A convenient synthesisof water-soluble carbodiimides.
Notes- A Convenient Synthesis of Water-Soluble ..
One of the important factors for good solid-phase reactivity in water is the homogeneous mixing of the nanoparticulate amino acids and a resin. Since active surfactants are known as excellent dispersible agents, nanosuspensions of protected amino acids dispersed with active surfactants would lead to further good reactivity even in water. Triton X-100 is known to inhibit aggregation of the peptide chain. We examined preparation of dispersible Fmoc-amino acid nanoparticles in water containing Triton X-100 as a dispersion agent. The sizes of the resulting water-dispersible nanoparticles were summarized in Table . The best condition is entry 2 in which nanoparticles were prepared in aqueous 0.2% Triton X-100 solution using 0.5 mm zirconium oxide beads. The minimum average particle size observed was 217 nm. It was not possible to reduce the sizes of all particles to 100 nm or less. Next we synthesized Leu-enkephalinamide by in-water solid-phase method described in Table using dispersible Fmoc-amino acid nanoparticles in water containing Triton X-100 . HPLC analysis showed a single major peak corresponding to Leu-enkephalinamide, and the total yield was 79%. The purities of crude peptides cleaved from the resin were over 90% and similar to the results by the general Fmoc synthesis method using organic solvents.
Notes- A Convenient Synthesis of Water-Soluble Carbodiimides.
Amphotericin B (AmB), a well-known polyene antifungal agent displays a marked tendency to self-associate and, as a consequence, exhibits very poor solubility in water. The therapeutic index of AmB is low, and is associated with significant dose-related nephrotoxicity, as well as acute, infusion-related febrile reactions. Reports in the literature indicate that that toxicity of AmB may be related to the physical state of the drug. Reaction of AmB in dimethylformamide with bis(dimethylaminopropyl)carbodiimide yielded an unexpected N-alkylguanidine/N-acylurea bis-adduct of AmB which was highly water soluble. The absorption spectrum of the AmB derivative in water indicated excellent monomerization, and the anti-fungal activities of reference AmB and its water-soluble derivative against C. albicans were found to be virtually identical. Furthermore, the water-soluble adduct is significantly less active in engaging TLR4 which would suggest that the adduct may be less proinflammatory.