4 with thionyl chloride gave a mixture of the diastereomeric cyclic sulfites, the structures of which were established by X-ray crystallography. Their oxidation with sodium periodate afforded the corresponding cyclic sulfate 23. Treatment of 23 with potassium thioacetate gave the potassium salt of 5-S-acetyl-1,2-O-isopropylidene-alpha-D-xylofuranose 3-O-sulfonic acid (26) which, after methanolysis, acetylation and subsequent acetolysis afforded 14 in an overall yield of 56%. Treatment of 4 with sulfuryl chloride gave a mixture containing 5-chloro-3-O-chlorosulfonyl-5-deoxy-1,2-O-isopropylidene-alpha-D- xylofuranose, 3,7,9,11-tetraoxa-4-thia-10-dimethyl-tricyclo[6,3,0, 0(2,6)]undecane S-dioxide and 23 in a 2:3:7 ratio. Tetraacetate 14 was converted into the alpha-1-bromide 18 as well as into the alpha-1-O-trichloroacetimidate 17. These three compounds were used as donors for the glycosylation with 4-cyanothiophenol, affording the 4-cyanophenyl 2,3,4-tri-O-acetyl-1,5-dithio-alpha- (29) and beta-D-xylopyranoside (30) in different ratios, depending on the reaction conditions. When donor 18 was used in the presence of potassium carbonate, besides 29 and 30 two aryl C-glycosylated-thioglycosides, i.e. 4-cyano-2-(2,3,4-tri-O-acetyl-5-thio-beta-D-xylopyranosyl)phenyl 2,3,4-tri-O-acetyl-1,5-dithio-alpha- and beta-D-xylopyranoside (32 and 33) as well as 4-cyano-2-(2,3,4-tri-O-acetyl-5-thio-beta-D-xylopyranosyl)phenyl disulfide 34 could be isolated as byproducts. Deacetylation of 30 with sodium methoxide in methanol afforded, besides 4-cyano-phenyl 1,5-dithio-beta-D-xylopyranoside (1), the corresponding 4-[(methoxy)(imino)methyl]phenyl glycoside 2. The 4-cyano group of 1 was converted into the 4-aminothiocarbonyl, the 4-(methyl-thio)(imino)methyl, the 4-amidino and the 4-(imino)(hydrazino)methyl group. All of these glycosides showed a significant antithrombotic activity on rats.

Triterpenoid saponins from Spergularia ramosa.

Six new oleanene glycosides were isolated from the MeOH extract of the aerial parts of Spergularia ramosa. They possess gypsogenin or quillaic acid as the aglycons. The disaccharide moiety linked to C-3 of the aglycons is made up of galactose (or glucose) and glucuronic acid (or glucose); the pentasaccharide moiety linked to C-28 is made up of glucose (or galactose), xylose, rhamnose, fucose, and arabinose. Their structures were elucidated by 1D and 2D NMR experiments including 1H-1H (DQF-COSY, 1D TOCSY, 2D HOHAHA, ROESY) and 1H-13C (HSQC, HMBC) spectroscopy.

Chemistry of indoles carrying a basic function, Part 3. Synthesis of spiro[cyclopropane-1,3'[3H]indol]-2'(1'H)-ones with antihypoxic effects.

Hydroxyindolones (1-6, 15-16) were transformed into isatinylidenes (7, 9-13, 17-19) by dehydration with 4-toluenesulfonic acid. The dimer-type compounds (14, 20) were also isolated in a few cases. The obtained isatinylidenes were transformed into 3-spiro-cyclopropane-oxindoles (21-32) with dimethyloxosulfonium methylide. Compound 22 shows protective effects against hypobaric hypoxia and triethyltin induced brain edema.

Synthesis of 6-deoxy-5-thio-D-glucose.

Three routes were investigated for the conversion of D-glucose into the title compound. In the first approach, reduction of the 5,6-thiirane ring of 5,6-dideoxy-5, 6-epithio-1,2-O-isopropylidene-alpha-D-glucofuranose (17) as well as that of its 3-O-allyl derivative (13) with lithium aluminium hydride was investigated; 17 afforded the corresponding 6-deoxy derivative besides di-, tri-, and poly-mers, whereas only polymers were formed from 13. In the second approach, the oxirane ring of 3-O-allyl-5,6-anhydro-1,2-O-isopropylidene-beta-L-idofuranose was reduced by sodium borohydride and the resulting 6-deoxy derivative was converted into the 5-thiobenzoate; the corresponding hex-4-enofuranose was formed as a byproduct. In the third approach partial mesylation of methyl 5-thio-alpha-D-glucopyranoside was attempted, but the 6-mesylate 27 could be isolated only in modest yield (28%) together with rearranged 2,5-thioanhydromannofuranoside derivatives. The mechanism of this rearrangement is discussed in detail. The 6-mesylate 27 was converted via the 6-iodo derivative into the title compound.

Synthesis, anti-GABA activity and preferred conformation of bicuculline and norbicuculline enantiomers.

Synthesis of erythro-(±)-[1SR,9RS]-norbicuculline and threo-(±)-[1SR,9SR]-noradlumidine from piperonal was performed using Bischler-Napieralski cyclization as a key step. Resolution gave rise to (+)-[1S,9R]-norbicuculline ([1S,9R] norBIC) and (-)-[1R,9S]-norbicuculline ([1R,9S] norBIC) in >99.5% enantiomeric purity. Bicuculline enantiomers were readily obtained by methylation of the latter products. [1S,9R]BIC was about 70 times more potent than [1R,9S] BIC as an inhbitor of GABA(A) receptor binding and was about 100 and 900 times more potent than [1S,9R] norBIC at pH 7.1 and 5.0 respectively. Similarly, [1S,9R] norBIC was much less potent than [1S,9R] BIC as an inhibitor of GABA-specific (36)Cl(-) ion flux. The observed increase of about two orders of magnitude in the in vitro biological activity caused by N2-CH(3) substitution in [1S,9R] norBIC was attributed to different conformations for erythro- and nor-erythro-bicucullines indicated by (1)H nuclear Overhauser enhancements of [1S,9R] BIC and [1S,9R] norBIC.

cis-trans-isomerization of [E]-5-(2-bromovinyl)-2,2'-anhydrouridine in vivo in rats.

1. [E]-5-(2-bromovinyl)-2,2'-anhydrouridine [( E]BVANUR) has considerable antiviral activity against herpes simplex virus type 1 (HSV-1). 2. [E]BVANUR is not a substrate of pyrimidine nucleoside phosphorylases, but it is an inhibitor of uridine phosphorylase (Ki = 450 nM). 3. [E]BVANUR (trans-isomer, parent compound) undergoes isomerization to [Z]BVANUR (cis-isomer), the only metabolite in rat, which was identified by h.p.l.c., mass spectra and n.m.r. spectroscopy. 4. Absorption of the drug from the gastrointestinal tract after oral administration is minimal. Absorption of [E]BVANUR from the abdominal cavity after i.p. administration was slow.

New polyhydroxylated triterpenes from Uncaria tomentosa.

Three novel polyhydroxylated triterpenes have been isolated from Uncaria tomentosa. Their structures were established as 1, 2, and 3 by detailed spectral studies including 1H-13C correlations via long range couplings using the INAPT pulse sequence, nOeds, and 2D 1H-13C direct chemical shift correlation (HETCOR) nmr techniques.

Identification of in vitro metabolites of 3-ethyl-2,6-dimethyl-4H-pyrido(1,2a)pyrimidin-4-one.

(2-14C)3-Ethyl-2,6-dimethyl-4H-pyrido(1,2a)pyrimidin-4-one is metabolized in vitro by liver microsomes to at least 12 metabolites. The metabolites were isolated and purified by thin-layer chromatography and high-performance liquid chromatography and identified by mass spectrometry and nuclear magnetic resonance spectroscopy. The mostly mono- and dihydroxylated isomers were distinguished on the bases of their electron ionization mass spectra and the metastable daughter ion spectra of selected ions.

Metabolism of mesocarb in the rat.

1. Rats treated orally with [14C]mesocarb (I; 3-(1-methyl-2-phenyl[2-(14C]ethyl)-N-(phenylaminocarbonyl)sydnone imine) (50 mg/kg) excrete 35% of the radioactivity in 24 h urine and 51% in 48 h urine. 2. Only traces of unchanged drug were found in urine. Hydroxy-mesocarb (II), dihydroxy-mesocarb (III), amphetamine (VII) and the conjugates of II and III account for 86% of the urinary radioactivity. 3. Cannulated male rats excrete about 40% of the radioactivity in 30 h in bile, mainly as conjugates of II and III.