Straightforward Access to Spisulosine and 4,5-Dehydrospisulosine Stereoisomers: Probes for Profiling Ceramide Synthase Activities in Intact Cells

Abad, José Luı́s; Nieves, Ingrid; Rayo, Pedro; Casas, Josefina; Fabriás, Gemma; Delgado, Antonio

doi:10.1021/jo400440z

Cited by 48 publications

(47 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reaction rendered the acylated product ( R , R )‐ 14 in 39 % yield and 85 % ee , whereas the starting material was recovered in 40 % yield and 61 % ee , with an s ‐factor of 23. The absolute configuration of compound ( S , S )‐ 13 was assigned by comparison of the HPLC traces with the same product prepared from Garner's aldehyde by applying a stereospecific synthetic route (see the Supporting Information) . These results confirmed that the configuration of the carbon atom with the amino function determined the enantiomer being acylated, for a specific enantiomer of a catalyst, whereas the adjacent stereocentre had little influence on the final outcome of the KR process.…”

Section: Resultsmentioning

confidence: 72%

Enantioselective Synthesis of Aminodiols by Sequential Rhodium‐Catalysed Oxyamination/Kinetic Resolution: Expanding the Substrate Scope of Amidine‐Based Catalysis

Guasch

Giménez‐Nueno

Funes‐Ardoiz

et al. 2018

Chemistry A European J

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 72%

Enantioselective Synthesis of Aminodiols by Sequential Rhodium‐Catalysed Oxyamination/Kinetic Resolution: Expanding the Substrate Scope of Amidine‐Based Catalysis

Guasch

Giménez‐Nueno

Funes‐Ardoiz

et al. 2018

Chemistry A European J

View full text Add to dashboard Cite

show abstract

“…The 1-deoxysphinganine (1-deoxySA), which is formed by SPT through the condensation of palmitoyl-CoA and alanine, is N-acylated to 1-deoxy-dihydroceramides (5,16,17). However, while canonical dihydroceramides are converted to ceramides by the introduction of a 4,5 trans double bond (DB) (18,19), a 14,15 cis DB is most commonly introduced in 1-deoxy-dihydroceramides (20), indicating that 1-deoxySLs follow a different metabolic route than canonical SLs.…”

Section: Extraction and Analysis Of Sphingoid And Deoxysphingoid Basesmentioning

confidence: 99%

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Alecu¹,

Othman²,

Penno³

et al. 2017

Journal of Lipid Research

View full text Add to dashboard Cite

This article is available online at http://www.jlr.org Sphingolipid (SL) de novo synthesis typically starts with the condensation of serine and palmitoyl-CoA, a reaction catalyzed by serine palmitoyltransferase (SPT) (1-3). SPT can also use alanine in certain conditions (4), which results in the formation of the atypical cytotoxic 1-deoxysphingolipids (1-deoxySLs). These lack the C1-hydroxyl group of regular SLs, which is essential for further metabolic steps and degradation (4, 5). As such, 1-deoxySLs are commonly believed to be "dead-end" metabolites that accumulate within cells, tissues, and body fluids.Pathologically elevated 1-deoxySLs have been found in a number of neurological and metabolic disorders. They are a hallmark of hereditary sensory autonomic neuropathy type 1 (HSAN1), a rare autosomal dominant inherited peripheral neuropathy that is caused by various mutations in SPT. Plasma 1-deoxySLs are also elevated in patients with nondiabetic metabolic syndrome (MetS) and T2D (6) and may contribute to the development of diabetic sensory polyneuropathy (DSN), which is clinically very similar to HSAN1 (7,8). Both conditions start in the lower extremities with a loss of sensation often accompanied by positive sensory symptoms such as hyperpathia and neuropathic pain, as well as the development of painless wounds leading to ulcers (9, 10). L-serine supplementation was shown to effectively lower 1-deoxySL levels while improving Abstract The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic -cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D. (I.A., A.O., T.H., and A.v.E.) Abbreviations: ATRA, all-trans retinoic acid; CYP, cytochrome P450; DB, double bond; 1-deoxySA, 1-deoxysphinganine; 1-deoxySAdiene, deoxysphingadiene; 1-deoxySA-OH, hydroxyl-deoxysphinganine; 1-deoxySA-2OH, dihydroxyl-deoxysphinganine; 1-deoxySL, 1-deoxysphingolipid; 1-deoxySO, 1-deoxysphingosi...

show abstract

“…The nucleophilic addition of zirconocene compounds to aldehydes was reported by Delgado and co‐workers. This stereoselective method was used in the first step of the total synthesis of Spisulosine ( 117 ) and 4,5‐dehydrospisulosine ( 118 ) (Scheme ) . The hydrozirconation of 1‐pentadecyne ( 113 ) with Schwartz's reagent followed by the addition into N ‐Boc‐ l ‐alaninal, afforded the desired sphingoid base ( 116 ) as a mixture of diastereomers.…”

Section: Addition Of Organozirconium Species Into Imines and Aldehydesmentioning

confidence: 99%

Recent Developments and Synthetic Applications of Nucleophilic Zirconocene Complexes from Schwartz's Reagent

2018

View full text Add to dashboard Cite

Organozirconium chemistry has been widely employed in organic synthesis since its discovery in the last century. In this context, Schwartz's reagent stands out as a powerful tool that has been applied in several chemical transformations. This chemistry has attracted considerable attention due to its versatility, allowing chemoselective C–C, C–N, and C–X bond formation, as well as hydrozirconation. The reagent is in fact a zirconium‐containing metallocene, which is compatible with the presence of various metals in cross‐coupling reactions. Enantioselective transformations of organozirconium are described here, which have recently found wide applications in total synthesis. Furthermore, aspects covering ring‐closure reactions, affording complex stereoenriched cycles and heterocycles, such as substituted cyclopropanes and pyrrolidines, are hereby disclosed.

show abstract

Straightforward Access to Spisulosine and 4,5-Dehydrospisulosine Stereoisomers: Probes for Profiling Ceramide Synthase Activities in Intact Cells

Cited by 48 publications

References 43 publications

Enantioselective Synthesis of Aminodiols by Sequential Rhodium‐Catalysed Oxyamination/Kinetic Resolution: Expanding the Substrate Scope of Amidine‐Based Catalysis

Enantioselective Synthesis of Aminodiols by Sequential Rhodium‐Catalysed Oxyamination/Kinetic Resolution: Expanding the Substrate Scope of Amidine‐Based Catalysis

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Recent Developments and Synthetic Applications of Nucleophilic Zirconocene Complexes from Schwartz's Reagent

Contact Info

Product

Resources

About