Herein, we applied PmST1 (a sialyltransferase) to achieve acceptor-mediated regioselective sialylation (AMRS) on the nonreducing end GalNH2 or GalAz (N-azidogalactosamine). Thus, C5 and C8-modified sialic acid was efficiently assembled on...
LLG‐5 1 is a Neu5Gc8Me‐containing echinoderm ganglioside (EG) isolated from starfish Linckia laevigata. It showed neuritogenic activity toward the rat adrenal pheochromocytoma cell line PC‐12. The first chemoenzymatic total synthesis of the trisialoganglioside LLG‐5 1 has been accomplished by utilizing a convergent [2+3] coupling between a Neu5Gc8Meα(2→5)Neu5Gc‐linked disialoside and a C5‐amino GM3 ceramide, Neu5NH2(2→3)Galβ(1→4)Glcβ‐Cer. A photoactivatable lactosyl phytosphingosine bearing a sulphonate moiety was developed to permit aqueous buffer solubility of the hydrophobic glycolipid acceptor for enzymatic α(2,3) sialylation. In addition, the synthetic route is flexible, allowing non‐natural LLG‐5 analogues in native lengths with or without modification at C8 of the terminal Neu5Gc and/or N‐acyl component, further expanding the diversity of LLG‐5 structures that could be achieved. The developed synthetic strategy may enable access to other EGs.
Structural variants of α-galactosylceramide (α-GalCer) that stimulate invariant natural killer T (iNKT) cells constitute an emerging class of immunomodulatory agents in development for numerous biological applications. Variations in lipid chain length and/or fatty acids in these glycoceramides selectively trigger specific pro-inflammatory responses. Studies that would link a specific function to a structurally distinct α-GalCer rely heavily on the availability of homogeneous and pure materials. To address this need, we report herein a general route to the diversification of the ceramide portion of α-GalCer glycolipids. Our convergent synthesis commences from common building blocks and relies on the Julia–Kocienski olefination as a key step. A cleavable fluorous tag is introduced at the non-reducing end of the sugar that facilitates quick purification of products by standard fluorous solid-phase extraction. The strategy enabled the rapid generation of a focused library of 61 α-GalCer analogs by efficiently assembling various lipids and fatty acids. Furthermore, when compared against parent α-GalCer in murine cells, many of these glycolipid variants were found to have iNKT cell stimulating activity similar to or greater than KRN7000. ELISA assaying indicated that glycolipids carrying short fatty N-acyl chains (1fc and 1ga), an unsubstituted (1fh and 1fi) or CF3-substituted phenyl ring at the lipid tail, and a flexible, shorter fatty acyl chain with an aromatic ring (1ge, 1gf, and 1gg) strongly affected the activation of iNKT cells by the glycolipid-loaded antigen-presenting molecule, CD1d. This indicates that the method may benefit the design of structural modifications to potent iNKT cell-binding glycolipids.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.