Synthesis of long chain fatty acid esters of N-acetylmuramyl-L-alanyl-D-isoglutamine in relation to antitumor activity

Kusumoto, Shoichi; Inage, Masaru; Shiba, Tetsuo; Azuma, Ichiro; Yamamura, Yuichi

doi:10.1016/s0040-4039(01)85765-8

Cited by 81 publications

(38 citation statements)

References 4 publications

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“…The MDP derivatives used in this study were synthesized as reported previously (22)(23)(24). Briefly, MDP with 6-O-acylation and those with long fatty acid chains were synthesized by the method of Kusumoto et al (22)(23)(24).…”

Section: Synthetic Mdp Derivativesmentioning

confidence: 99%

“…Briefly, MDP with 6-O-acylation and those with long fatty acid chains were synthesized by the method of Kusumoto et al (22)(23)(24). Fig.…”

Section: Synthetic Mdp Derivativesmentioning

confidence: 99%

“…1, and other derivatives with different lengths of fatty acids were synthesized as described previously (22)(23)(24)(25). Diacylated and monoacylated MDPs with different lengths of chains were used to test their functions.…”

Section: Structures Of Mdp Derivativesmentioning

confidence: 99%

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Dendritic Cell Maturation Induced by Muramyl Dipeptide (MDP) Derivatives: Monoacylated MDP Confers TLR2/TLR4 Activation

Uehori

Fukase

Akazawa

et al. 2005

The Journal of Immunology

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6-O-acyl-muramyldipeptides (MDP) with various lengths of fatty acid chains were examined for their dendritic cell (DC) maturation activity expressed through TLRs. Judging from anti-TLR mAb/inhibitor-blocking analysis, MDP derivatives with a single octanoyl or stearoyl fatty acid chain were found to activate TLR2 and TLR4 on human DCs, although intact and diacylated MDP expressed no ability to activate TLRs. Human DC activation profiles by the monoacylated MDP were essentially similar to those by Calmette-Guérin (BCG)-cell wall skeleton (CWS) and BCG-peptidoglycan (PGN) based on their ability to up-regulate costimulators, HLA-DR, β2-microglobulin, and allostimulatory MLR. Monoacylated MDP induced cytokines with similar profiles to BCG-CWS or -PGN, although their potency for induction of TNF-α, IL-12p40, and IL-6 was less than that of BCG-CWS or -PGN. The MDP derivatives initiated similar activation in normal mouse macrophages, but exhibited no effect on TLR2/4-deficient or MyD88-deficient mouse macrophages. Mutation of d-isoGln to l-isoGln in monoacylated MDP did not result in loss of the DC maturation activity, suggesting marginal participation of nucleotide-binding oligomerization domain 2, if any, in monoacyl MDP-dependent DC maturation. These results define the adjuvant activity of 6-O-acyl MDP compounds at the molecular level. They target TLR2/TLR4 and act through the MyD88-dependent pathway in DCs and macrophages. Hence, the unusual combined activation of TLR2 and TLR4 observed with Mycobacterium tuberculosis is in part reflected in the functional properties of monoacylated MDP compounds. These findings infer that the essential minimal requirement for TLR2/4-mediated adjuvancy of BCG lies within a modified MDP.

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Section: Synthetic Mdp Derivativesmentioning

confidence: 99%

“…Briefly, MDP with 6-O-acylation and those with long fatty acid chains were synthesized by the method of Kusumoto et al (22)(23)(24). Fig.…”

Section: Synthetic Mdp Derivativesmentioning

confidence: 99%

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Dendritic Cell Maturation Induced by Muramyl Dipeptide (MDP) Derivatives: Monoacylated MDP Confers TLR2/TLR4 Activation

Uehori

Fukase

Akazawa

et al. 2005

The Journal of Immunology

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“…We used tetracosanoic, 2-tetradecylhexadecanoic, 3-hydroxy-2-tetradecyloctadecanoic, 3-hydroxy-2-docosylhexacosanoic, and mycolic acids, 14,15) as the long-chain fatty acid.…”

Section: Chemical Synthesismentioning

confidence: 99%

Synthesis and Immunoadjuvant Activity of Acylamino Analogs ofN-Acetylmuramoyl-l-alanyl-d-isoglutamine

Okumura

Kamisango

Saki

et al. 1982

Agricultural and Biological Chemistry

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“…We now describe the synthesis of lipophilic derivatives at both C-l or C-6 and the dipeptide moiety in N-acetyl-lthiomuramoyl-L-alanyl-D-isoglutamine methyl ester, 8) and their biological activities. RESULTS (2). In the same way, condensation of 1 with tetradecanoyl or octadecanoyl chloride afforded the corresponding N-(fatty acyl) derivatives (3 and 4), respectively.…”

mentioning

confidence: 94%

Synthesis and Biological Activity of the Lipophilic Derivatives ofN- Acetyl-1-thiomuramoyl-l-alanyl-d-isoglutamine

Hasegawa

Hara

Kiso

et al. 1986

Agricultural and Biological Chemistry

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A variety of the lipophilic derivatives at C-l and C-6 in N-[2-0-(2-acetamido-2,3-dideoxy-lthio-{3-D-glucopyranose-3-yl)-D-Iactoyl]-L-alanyl-(N1-fatty acyl)-D-isoglutamine methyl esters were synthesized from 2-N-acetyl-l-S-acetyl-4,6-0-isopropylidene-l-thiomuramoyl-L-alanyl-D-isoglutamine methyl ester. Their immunoadjuvant activity in guinea-pigs, and the protective effect in mice infected with Escherichia coli (E-77156) were examined. 2095Recently, it has been shown that the introduction 1 '" 7) of fatty acyl groups as a lipophilic character at the restrict~d position of the sugar skeleton or dipeptide moiety in N-acetylmuramoyl-L-alanyl-D-isoglutamine (MDP) and in its carbohydrate analogs that carry strong immunoadjuvant activity causes potent antitumor or anti-infection activity, based on the immune reaction, that is not found with MDP itself, and abolishes the pyrogenicity ·or necrotic inflammation that is a side effect with MDP.

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Synthesis of long chain fatty acid esters of N-acetylmuramyl-L-alanyl-D-isoglutamine in relation to antitumor activity

Cited by 81 publications

References 4 publications

Dendritic Cell Maturation Induced by Muramyl Dipeptide (MDP) Derivatives: Monoacylated MDP Confers TLR2/TLR4 Activation

Dendritic Cell Maturation Induced by Muramyl Dipeptide (MDP) Derivatives: Monoacylated MDP Confers TLR2/TLR4 Activation

Synthesis and Immunoadjuvant Activity of Acylamino Analogs ofN-Acetylmuramoyl-l-alanyl-d-isoglutamine

Synthesis and Biological Activity of the Lipophilic Derivatives ofN- Acetyl-1-thiomuramoyl-l-alanyl-d-isoglutamine

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