Robert L. Bugianesi

Preparation of sepharose-bound poly (rI:rC)

Abstract Poly rI was covalently bound through its terminal 5′-phosphate moiety to Sepharose and then annealed with poly rC to yield insoluble matrix bound poly (rI:rC). The method has no serious deleterious effects on the integrity or in vitro biological activity of the double stranded complexes.

Modified in vivo behavior of liposomes containing synthetic glycolipids.

Liposomes with synthetic saccharide determinants were prepared from synthetic cholesterol conjugates of D-mannose and 6-amino-6-deoxy-D-mannose and labeled with [51Cr]chromate. The kinetics and tissue distribution of label in mice were determined after footpad and subcutaneous injection. Liposomes bearing either of these saccharide determinants greatly increased retention of label at the injection sites compared to control liposomes, which contain no glycolipid, and to free [51Cr]chromate. Draining lymph nodes contained small fractions of the injected radioactivity but in some cases this retention was saccharide-dependent and highly concentrated. These results show that incorporation of synthetic glycolipids can substantially alter the in vivo lifetime and distribution of liposomes outside the bloodstream. Such surface-modified liposomes may be useful for sustained release or selective delivery of therapeutic or diagnostic agents.

(±)-Trans-2-(3-methoxy-5-methylsulfonyl-4-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (L-659,989), a novel, potent PAF receptor antagonist

The title compound, L-659,989, is a highly potent, competitive, and selective antagonist of the binding of [3H]PAF to its receptors in platelet membranes from rabbits and humans. It exhibits equilibrium inhibition constants for PAF binding of 1.1 nM (rabbit) to 9.0 nM (human), values that are at least 1-2 orders of magnitude lower than those of other PAF antagonists tested. L-659,989 potently inhibits PAF-induced aggregation of rabbit platelets and degranulation of rat (ED50 4.5 nM) and human (ED50 10 nM) neutrophils. L-659,989 inhibits PAF-induced extravasation and lysosomal enzyme release in rats, and is active orally in female rats (ED50 0.2 mg/kg) with an extraordinary oral duration of action of 12 to 16 hours at 1.0 mg/kg p.o.

Total synthesis of kadsurenone and its analogs

Abstract Kadsurenone, a specific receptor antagonist of platelet-activating factor and a natural product isolated from Piper futokadsura was prepared in three steps from 3,4-dimethoxycinnamyl alcohol and allyloxyphenol via rac -(2S,3S)-5-allyl-6-hydroxy-2-(3,4-dimethoxyphenyl)-3-methyl-2,3-dihydrobenzofuran.

Synthesis and biological activity of MK 287 (L-680,573): a potent, specific and orally active paf receptor antagonist

Abstract An enantioselective synthesis of MK 287 (L-680,573), a member of a family of trans-,5-diaryltetrahydrofurans, and its biological activity are described.

Modification of the pyridine moiety of non-peptidyl indole GnRH receptor antagonists

The synthesis of a number of indole GnRH antagonists is described. Oxidation of the pyridine ring nitrogen, combined with alkylation at the two position, led to a compound with an excellent in vitro activity profile as well as oral bioavailability in both rats and dogs.

A chemical synthesis of I-O-indomethacin-β-D-glucosyluronic acid

Abstract A new synthetic route to labile acyl D -glucosyluronic acids was developed by using 2,2,2-trichloroethoxycarbonyl as the hydroxy-protecting group. Condensation of 2,2,2-trichloroethyl 2,3,4-tri- O -(2,2,2-trichloroethoxycarbonyl)-β- D -glucopyranuronate with indomethacin, followed by treatment with zinc dust in acetic acid, afforded the zinc salt of indomethacin-β- D -glucosyluronic acid.

Synthesis of chiral β-methyl tryptamine-derived GnRH antagonists

Abstract The stereospecific formation of 2-aryl-β-methyl tryptamine derivatives 15 and 16 from chiral 4-chloro-1-(3,5-dimethylphenyl)-3-methylbutanones is described. These intermediates were further manipulated into the GnRH antagonists 1b and 1c in five steps.

Targeting of synthetically glycosylated human placental glucocerebrosidase

Human placental beta-glucocerebrosidase modified by covalent attachment of N2-(N2, N6-bis [3-(alpha-D-mannopyranosylthio)propionyl]-L- lysyl)-N6-[3-(alpha-D-mannopyranosylthio)propionyl]-L-lysine was administered to rats by intravenous injection. Comparison of enzyme distribution in isolated liver cell populations indicates an increase in enzyme-specific activity of 18-fold in nonparenchymal cells and only 1.5-fold to hepatocytes compared to uninjected control animals. This macrophage-specific delivery of an active lysosomal enzyme has potential for application in enzyme replacement trials.

Bioactive carbohydrate derivatives : I. Analogs of the glycopeptide juncture in immunoglobulins

Abstract A group of novel analogs of 2-acetamido-1- N -(β- L -aspartyl)-2-deoxy-β-glucospyranosylamine ( 1 ), the glycopeptide junction in immunoglobulins, were synthesized as potential regulators of the biosynthesis, secretion, and function of immunoglobulins. The 2-amino and carboxyl groups in the aspartyl moiety were incorporated into hydantoin, thiohydantoin, and dioxopiperazine systems, and converted into an N 2 -toluenesulfonamide to mimic the neighboring peptide-linkages of this juncture. The amide linkage in 1 was replaced by glycosidic and by a sulfonamide linkage. The latter represents a new type of glycosylamine, the chemical stability of which was examined. The o.r.d. and c.d. spectra of these novel glycosyl derivatives are compared.