Yushun Fujishima

Synthesis of the optically active 4-O-phosphono-d-glucosamine derivatives related to the nonreducing-sugar subunit of bacterial lipid A

The optically active lipid A-subunit homologs named GLA-46, GLA-47, GLA-59, and GLA-60 have been synthesized stepwise by successive acylation at N-2 and O-3 of benzyl 2-amino-2-deoxy-4,6-O-isopropylidene-beta-D-glucopyranoside with the 3-9O-(benzyloxy)methyl or 39O-tetradecanoyl derivative of optically active 3-hydroxytetradecanoic acid, and phosphorylation at O-4 of the D-glucosamine residue.

Synthesis of 2-deoxy-4-O-phosphono-3-O-tetradecanoyl-2-[(3R- and (3S)-3-tetradecanoyloxytetradecanamido]-d-glucose: a diastereoisomeric pair of 4-O-phosphono-d-glucosamine derivatives (GLA-27) related to bacterial lipid A

The diastereoisomeric, 4-O-phosphono-D-glucosamine derivatives named in the title have been synthesized, starting from benzyl 2-amino-2-deoxy-4,6-O-isopropylidene-beta-D-glucopyranoside and (3RS)-3-hydroxytetradecanoic acid.

Synthesis of nonreducing-sugar subunit analogs of bacterial lipid a carrying an amide-group (3R)-3-acyloxytetradecanoyl group

Abstract Two types of optically active, 4- O -phosphono- d -glucosamine derivatives related to the nonreducing-sugar subunit of bacterial lipid A, one being 2-[(3 R )-3-acyloxytetradecanamido]-2-deoxy-4- O -phosphono-3- O -tetradecanoyl- d -glucose (GLA-27 type; GLA-57 and GLA-58), and the other 2-[(3 R )-3-acyloxytetradecanamido]-2-deoxy-3- O -[(3 R )-3-hydroxytetradecanoyl]-4- O -phosphono- d -glucose (GLA-59 type; GLA-61 and GLA-62), have been synthesized. The amino group of benzyl 2-amino-2-deoxy-4,6- O -isopropylidene-β- d -glucopyranoside was first acylated with the (3 R )-3-dodecanoyloxytetradecanoyl or (3 R )-3-hexadecanoyloxytetradecanoyl group, and then the remaining hydroxyl group was esterified with the tetradecanoyl or (3 R )-3-(benzyloxymethoxy)tetradecanoyl group, respectively. The resulting protected intermediates were each converted, by the sequence of O -deisopropylidenation, 6- O -trityltion, and 4- O -phosphorylation, into the desired compounds.

Nonreducing-Sugar Subunit Analogs of Bacterial Lipid a Carrying the Ester-Bound (3R)-3-(Acyloxy)Tetradecanoyl Group

Abstract In order to elucidate further the relationship between the composition of the fatty acyl groups in the nonreducing-sugar subunit of bacterial lipid A and its biological activity, 3-O-[(3R)-3-(acyloxy)tetradecanoyl]-2-deoxy-2-[(3R)-3-hydroxytetradecanamido]-4-O-phosphono-D-glucose [GLA-63(R, R) and GLA-64(R, R)], and 3-O-[(3R)-3-(acyloxy)tetradecanoyl]-2-deoxy-4-O-phosphono-2-tetradecanamido-D-glucose [GLA-67(R), GLA-68(R) and GLA-69(R)] have been synthesized. Benzyl 2-[(3R)-3-(benzyloxymethoxy)tetradecanamido]-2-deoxy-4,6-O-isopropylidene-β-D-glucopyranoside (5) and benzyl 2-deoxy-4,6-O-isopropylidene-2-tetradecanamido-β-D-glucopyranoside (6) were each esterified with (3R)-3-dodecanoyloxytetradecanoic acid (1), (3R)-3-tetradecanoyloxytetradecanoic acid (2) or (3R)-3-hexadecanoyloxy-tetradecanoic acid (3), to give 7-11, which were then transformed, by the sequence of deisopropylidenation, 6-O-tritylation and 4-O-phosphorylation, into a series of desired compounds.

Conjugates of biologically active lipid A-subunit analogs with 3-deoxy-D-manno-2-octulosonic acid (KDO) and its methyl ester

Abstract The previously described, biologically active 4- O -phosphono- d -glucosamine derivatives GLA-27, GLA-47, and GLA-60 (all related to bacterial lipid A) were converted into their respective conjugates with 3-deoxy- d - manno -2-octulosonic acid (KDO). The methyl and benzyl esters of [4,5,7,8-tetrakis- O -(chloroacetyl)-3-deoxy- d - manno -2-octulopyranosyl fluoride]onic acid and the corresponding glycosyl bromide were prepared, by starting from methyl 2,4,5,7,8-penta- O -acetyl-3-deoxy- d - manno -2-octulopyranosonate, and coupled to O-6 of suitably protected precursors of the phosphono- d -glucosamines. This gave a series of fully substituted disaccharides that were transformed, by O-de(chloroacetyl)ation and successive hydrogenolytic removal of benzyl, benzyloxymethyl, and phenyl groups, into the target conjugates (KDO methyl ester α- and β-linked to GLA-27, and KDO α-linked to GLA-27, GLA-47, and GLA-60).

Chemical Combination of Biologically Active Derivatives ofN-Acetylmuramoyl Dipeptide and Lipid-A, and Their Biological Activities

Abstract Chemical coupling of biologically active derivatives of N-acetyl-muramoyl dipeptide with a derivative related to the nonreducing sub-unit of lipid A was carried out using acyl groups as a spacer. The products exhibited efficient antitumor activity, as well as strong, immunoadjuvant activity.

The Chemical Modification of the C-1 Substituent of A 4-O-Phosphono-O-Glucosamine Derivative (GLA-27) Related to Bacterial Lipid A

Abstract 1-Thio and 1-O-phosphono derivatives (9-11 and 15) of 2-deoxy–4-O-phosphono-3-O-tetradecanoyl-2-[(3RS)-3-tetradecanoyloxytetradecan-amido]-D-glucose (GLA-27-RS), which exhibits some of the beneficial biological activities of bacterial endotoxin, have been synthesized from benzyl 2-deoxy-4,6-O-isopropylidene-3-O-tetradecanoyl-2-[(3RS)-3-tetradecanoyloxytetradecanamido]-β-O-glucopyranoside (1), and 2-deoxy-4-O-diphenylphosphono-3-O-tetradecanoyl-2-[(3RS)-3-tetra-decanoyloxytetradecanamido]-D-glucopyranose (12), respectively.

Synthesis of 2-Deoxy-2-[(3R)-3-Hydroxyacyl]Amino-4-O-Phosphono-3-O-[(3R)-3-Tetradecanoyloxytetradecanoyl]-D-Glucopyranose Derivatives Related to Bacterial Lipid A

ABSTRACT Lipid A subunit analogs, the 4-O-phosphono-D-glucosamine derivatives (14-16: GLA 93-95) which carry 2-N-linked 3-hydroxyacyl groups, were synthesized. 2-(Trimethylsilyl)ethyl 2-amino-2-deoxy-4,6-O-isopropylidene-s-D-glucopyranoside (1) was transformed into 2-(trimethylsilyl)ethyl 2-amino-6-O-tert-butyldimethylsilyl-2-deoxy-4-O-diphenylphosphono-3-O-[(3R)-3-tetradecanoyloxytetradecanoyl]-s-D-glucopyranoside (7) through several steps. N-Acylation of 7 with 3-hydroxyl fatty acids gave the corresponding 8-10, which were converted, via the cleavage of protecting groups, into a series of desired compounds.

Synthesis of a novel series of 4-O-phosphono-d-glucosamine derivatives (lipid A subunit analogs) carrying the C-branched 2-tetradecylhexadecanoyl group

Abstract A novel series of 4- O -phosphono- d -glucosamine derivatives (lipid A subunit analogs) carrying the 3- O -linked or 2- N -linked C -branched 2-tetradecylhexadecanoyl group have been synthesized starting from benzyl 2-amino-2-deoxy-4,6- O -isopropylidene-β- d -glucopyranoside and benzyl 2-amino-6- O -benzyloxymethyl-2-deoxy-4- O -(diphenoxyphosphinyl)-β- d -glucopyranoside, respectively. Some of the new compounds were potent inducers of phagocytic activity in macrophages and showed antiviral activity against vaccinia virus.