Chemoenzymatic Total Synthesis of the Neuritogenic Echinoderm Ganglioside LLG-5 and Related Analogues

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 Neu5Gc8Me alpha(2 -> 5)Neu5Gc-linked disialoside and a C5-amino GM3 ceramide, Neu5NH(2)(2 -> 3)Gal beta(1 -> 4)Glc beta-Cer. A photoactivatable lactosyl phytosphingosine bearing a sulphonate moiety was developed to permit aqueous buffer solubility of the hydrophobic glycolipid acceptor for enzymatic alpha(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.

Automated summary

In this study, a chemoenzymatic synthesis of the trisialoganglioside LLG-5 1 was accomplished, exhibiting neuritogenic activity. A photoactivatable lactosyl phytosphingosine was developed to enable solubility in enzymatic reactions. This synthetic strategy may be applicable for the synthesis of other gangliosides.