Development of solvent-free protocols for obtaining highly substituted maleates of hyaluronic acid and other glycosaminoglycans

摘要

Solvent-free protocols using microwave-assisted heating (i) or conventional heating without additives (ii) or adding K2CO3 (iii), or triturating at room temperature in the presence of K2CO3 (iv) were first used to esterify glycosaminoglycans (GAG) with maleic anhydride. High and low molecular weight hyaluronic acid (HMW and LMW HA), dermatan sulfate (Ds), heparin (HEP) and C6-oxidized HA (carboxy-HA) were used as substrates for maleation. Protocols (i)-(iii) were most effective for obtaining maleates with high DS (1.39-2.47), but had a strong degrading effect on GAG. Protocol (iv) did not have destructive effect, but was suitable for obtaining only HMW HA maleate (DS 0.71-1.15). Primary hydroxyl groups of HA and Ds showed a higher reactivity compared to the secondary ones. A specific feature of the HEP maleation was substitution of N-sulfate groups for N-maleate groups. To demonstrate the potential of the obtained maleates for thiol-ene click-chemical strategies, the reaction with L-cysteine was performed.