Synthesis of New Polysialic Acid Derivatives

Abstract

In this paper we report the first synthesis of novel polysialic acid derivatives which is initiated by treatment of polysialic acid with EDC-HCl to yield the inter-residual delta-lactone. Subsequent reaction with amines or hydrazine gives the corresponding polysialic acid amides and hydrazide. Alkylation of the tetrabutylammonium salt of polysialic acid yields polysialic acid esters. In contrast a variety of N-derivatives of polysialic acid can be prepared starting from deacetylated polysialic acid. The N-derivatives prepared in this communication can be used for the Cu-catalyzed as well as Cu-free "click" chemistry.

Copper Mediated and Copper Free “Click” Decoration of Polysialic Acid for RGD‐Modification and Hydrogel Formation

“…The theoretical C/N quotient was corrected with respect to the degree of derivatization measured by integration of 1 H-NMR spectra. Polysialic Acid Hydrogel Formation Using Cu-Catalyzed "Click" Chemistry N-(4-Azidobutyryl) polysialic acid 2 [6] (10 mg, ds ¼ 60%) and N-(4-pentynoyl) polysialic acid 3 [6] (10 mg, ds ¼ 60%) were dissolved in distilled water (160 ml). Aqueous CuSO 4 (16 mL, 0.1 M) and sodium ascorbate (24 mL in water, 0.1 M) were added.…”

“…The heterogeneous system was heated at 80 C for 1 h and a sample was analyzed directly by UPLC-MS. Besides N- (4- Polysialic Acid Hydrogel Formation Using Metal-Free "Click" Chemistry N-(4-Azidobutyryl) polysialic acid 2 [6] (10 mg, ds ¼ 25-60%) and N-oxanorbornadiene polysialic acid 4 [6] (10 mg, ds ¼ 20-25%) were dissolved in distilled water (200 ml). After short vigorous shaking the reaction mixture was incubated at room temperature for 2-3 days to give a stable hydrogel.…”

“…The heterogeneous system was heated at 80 C for 1 h and a sample was analyzed directly by UPLC-MS. Besides N-(4-azidobutyryl) sialic acid (ESI, Preparation of cRGD-Polysialic Acid Via Cu-Catalyzed "Click" Reaction N-(4-Pentynoyl) poly sialic acid 3 [6] (5 mg, 0.016 mmol) and azido-cRGD 6 [7] (2 mg, 0.003 mmol) were dissolved in distilled water (1 mL). Aqueous CuSO 4 solution (40 mL, 0.1 M) and Na-ascorbate solution (60 mL, 0.1 M) were added to the reaction mixture.…”

“…The aqueous layer was finally concentrated to yield 12 as colorless oil (2.34 g, 11.4 mmol, 82%). Preparation of N-(1,2-Diol) Polysialic Acid 14 The tetra-N-butylammonium salt of g-amino polysialic acid 13 [6] (1.10 g, 2.2 mmol) was dissolved in anhydrous dimethylformamide (20 mL) and cooled to 0 C. N-Hydroxybenzotriazole (HOBt) (0.76 mg, 5.6 mmol), N,Ndiisopropylethylamine (DIPEA) (1.1 mL, 6.3 mmol) and EDC•HCl (1.07 g, 5.6 mmol) were added to the reaction mixture followed by carboxylic acid 12 (861 mg, 4.2 mmol) and stirred at room temperature over night. To acetylate the remaining free amino groups the reaction mixture was cooled to 0 C and acetic anhydride (0.5 mL) was added.…”

“…This encouraged us to design and synthesize polysialic acid derivatives that contain azido (2), alkynoyl (3) and oxanorbornadienyl (4) groups for performing selective Cu-catalyzed and Cu-free "click" cross-linking and grafting reactions (see Figure 1). [6] Especially the Cu-free click chemistry for grafting signal molecules such as cyclic RGD-peptides was already successfully applied to alginate. [7] In this paper, we describe the hydrogel formation and RGD decoration of polysialic acid based on Cucatalyzed and Cu-free [2 þ 3] cycloadditions of polysialic acid derivatives and azidomodified cyclic RGD peptide 6.…”