Mitree M. Ponpipom

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.

Synthesis of 3-O Substituted D-Mannoses

Abstract 1,2,4,6-Tetra-O-acetyl-3-O-benzyl-α- D -mannopyranose (7) was obtained in good yield from 3,4,6-tri-O-benzyl-1,2-O-(1-methoxyethylidene)-β- D -mannopyranose (1) by acetolysis. Hydrogenolysis of 7 afforded 1,2,4,6-tetra-O-acetyl-α- D -mannopyranose which is a versatile intermediate for the preparation of other 3-O-substituted D -mannoses, such as 3-O-methyl- D -mannose and 3-O-α- D -mannopyranosyl- D -mannose. 3,4-Di-O-methyl- D -mannose was readily prepared from 1,2,6-tri-O-acetyl-3,4-di-O-benzyl-α- D -mannopyranose, which was also obtained from 1 by controlled acetolysis.

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.

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.

ω-Aminoalkyl β-glycosides of N-acetylmuramyl-l-alanyl-d-isoglutamine, and their conjugates with meningococcal group C polysaccharide

The 6-aminohexyl beta-glycoside of N-acetylmuramyl-L-alanyl-D-isoglutamine and its spacer-arm-linked analog (3.8 nm) were synthesized from 2-methyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-alpha-D-glucopyrano)-[2,1-d]-2- oxazoline, and coupled with meningococcal group C polysaccharide in attempts to enhance the immunogenicity of the polysaccharide antigen.

Chemoselective removal and replacement of the C-4′ and C-6 acyl esters of zaragozic Acid A

Abstract An efficient chemical sequence is described for the modification of the C-4′ and C-6 positions of zaragozic acid A. Key reactions include the specific conditions devised for selective removal of either the C-4′ acetate or the C-6 acyl chain. The resultant hydroxy intermediates were then derivatized as esters, ethers, carbamates, and carbonates.