D-Isoglutamine

The structure of the native immunostimulatory MDPs was found to be IV-acetyl muramyl-L-alanyl-D-isoglutamine. (/V-Acetyl muramic acid is a base component of bacterial peptidoglycan.) Native TDM is a potent pyrogen and is too toxic for general use as an adjuvant. The molecular basis underlining MDP s adjuvanticity remains to be fully elucidated. Administration of MDP, however, is known to activate a number of cell types that play direct/indirect roles in immune function, and induces the secretion of various immunomodulatory cytokines (Table 13.14). 

Figure 6.51 Fluoroalkyl derivatives of AFacetylmuramyl-L-alanyl-D-isoglutamine.

Barton, D H R, Augy-Dorey, S, Camara, J, DaUco, P, Delaumeny, J M, Gero, S D, Quiclet-Sire, B, Stutz, P, Synthetic methods for the preparation of basic D-pseudo-sugars and L-pseudo-sugars — synthesis of carbocyclic analogs of A-acetyl-muramyl-L-alanyl-D-isoglutamine (Mdp), Tetrahedron, 46, 215-230, 1990. 

J. Farkas, M. Ledvina, J. Brokes, J. Jezek J. Zajicek and M. Zaoral, The synthesis of 0-(2-acetamido-2-deoxy-/3-D-glucopyranosyl)-(l— 4)-N-acetylnormuramoyl-L-a-aminobutanoyl-D-isoglutamine, Carbohydr. Res., 1987,163, 63-72. 

C -(2-Acetamido-2-deoxy 3-D-glucosyl)-(l 4)-iV-acetyl muramoyl-L-alanyl-D-isoglutamine (31), the dipeptide derivative of the disaccharide isolated from lysozyme digests of bacterial cell walls, has been prepared in a fourteen-step sequence from 2-acetamido-2-deoxy-D-glucose. The dipeptide disaccharide derivative (32) isolated from lysostaphin endo-l3-D-2-acetamido-2-deoxy-glucan-ase digests of cell walls has also been synthesized (Scheme 5). ... 

The adjuvant and anti-tumour activities of synthetic 6-O-corynomycoloyl, 6-0-nocardomycoloyl, and 6-(7-mycoloyl derivatives of iV-acetylmuramyl-L-alanyl-D-isoglutamine have been evaluated. The preparation of the mycoloyl derivatives by acylation of A-acetylmuramyl-L-alanyl-D-isoglutamine was... 

MDP muramyl dipeptide (N-acetyl-muramyl-L-alanyl-D-isoglutamine) WSA Water Soluble Adjuvant AL multi-poly-D, L-alanyl-poly-L-lysine... 

Further degradation of low molecular weight fractions obtained from lysozyme digestion of cell walls then led to the conclusion that an N-acyl muramyl dipeptide should be the minimal adjuvant active structure (small square frame of Fig. 2). And indeed, N-acetyl-muramyl-L-alanyl D-isoglutamine (1) first synthesized by Merser et al. (49, 50) was found to be fully active (16). Kotani et al. (29, 30) independently came to the same conclusion. 

Fig. 3. Synthesis of r-butyloxycarbonyl-L-alanyl-D-isoglutamine benzyl ester (43)...

The ot-amino and y-carboxyl functions are blocked by t-butyloxy-carbonyl and benzyl ester groups respectively. The coupling is performed using the N,N -dicyclohexylcarbodiimide with N-hydroxysuccinimide (55), mixed anhydride (55, 43), or activated ester 43) methods. The key intermediate, BOC-D-isoglutamine benzyl ester, is prepared by a process which allows the non-equivocal synthesis of this isoglutamine derivative (Fig. 3) 43). 

The preparation of another protected dipeptide derivative, BOC-L-alanyl-D-isoglutamine r-butyl ester, was reported without details, the coupling being performed by means of the succinimide ester method (55). 

Activated ester coupling methods have also been used. The 1-suc-cinimidyl ester of l-a-0-benzyl-4,6-0-benzylidene-N-acetyl-muramide, prepared using N,N- -dicyclohexylcarbodiimide, was allowed to react with the dipeptide derivative (33). The 5-norbomene-2,3-dicarboxyimidyl ester of 4,6-O-anisylidene-N-acetyl-muramide can be readily coupled with the triethyl-ammoniinn salt of L-alanyl-D-isoglutamine (55). 

Recently, a modified procedure was employed giving 4,6-0-anisylidene-N-acetyl-muramyl-L-alanyl-D-isoglutamine. The single blocking group was easily removed with 60% acetic acid at room temperature (35). 

Fig. 5. Synthesis of [6- H)-N-acetyl-muramyl-L-alanyl-D-isoglutamine IS) References, pp. 38—47...

The preparation of benzyl-2,3,6-0-benzyl-4-0-(D-l-carboxyethyl)-P-D-glucopyranoside (67) allowed the synthesis of 4-0-(D-2-propionyl-L-alanyl-D-isoglutamine)-D-glucopyranose (37) (47). 

After debenzylidenation of benzyl-4,6-0-benzylidene-N-acetyl-mura-myl-L-alanyl-D-isoglutamine benzyl ester in the usual manner by 60% acetic acid at 100°, the ensuing 4,6-diol derivative can be acylated spe-... 

To study the influence on the immunostimulant activity of MDP of a longer carbohydrate moiety, which mimics more closely the glycan strand of the peptidoglycan, N-acetyl-P-D-glucosaminyl-(l-4)-N-acetyl-muramyl-L-alanine and -L-alanyl-D-isoglutamine, (74) and (75) respectively, were synthesized. 

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