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Chemistry. 2016 Dec 5;22(49):17514-17525. doi: 10.1002/chem.201602947. Epub 2016 Sep 15.

Chemistry and Biology of HPAs: A Family of Ceramide Trafficking Inhibitors.

Author information

1
Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, 81237, Bratislava, Slovak Republic.
2
Normandie Univ, UNIHAVRE, CNRS, URCOM, Université du Havre, URCOM EA-3221, INC3 M CNRS FR-3038, UFR des Sciences et Techniques, 25 rue Philippe Lebon, B.P. 1123, 76063, Le Havre Cedex, France.
3
SPCMIB, UMR5068 CNRS-, Université Paul Sabatier-Toulouse III, 118 route de Narbonne, 31062, Toulouse, France.

Abstract

In 2001, two years before the disclosure of the CERT-associated Cer transfer machinery, N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)alkanamides (HPAs) were described as the first, and to date unique, family of intracellular Cer trafficking inhibitors. The dodecanamide derivative, HPA-12, turned out to be a benchmark as a cellular inhibitor of CERT-mediated de novo sphingomyelin biosynthesis. In only 15 years after its first disclosure, this compound has prompted a growing number of biological and chemical studies. Its initial chemical development closely paralleled the study of the CERT protein. It was only after its structural revision in 2011 that HPA-12 received broad attention from the synthetic chemistry community, leading to novel analogues with enhanced protein binding. This Minireview aims at presenting an exhaustive report of the syntheses of HPA-12 and analogues. Biological activities of this CERT inhibitor and structure-activity relationships are also presented to afford a comprehensive overview of the chemistry and biology of the HPA series.

KEYWORDS:

1,3-amino alcohol; CERT protein; HPA-12; ceramide; sphingolipids

PMID:
27628428
DOI:
10.1002/chem.201602947
[Indexed for MEDLINE]

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