Stereoselective Synthesis of Novel Sphingoid Bases Utilized for Exploring the Secrets of Sphinx

Abstract

Sphingolipids are ubiquitous in eukaryotic plasma membranes and play major roles in human and animal physiology and disease. This class of lipids is usually defined as being derivatives of sphingosine, a long-chain 1,3-dihydroxy-2-amino alcohol. Various pathological conditions such as diabetes or neuropathy have been associated with changes in the sphingolipidome and an increased biosynthesis of structurally altered non-canonical sphingolipid derivatives. These unusual or non-canonical sphingolipids hold great promise as potential diagnostic markers. However, due to their low concentrations and the unavailability of suitable standards, the research to explore the secret of this class of ‘Sphinx’ lipids is ultimately hampered. Therefore, the development of efficient and facile syntheses of standard compounds is a key endeavor. Here, we present various chemical approaches for stereoselective synthesis and in-depth chemical characterization of a set of novel sphingoid bases which were recently utilized as valuable tools to explore the metabolism and biophysical properties of sphingolipids, but also to develop efficient analytical methods for their detection and quantification.

1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development

“…To determine structure-activity relationship, we tested variants of active 1-deoxysphingolipids (Saied and Arenz, 2021;Saied et al, 2018). 1-deoxySO with D14 double bond in the sphingoid base (Steiner et al, 2016) promoted transcriptional activity of native full-length NR2F2 in HeLa cells with a Kd = 126 nM (Figure 2C).…”

The Role of Sphingolipid Signaling in Oxidative Lung Injury and Pathogenesis of Bronchopulmonary Dysplasia

“…BPD [29,30] Pulmonaryfibrosis [79,100] Cancer [101] SK2 modulators ABC294640 (Opaganib) Cancer [102] CERS inhibitors CERS 2, 4, and 6 Cancer [103] Cerk inhibitors NVP-231 Cancer [104] Recently the role of deoxysphingolipids came to light in various pathological disorders [105]. As explained earlier, SPT, physiologically conjugates l-serine and palmitoyl-CoA to form 3-keto-phinganine, which is converted to sphinganine [54,106]. However, in an alternative reaction, SPT promotes binding of L-alanine with palmitoyl-CoA to form 1-deoxysphinganine or conjugation of glycine with palmitoyl-CoA to form 1-deoxymethylsphinganine [107,108].…”

“…Deoxyshingolipids lacks C1-OH-group present in canonical sphingolipids. Due to the absence of C1-OH-group, deoxysphingolipids are not terminally degraded by S1P-lyase, leading to their accumulation in the tissues [106,108]. L-serine depletion leads to formation of 1-deoxysphingolipids, which promotes senescence [109,110].…”

Bile acids and sphingolipids in non-alcoholic fatty liver disease

“…Ceramide can then be further transformed into ceramide-1 phosphate, acyl ceramide, sphingomyelin, glycoceramides, or sphingosine. [ 21 , 35 ] Like sphingosine-1 phosphate (S1P), ceramide is also an important bioactive molecule. So far, over 200 ceramides and 28 ceramide synthases (CerS) have been discovered in mammals.…”