Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular receptor that recognizes the bacterial peptidoglycan fragment, muramyl dipeptide (MDP). Our group has synthesized and biologically evaluated desmuramyl peptides containing adamantane and...

The century-old, well-known odd–even effect phenomenon is still a very attractive and intriguing topic in supramolecular and nano-scale organic chemistry. As a part of our continuous efforts in the study of supramolecular chemistry, we have prepared three novel aromatic alcohols (1,2-bis [2-(hydroxymethyl)phenoxy]butylene (Do4OH), 1,2-bis[2-(hydroxymethyl)phenoxy]pentylene (Do5OH) and 1,2-bis[2-(hydroxymethyl)phenoxy]hexylene (Do6OH)) and determined their crystal and molecular structures by single-crystal X-ray diffraction. In all compounds, two benzyl alcohol groups are linked by an aliphatic chain of different lengths (CH2)n; n = 4, 5 and 6. The major differences in the molecular structures were found in the overall planarity of the molecules and the conformation of the aliphatic chain. Molecules with an even number of CH2 groups tend to be planar with an all-trans conformation of the aliphatic chain, while the odd-numbered molecule is non-planar, with partial gauche conformation. A direct consequence of these structural differences is visible in the melting points—odd-numbered compounds of a particular series display systematically lower melting points. Crystal and molecular structures were additionally studied by the theoretical calculations and the melting points were correlated with packing density and the number of CH2 groups. The results have shown that the generally accepted rule, higher density = higher stability = higher melting point, could not be applied to these compounds. It was found that the denser packaging causes an increase in the percentage of repulsive H‧‧‧H interactions, thereby reducing the stability of the crystal, and consequently, the melting points. Another interesting consequence of different molecular structures is their electrochemical and antioxidative properties—a non-planar structure displays the highest oxidation peak of hydroxyl groups and moderate antioxidant activity.

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Immune adjuvants are added to vaccines in order to enhance the immune response to an antigen. Muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine, is the smallest structural unit of peptidoglycans showing the immunostimulating activity. Muramyl dipeptide analogues without the hydrophilic N-acetylmuramyl moiety are called desmuramyl peptides. Here, we provide review of desmuramyl peptides which were synthesized in order to improve the pharmacological properties of parent muramyl dipeptide, including our results regarding adamantane containing derivatives. Approach for future design of novel immunostimulators based on multiple pathogen recognition receptor activation was also considered.

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Muramyl dipeptide (N-acetylmuramyl-L-alanyl-D-isoglutamine, MDP) is the smallest peptidoglycan fragment able to trigger an immune response by activating the NOD2 receptor. Structural modification of MDP can lead to analogues with improved immunostimulating properties. The aim of this work was to prepare mannosylated desmuramyl peptides (ManDMP) containing lipophilic triazole substituents to study their immunomodulating activities in vivo. The adjuvant activity of the prepared compounds was evaluated in the mouse model using ovalbumin as an antigen and compared to the MDP and referent adjuvant ManDMPTAd. The obtained results confirm that the α-position of D-isoGln is the best position for the attachment of lipophilic substituents, especially adamantylethyl triazole. Compound 6c exhibited the strongest adjuvant activity, comparable to the MDP and better than referent ManDMPTAd.

Muramyl dipeptide (MDP, N-acetylmuramyl-L-alanyl-D-isoglutamine) is known as the smallest synthetic adjuvant molecule capable of replacing whole Mycobacteria in Freund's adjuvant. Numerous MDP derivatives were synthesized with the aim to avoid MDP unwanted side-effects. Many of them have therapeutic potential, including clinical use. A very important parameter in the improvement of pharmacological properties of MDP is lipophilicity, e.g., it eliminates drawbacks caused by poor macrophage penetration and rapid elimination. On the other side, mannose receptors (MR), present on immunocompetent cells (such as macrophages and dendritic cells), are considered to be pattern-recognition receptors and responsible for the binding, among others, of mannosylated antigens or relevant biologically active molecules containing mannose, thus affecting the immune reactions. Up to now, our research was directed towards desmuramyl peptides which contain adamantylglycine and mannosylated adamantylglycine moieties bound to the essential part of MDP, L-Ala-D-isoGln. Here, we present the design and synthesis of novel mannosylated muropeptide analogs containing 2-aminoadamantane-2-carboxylic acid. Prepared desmuramyl peptides have lipophilic 2-aminoadamantane-2-carboxylic acid attached at the N-terminus of desmuramy dipeptide core and mannose connected to the tripeptide over a glycolyl linker. Immunostimulating activities of prepared compounds will be evaluated in the mice model using ovalbumin as an antigen and compared with previously prepared derivatives.