Biodiversity of sphingoid bases ("sphingosines") and related amino alcohols

Abstract

"Sphingosin" was first described by J. L. W. Thudichum in 1884 and structurally characterized as 2S,3R,4E-2-aminooctadec-4-ene-1,3-diol in 1947 by Herb Carter, who also proposed the designation of "lipides derived from sphingosine as sphingolipides." This category of amino alcohols is now known to encompass hundreds of compounds that are referred to as sphingoid bases and sphingoid base-like compounds, which vary in chain length, number, position, and stereochemistry of double bonds, hydroxyl groups, and other functionalities. Some have especially intriguing features, such as the tail-to-tail combination of two sphingoid bases in the alpha,omega-sphingoids produced by sponges. Most of these compounds participate in cell structure and regulation, and some (such as the fumonisins) disrupt normal sphingolipid metabolism and cause plant and animal disease. Many of the naturally occurring and synthetic sphingoid bases are cytotoxic for cancer cells and pathogenic microorganisms or have other potentially useful bioactivities; hence, they offer promise as pharmaceutical leads. This thematic review gives an overview of the biodiversity of the backbones of sphingolipids and the broader field of naturally occurring and synthetic sphingoid base-like compounds.

Fig. 1.

Biosynthesis and turnover of the three major categories of sphingoid bases in mammalian cells. DHR, dihydroceramide; SPT, serine palmitoyltransferase.

Fig. 2.

Sphingoid bases of mammalian tissues.

Fig. 3.

Sphingoid bases found in diverse organisms other than mammals.

Fig. 4.

Sphingoid base-like compounds that mimic metabolites and/or inhibit early steps of sphingolipid metabolism. In the category “not sphingoid bases” are tricarballylic acid, which is the “R” group found on fumonisins and AAL toxins, and australifungin, which is shown as an example of a ceramide synthase inhibitor that is not a sphingoid base-like compound.

Fig. 5.

Structures of the major members of the fumonisin (A) and AAL toxin (C) families. Also shown are a compound with a fumonisin-like backbone but without side chain hydroxyls (B) and the sphingomyelinase inhibitor scyphostatin (D).

Fig. 6.

Novel sphingoid base-like compounds. A: 1-Deoxy compounds. B: α,ω-Bifunctional sphingoid bases. C: Sphingoid base-like compounds with sulfonic acid.

Fig. 7.

Sphingoid base-like compounds with heterocyclic rings.

Fig. 8.

Common chemical reactions that modify sphingoid bases. A: The formation and decomposition of sphingoid base chloramines due to myeloperoxidase generated reactive chlorination species. B, C: Reactions of sphingoid bases and ceramides under acidic conditions.

Fig. 9.

Examples of compounds of interest as sphingoid base/ceramide analog pharmaceutical leads.