A Straightforward Protocol for the Solution‐Phase Parallel Synthesis of Ceramide Analogues

Grijalvo, Santiago; Matabosch, Xavier; Llebaría, Amadeu; Delgado, Antonio

doi:10.1002/ejoc.200700814

Cited by 7 publications

(4 citation statements)

References 15 publications

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“…ture, 7 no ensuing elimination products are usually found, as illustrated in our previous work involving a similar process from an aryloxy derivative structurally related to 2A. 8 We rationalize the unexpected reaction outcome from 2A as a result of the higher acidity of the vicinal methylene protons a to the sulfur atom in intermediate 5A, thus triggering the observed elimination process.…”

supporting

confidence: 69%

An Unexpected Access to a New Sphingoid Base Containing a Vinyl Sulfide Unit

Nieves¹,

Garrido²,

Abad³

et al. 2010

Synlett

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An unexpected access to a new sphingoid base containing a vinyl sulfide unit is described. The process involves the 'onepot' regioselective opening of an epoxide with a thiolate, followed by intramolecular acyl transfer, base-promoted elimination, and final hydrolysis. Excess sodium hydride and high dilution conditions are required for optimal yields. The process is amenable to a variety of thiolates. The resulting compounds can be regarded as new hybrid sphingoid bases that combine some structural motifs present in other reported sphingolipid analogues.

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supporting

confidence: 69%

An Unexpected Access to a New Sphingoid Base Containing a Vinyl Sulfide Unit

Nieves¹,

Garrido²,

Abad³

et al. 2010

Synlett

Self Cite

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“…Recognising that variation in the sphingosine and fatty acid alkyl chains could be introduced by simple cross metathesis and amine acylation respectively, 46 the problem simplified to generation of a set of core hydroxybutenyl amine scaffolds, which in turn could be accessed from readily available a-amino acids, Scheme 1. [26][27][28][29][30][31][32][33][34] Scheme 1 Retrosynthetic Analysis of the common scaffold.…”

Section: Synthesis Of Ceramide Analogue Librarymentioning

confidence: 99%

Exploring Leishmania major Inositol Phosphorylceramide Synthase (LmjIPCS): Insights into the ceramide binding domain

et al. 2011

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The synthesis of set of ceramide analogues exploring hydrophobicity in the acyl chains and the degree and nature of hydroxylation is described. These have been assayed against the parasitic protozoan enzyme LmjIPCS. These studies showed that whilst the C-3 hydroxyl group was not essential for turnover it provided enhanced affinity. Reflecting the membrane bound nature of the enzyme a long (C 13 ) hydrocarbon ceramide tail was necessary for both high affinity and turnover. Whilst the N-acyl chain also contributed to affinity, analogues lacking the amide linkage functioned as competitive inhibitors in both enzyme and cell-based assays. A model that accounts for this observation is proposed.

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“…[37] Delgado also published the solid phase synthesis of relatedp henyl ether-containing truncated Cer analogues( 6,Scheme 1). [38] No biological activities were associated to these derivatives. On the other hand, Park described pharmacologically relevant modifications of the sphingosine backbone in as eries of analogues of the immunostimulatory a-galactosylphytoceramide KRN7000( 10-12, Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

“…Bittman described a Cer analogue with the double bond of the sphingoïd base as part of the phenyl (or pyridyl) moiety ( 7 and 8 , Scheme ), whereas Reissig reported the corresponding Cer‐1‐phosphate derivative ( 9 , Scheme ) . Delgado also published the solid phase synthesis of related phenyl ether‐containing truncated Cer analogues ( 6 , Scheme ) . No biological activities were associated to these derivatives.…”

Section: Resultsmentioning

confidence: 99%

Asymmetric Synthesis and Binding Study of New Long‐Chain HPA‐12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT

Ďuriš

Daı̈ch

Santos

et al. 2016

Chemistry A European J

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A series of 12 analogues of the Cer transfer protein (CERT) antagonist HPA-12 with long aliphatic chains were prepared as their (1R,3S)-syn and (1R,3R)-anti stereoisomers from pivotal chiral oxoamino acids. The enantioselective access to these intermediates as well as their ensuing transformation relied on a practical crystallization-induced asymmetric transformation (CIAT) process. Sonogashira coupling followed by triple bond reduction and thiophene ring hydrodesulfurization (HDS) into the corresponding alkane moieties was then implemented to complete the synthetic routes delivering the targeted HPA-12 analogues in concise 4- to 6-step reaction sequences. Ten compounds were evaluated regarding their ability to bind to the CERT START domain by using the recently developed time-resolved FRET-based homogeneous (HTR-FRET) binding assay. The introduction of a lipophilic appendage on the phenyl moiety led to an overall 10- to 1000-fold enhancement of the protein binding, with the highest effect being observed for a n-hexyl residue in the meta position. The importance of the phenyl ring for the activity was indicated by the reduced potency of the 3-deoxyphytoceramide aliphatic analogues. The 1,3-syn stereoisomers were systematically more potent than their 1,3-anti analogues. In silico studies were used to rationalized these trends, leading to a model of protein recognition coherent with the stronger binding of (1R,3S)-syn HPAs.

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A Straightforward Protocol for the Solution‐Phase Parallel Synthesis of Ceramide Analogues

Cited by 7 publications

References 15 publications

An Unexpected Access to a New Sphingoid Base Containing a Vinyl Sulfide Unit

An Unexpected Access to a New Sphingoid Base Containing a Vinyl Sulfide Unit

Exploring Leishmania major Inositol Phosphorylceramide Synthase (LmjIPCS): Insights into the ceramide binding domain

Asymmetric Synthesis and Binding Study of New Long‐Chain HPA‐12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT

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