Chemical Synthesis of Marine-Derived Sulfoglycolipids, a New Class of Molecular Adjuvants

Abstract

Vaccines play a primary role in the protection of human health by preventing infectious and chronic diseases. Recently we have reported 1,2-O-distearoyl-3-O-β-d-sulfoquinovosylglycerol (β-SQDG18), here named Sulfavant A (1), which shows promising properties as a new molecular adjuvant in in vitro and in vivo tests. In the present manuscript, we provide full details about a synthetic strategy for the preparation of 1, including a discussion of chemical determinants of the activity and the major technical hurdles we faced during the study. Synthesis of Sulfavant A (1) is achieved by a versatile procedure based on a trichloroacetimidate methodology and peracetate sugar precursors. The final design opens possibilities for the preparation of a series of interesting analogs for further pharmacological optimization and development, including derivatives containing different saturated and polyunsaturated fatty acids (e.g., 17 and 22).

Preparation, Supramolecular Aggregation and Immunological Activity of the Bona Fide Vaccine Adjuvant Sulfavant S

“…Sulfavants are bioactive molecules able to induce DC maturation and trigger an adaptive immune response in vivo [13][14][15]. The activity of these products is largely dependent on the formation of colloidal particles under aqueous conditions [12].…”

“…In this context, we recently characterized β-sulfoquinovosyl-diacyl glycerols (β-SQDGs) as a novel class of vaccine adjuvants collectively named Sulfavants. These synthetic molecules were inspired by natural and marine α-sulfoquinovosyl-diacylglycerols (α-SQDGs) occurring as membrane constituents in photosynthetic organisms [12][13][14][15].…”

“…In this context, we recently characterized β-sulfoquinovosyl-diacyl glycerols (β-SQDGs) as a novel class of vaccine adjuvants collectively named Sulfavants. These synthetic molecules were inspired by natural and marine α-sulfoquinovosyl-diacylglycerols (α-SQDGs) occurring as membrane constituents in photosynthetic organisms [ 12 , 13 , 14 , 15 ]. Sulfavant A ( 1 ) (1,2- O -distearoyl-3- O -(β-sulfoquinovosyl)- R/S -glycerol), the prototype of the family, induces maturation of human dendritic cells (hDCs) at micromolar concentrations with a typical “bell-shaped” dose–response curve that is featured by a maximum around 10 μM.…”

“…Sulfavant A ( 1 ) (1,2- O -distearoyl-3- O -(β-sulfoquinovosyl)- R/S -glycerol), the prototype of the family, induces maturation of human dendritic cells (hDCs) at micromolar concentrations with a typical “bell-shaped” dose–response curve that is featured by a maximum around 10 μM. Sulfavant A ( 1 ) also showed promising adjuvant activity in in vivo experiments, as it was able both to boost immune protection in mice and to inhibit tumor growth in an experimental model of cancer vaccine against melanoma [ 13 , 14 , 15 ].…”

Monoacylglycerides from the Diatom Skeletonema marinoi Induce Selective Cell Death in Cancer Cells

“…Miralto et al [14] reported that diatom unsaturated aldehydes had antiproliferative effects on Caco-2 cells derived from a human colon adenocarcinoma; Sansone et al [15] showed similar effects on colon COLO-205 and lung A-549 adenocarcinoma cell lines. Manzo et al [16,17] claimed immunomodulatory activity of Sulfavant A, a synthetic glycolipid, which is a prototype for a new class of molecular vaccine adjuvants based on a sulfolipid skeleton and structurally inspired by natural α-D-sulfoquinovosyl-diacylglycerols purified from the marine diatom Thalassiosira weissflogii . Furthermore, from the same diatom species, very recently, a novel phosphatidylmonogalactosylglycerol lipid (PGDG) rich in polyunsaturated fatty acids (PUFA) was isolated, which showed immunostimulatory activity mediated by Toll-like receptor-4 in dendritic cells [18].…”