The vasorelaxant effect of (±)-15-deoxy-16-hydroxy-16(α/β)-vinyl-prostaglandin E2 (CL 115,129) and its methyl ester (CL 115,347) on the isolated ductus arteriosus preparation

CL 115,129 and its methyl ester, CL 115,347, were studied for their vasorelaxant effects and compared to that of prostaglandin (PG) E₂ and its methyl ester on isolated ductus arteriosus (DA) from fetal lambs and rabbits. CL 115,129 and CL 115,347 potently relaxed the oxygen-indomethacin constricted ductus in a concentration dependent manner. The threshold concentration was 1×10^?13M and the estimated EC₅₀'s (M) were 6.9×10^?8 and 4.3×10^?8, respectively, for CL 115,129 and CL 115,347. Also confirmed was the vasorelaxant ability of PGE₂. These studies indicate that the CL compounds possess potent vasorelaxant effects on the DA although less potent than PGE₂ or its methyl ester.     

The diuretic effects of CL 115,129 (d,1-15-deoxy-16-hydroxy-16(α/β)-vinyl-prostaglandin E2) and ℓ-prostaglandin E2 in dogs

CL 115,129, the corresponding carboxylic acid and major metabolite of CL 115,347 (d,1-15-deoxy-16-hydroxy-16(α/β)-vinyl-prostaglandin E₂ methyl ester), a potent orally and transdermally long acting antihypertensive agent, infused at 0.1 μg/kg/min into the left renal artery of sodium pentobarbital anesthetized beagle dogs increased urinary volume, sodium (Na⁺), potassium (K⁺) and chloride (Cl⁻) excretion of the left kidney 289, 201, 101 and 229%, respectively, over the 30 min vehicle-treated control periods. At 0.3 μg/kg/min CL 115,129 caused a 475 and 336% increase in urinary volume and Na , respectively. ℓ-Prostaglandin E₂ (ℓ-PGE₂) infused at 0.1 μg/kg/min into the left renal artery increased urinary volume, Na⁺, K⁺ and Cl⁻ excretion of the left kidney of anesthetized beagle dogs 416, 234, 112 and 255%, respectively, over the control. Both CL 115,129 and ℓ-PGE₂ did not affect the systemic arterial blood pressure or the electrolyte excretion of the contralateral kidney. It is concluded that in contrast to other conventional vasodilators, which may cause severe water and electrolyte retention, CL 115,347, via its metabolite CL 115,129, may cause diuresis and natriuresis in many clinical settings when used as an antihypertensive.     

Plasma levels of the methyl ester of 15-methyl PGF2α in connection with intravenous and vaginal administration to the human

After intravenous injection of the methyl ester of 15-methyl-PGF_2α the drug initially disappeared faster than the corresponding free acid, but still after one hour, about 1% of the active drug is circulating in plasma. Vaginal administration of single suppositories containing 1 mg of 15-methyl-PGF_2α methyl ester and determination of plasma levels using gas chromatography - mass spectrometry demonstrated that the highest plasma levels were reached after 1.5 - 3 hours.Vaginal suppositories were administered according to different dose schedules for induction of abortion and plasma levels of 15-methyl-PGF_2α and it's ester were determined. There seemed to be a gross correlation between given doses and obtained plasma level. The data will serve as basis for further development of vaginal delivery devices.     

Synthesis of methyl O-(3-deoxy-3-fluoro-β-d-galactopyranosyl)-(1→6)-β-d-galactopyranoside and methyl O-(3-deoxy-3-fluoro-β-d-galactopyranosyl)-(1→6)-O-β-d-galactopyranosyl-(1→6)-β-d-galactopyranoside

Condensation of 2,4,6-tri-O-acetyl-3-deoxy-3-fluoro-α-d-galactopyranosyl bromide (3) with methyl 2,3,4-tri-O-acetyl-β-d-galactopyranoside (4) gave a fully acetylated (1→6)-β-d-galactobiose fluorinated at the 3′-position which was deacetylated to give the title disaccharide. The corresponding trisaccharide was obtained by reaction of 4 with 2,3,4-tri-O-acetyl-6-O-chloroacetyl-α-d-galactopyranosyl bromide (5), dechloroacetylation of the formed methyl O-(2,3,4-tri-O-acetyl-6-O-chloroacetyl-β-d-galactopyranosyl)-(1→6)- 2,3,4-tri-O-acetyl-β-d-galactopyranoside to give methyl O-(2,3,4-tri-O-acetyl-β-d-galactopyranosyl)-(1→6)-2,3,4-tri-O-acetyl-β-d-galactopyranoside (14), condensation with 3, and deacetylation. Dechloroacetylation of methyl O-(2,3,4-tri-O-acetyl-6-O-chloroacetyl-β-d-galactopyranosyl)-(1→6)-O-(2,3,4-tri-O-acetyl- β-d-galactopyranosyl)-(1→6)-2,3,4-tri-O-acetyl-β-d-galactopyranoside, obtained by condensation of disaccharide 14 with bromide 5, was accompanied by extensive acetyl migration giving a mixture of products. These were deacetylated to give, crystalline for the first time, the methyl β-glycoside of (1→6)-β-d-galactotriose in high yield. The structures of the target compounds were confirmed by 500-MHz, 2D, ¹H- and conventional ¹³C- and ¹⁹F-n.m.r. spectroscopy.     

Treatment of NZB/W (“lupus”) mice with 15(S)-15 methyl PGE1

The F₁ hybrid of New Zealand black and New Zealand white mice - the NZB/W mouse - spontaneously develops a disease similar to human systemic lupus erythematosus. Male NZB/W mice with established disease were treated with a stable derivative of prostaglandin E₁, 15(S)-15 methyl PGE₁ (4 μg twice daily) from 7 months of age. The PGE analog prolonged survival of these mice: At 14 months 7 of 10 control mice had died, whereas 9 of 10 15(S)-15 methyl PGE₁ treated mice remained alive. Thus a dose of 200 μg/Kg/day 15(S)-15 methyl PGE₁ retards progression of murine lupus.     

Synthesis of 2-acetamido-1-N[N-(tert-butoxycarbonyl)-l-aspart-1-oyl-(l-phenylalanyl-l-serine methyl ester)-4-oyl]-2-deoxy-β-d-glucopyranosylamine and analogs

2-Acetamido-1-N-[N-(tert-butoxycarbonyl)-l-aspart-1-oyl-(l-phenylalanyl-l-serine methyl ester)-4-oyl]-2-deoxy-β-d-glucopyranosylamine and analogs containing d-glucopyranosyl, 4-O-β-d-glucopyranosyl-d-glucopyranosyl, l-Phe-l-Ala, and d-Phe-l-Ser were synthesized by condensation of glycosylamines having free hydroxyl groups with tripeptide esters activated with N-hydroxysuccinimide.     

Synthesis and biological properties of 16(S)-amino-PGF2α methyl ester

A synthesis of 16-amino-derivatives of PGF_2α is reported. Introduction of an amino group into position 16 of PGF_2α has decreased the sensitivity of the compound to metabolic degradation. 16(S)-amino-PGF_2α methyl ester shows high abortifacient activity with reduced diarrhoeic side effect.     

Synthetic mucin fragments. Methyl 6-O-(2-acetamido-2-deoxy-β-D-glycopyranosyl)-β-D-galactopyranoside,methyl 3,4-di-O-(2-acetamido-2-deoxy-β-D-glycopyranosyl)-β-D-galactopyranoside,and methyl O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-(1 å 3)-O-β-D-galactopyranosyl-(1 å 3)-O-(2-acetamido-2-deoxy-β- D-glucopyranosyl)-(1 å 3)-β-D-galactopyranoside

Condensation of methyl 2,6-di-O-benzyl-β-d-galactopyranoside with 2-methyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-α-d-glucopyrano)-[2,1,-d]-2-oxazoline (1) in 1,2-dichloroethane, in the presence of p-toluenesulfonic acid, afforded a trisaccharide derivative which, on deacetylation, gave methyl 3,4-di-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-2,6-di-O-benzyl-β-d- glactopyranoside (5). Hydrogenolysis of the benzyl groups of 5 furnished the title trisaccharide (6). A similar condensation of methyl 2,3-di-O-benzyl-β-d-galactopyranoside with 1 produced a partially-protected disacchraide derivative, which, on O-deacetylation followed by hydrogenolysis, gave methyl 6-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-β-d-glactopyranoside (10). Condensation of methyl 3-O-(2-acetamido-4,6-O-benzylidene-2-deoxy-β-d-glucopyranosyl)-2,4,6-tri-O-benzyl-β-d- galactopyranoside with 3-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-2,4,6-tri-O-acetyl-α-d-galactopyranosyl bromide in 1:1 benzene-nitromethane in the presence of powdered mercuric cyanide gave a fully-protected tetrasaccharide derivative, which was O-deacetylated and then subjected to catalytic hydrogenation to furnish methyl O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-(1→3)-O-β-d-galactopyranosyl-(1å3)-O-(2-acetamido-2-deoxy- β-d-glucopyranosyl)-(1å3)-β-d-galactopyranoside (15). The structures of 6, 10, and 15 were established by ¹³C-n.m.r. spectroscopy.     

A convenient method for the synthesis of methyl 2-acetamido-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)-α-d-glucopyranoside

In the seeds of Tropaeolum and Tamarindus, which have been found to have the highest content of amyloids, these polysaccharides are associated with sucrose and O-d-galactosylsucroses of the raffinose-stachyose series. Balsamine seeds have a low content of amyloid and do not contain the aforementioned galactosides, which are otherwise widely distributed in plant seeds. They contain sucrose and a mono-O-D-galactosylsucrose that has been crystallized and identified as planteose. Planteose has previously been isolated from some Sympetalous plants. As far as we know, this is the first report of its occurrence in an Archichlamydeaeous plant seed.     

Stereocontrolled preparation of C-2-deoxy-α- and -β-d-glucopyranosyl compounds from tributyl-(2-deoxy-α- and -β-d-glucopyranosyl)stannanes

tributylstannyllithium treatment of 3,4,6-tri-O-benzyl-2-deoxy-α-d-arabino-hexopyranosyl chloride (2) provided selectively tributyl (3,4,6-tri-O-benzyl-2-deoxy-β-d-arabino-hexopyranosyl)stannane (3) in 85% yield. Isomeric tributyl (3,4,6-tri-O-benzyl-2-deoxy-α-d-arabino-hexopyranosyl)stannane (6) could be prepared in 70% yield by reductive lithiation of 2 and reaction with tributyltin chloride. Tin—lithium exchange reaction, performed on 3 and 6 with butyllithium in oxolane at −78°, generated the corresponding, configurationally stable 2-deoxy-β- and -α-d-hexopyranosyllithium compounds which reacted with electrophilic compounds with retention of configuration. Addition to these glycosyllithium reagents to prochiral carbonyl compounds gave variable degrees of facial selectivity. A significant diastereofacial discrimination (10:1) was observed by condensation of 3,4,6-tri-O-benzyl-2-deoxy-α-d-arabino-hexopyranosyllithium reagent with hexanal and isobutyraldehyde. The structure of all C-glycopyranosyl compounds obtained was established by ¹H-n.m.r. spectroscopy.     

Synthesis of methyl O-(3-deoxy-3-fluoro-β-d-galactopyranosyl)-(1→6)-O-β-d-galactopyranosyl-(1→6)-3-deoxy-3-fluoro -β-d-galactopyranoside and related n.m.r. studies

Sequential tritylation, benzoylation, and detritylation of methyl 3-deoxy-3-fluoro-β-d-galactopyranoside gave crystalline methyl 2,4-di-O-benzoyl-3-deoxy-3-fluoro-β-d-galactopyranoside (9), which was used as the initial nucleophile in the synthesis of the target oligosaccharide (16). Treatment of 9 with 2,3,4-tri-O-benzoyl-6-O-bromoacetyl-α-d-galactopyranosyl bromide gave the corresponding disaccharide derivative 13, having a selectively removable blocking group at O-6′. Debromoacetylation of 13 afforded the disaccharide nucleophile 14 which, when treated with 2,4,6-tri-O-benzoyl-3-deoxy-3-fluoro-α-d-galactopyranosyl bromide, gave the fully protected trisaccharide 15. Debenzoylation of 15 gave the title glycoside 16. Condensation reactions were performed with silver trifluoromethane-sulfonate as a promoter in the presence of sym-collidine under base-deficient conditions, and gave excellent yields of the desired β-(trans)-products. Analyses of the ¹H- and ¹³C-n.m.r. spectra, as well as determination of the J_CF and J_HF coupling constants, were made by using various one- and two-dimensional n.m.r. techniques.     

Syntheses of methyl ethers of methyl α-D-mannopyranoside,and hydrogen bonding in diastereoisomers of methyl 4-O-(1-ethoxyethyl)-α-D-mannopyranoside

The synthesis of the 4-methyl, the 2,4-dimethyl, and the 2,3,6-trimethyl ethers of methyl α-D-mannopyranoside has been accomplished by the use of selective, benzoyl protecting groups, the 1-ethoxyethyl protecting group, and methylation with diazomethane. Considerable differences were noted in the i.r.- and n.m.r.-spectroscopic and t.l.c. properties of the diastereoisomers of methyl 4-O-[1-ethoxyethyl]-α-D-mannopyranoside. A structure, analogous to that of trans-decalin, maintained by intramolecular hydrogen-bonding is proposed for these compounds. The differences in physical properties of the two diastereoisomers are interpreted on the basis that the (R) isomer has an axially attached methyl group, and, therefore, the ring involved cannot be so stable as that of the (S) isomer.     

The monohydroxylation of 17β-estradiol at the 15α-, 16α-, and 16β-positions by bovine adrenal perfusion

17β-Estradiol-4-¹⁴C was perfused through bovine adrenal glands. The bulk (65%) of the estradiol was recovered, but several metabolites, all in low rates of conversion, were isolated. Four of these were identified as esterone, estriol, 16β-epiestriol and 15-αhydroxy-17β- estradiol.     

The study of the reaction of terminated oligomerization in the synthesis of oligo-(β1-6)-glucosamines

The applicability of terminated oligomerization to the synthesis of oligo-(β1-6)-glucosamines, fragments of the intercellular polysaccharide adhesin of staphylococci, was studied. The reactions of terminated oligomerization were carried out with mono-, di-, and trisaccharide monomers and N-protected aminopropanol; and spacered mono-and disaccharides as terminating molecules were also attempted. The primary formation of cyclic products of monomer intramolecular glycosylation was observed in almost all the reactions. Only the experiments with the monomer based on the disaccharide bromide under the conditions of the Helferich reaction led to reduced yields (30%) of the cyclic products. However, even in this case, the desired terminated oligosaccharides were generated in approximately 10% yield and mainly were the products of single glycosylation of the terminator by the monomer. These experiments allow the conclusion that, under the examined conditions, the reaction of terminated oligomerization could not result in the synthesis of oligoglucosamines with a high molecular mass.     

The location of (1-3)-β-glucan in the nucellar projection and in the vascular tissue of the crease in developing barley grain using a (1-3)-β-glucan-specific monoclonal antibody

Immunocytochemical localization of the (1-3)-beta-glucan, callose, in developing barley (Hordeum vulgare L.) grain was investigated using a specific monoclonal antibody and observed by means of confocal laser-scanning microscopy. The nucellar projection (NP) and vascular tissue (VT) of the crease cells were specifically labelled by this antibody at all stages of grain development. Maximum intensity of label was found in the NP at 12-15 days post anthesis; thereafter, label was localized in the VT of the crease. The location of (1-3)-beta-glucan in the NP and VT of the crease was also monitored by means of aniline blue-induced fluorescence of callose. The results obtained using both methods were found to be similar. The possible significance of the presence of callose in these tissues is discussed in relation to the uptake of assimilates into the developing grain.     

Urinary metabolites of the new progestagen STS 557 (17α-cyanomethyl-17-hydroxy-4,9-estradien-3-one) in the dog and rat

Urinary metabolites of the new progestagen STS 557 (17α-cyanomethyl-17-hydroxy-4,9-estradien-3-one) were isolated and characterized following oral administration of the 14α, 15α-tritium labelled compound to dogs and rats. 17α-Cyanomethyl-11β, 17-dihydroxy-4, 9-estradien-3-one (11β-OH-STS 557) and 17α-cyanomethyl-1,3,5(10),9(11) -estratetraene-3, 17-diol were identified by comparison with synthesized reference compounds. Mass spectra data indicate the following other pathways of STS 557 biotransformation: Hydroxylation in other positions than 11; hydrogenation; hydroxylation + hydrogenation; alteration of the 17α-side chain.