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. 2023 Jun 12;24(6):2522-2531.
doi: 10.1021/acs.biomac.3c00045. Epub 2023 Apr 28.

Multi-step Strategies Toward Regioselectively Sulfated M-Rich Alginates

Fabiana Esposito  1 , Antonio Laezza  2 , Valentina Gargiulo  3 , Serena Traboni  1 , Alfonso Iadonisi  1 , Annalisa La Gatta  4 , Chiara Schiraldi  4 , Emiliano Bedini  1
Affiliations

Multi-step Strategies Toward Regioselectively Sulfated M-Rich Alginates

Fabiana Esposito et al. Biomacromolecules. .

Abstract

Sulfated alginates (ASs), as well as several artificially sulfated polysaccharides, show interesting bioactivities. The key factors for structure-activity relationships studies are the degree of sulfation and the distribution of the sulfate groups along the polysaccharide backbone (sulfation pattern). The former parameter can often be controlled through stoichiometry, while the latter requires the development of suitable chemical or enzymatic, regioselective methods and is still missing for ASs. In this work, a study on the regioselective installation of several different protecting groups on a d-mannuronic acid enriched (M-rich) alginate is reported in order to develop a semi-synthetic access to regioselectively sulfated AS derivatives. A detailed structural characterization of the obtained ASs revealed that the regioselective sulfation could be achieved complementarily at the O-2 or O-3 positions of M units through multi-step sequences relying upon a silylating or benzoylating reagent for the regioselective protection of M-rich alginic acid, followed by sulfation and deprotection.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Schematic representation of the chemical structure of alginate polysaccharides.
Scheme 1
Scheme 1. Different Strategies for the Regioselective Protection of M-rich Alginic Acid: (A) Direct Regioselective Protection of 2,3-Diols or (B) Installation and Regioselective Cleavage of Cyclic Protecting Groups
aH2SO4, CH3OH, 60 °C; bTBDMSCl (or TDMSCl, or TIPSCl), imidazole, DMF, 50 °C; cBz2O, DIPEA, DMF, rt; dBzCN, DMAP, 9:1 v/v DMF-pyridine, rt; ePhC(OCH3)3, CSA, DMF, rt; f9:1 v/v AcOH-H2O, rt; gPhCH(OCH3)2, CSA, DMF, 80 °C; hNaBrO3, Na2S2O4, H2O-ethyl acetate, rt; iBz2O, DMF, 85 °C; jDMAP, pyridine, rt; kNaOAc, CH3OH, rt.
Scheme 2
Scheme 2. Semi-synthesis of Sulfated Alginates AS-1-10 from M-rich Alginic Acid and Partially Protected Derivatives Thereof
aSO3·py, DMF, 50 °C; baq. H2SO4 (pH ∼ 2), 50 °C; caq. NaOH (pH ≥ 12), rt.
Figure 2
Figure 2
Superimposition of zoomed (A) 1H NMR, 1H,13C-HSQC (black), and 1H,13C-HMBC (blue) 2D-NMR (densities enclosed in dotted lines were integrated for DS estimation) and (B) 1H NMR, COSY (black), and NOESY (green) 2D-NMR spectra (600 MHz, 298 K, D2O) of AS-1 (only some correlations are indicated).
Figure 3
Figure 3
Superimposition of zoomed 1H NMR and 1H,13C-HSQC 2D-NMR spectra (600 MHz, 298 K, D2O) of AS-1 (red) and AS-3 (black) (the assignment only of the signals differing between the two derivatives is here indicated).
See this image and copyright information in PMC

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