Synthesis and convenient functionalization of azide-labeled diacylglycerol analogues for modular access to biologically active lipid probes

Matthew D. Smith, Denghuang Gong, Christopher G. Sudhahar, Justin C. Reno, Robert V. Stahelin, Michael D. Best

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Cell membrane lipids have been identified as key participants in cell signaling activities. One important role is their involvement as site-specific ligands in protein-membrane binding interactions, which result in the anchoring of peripheral proteins onto cellular membranes. These events generally regulate protein function and localization and have been implicated in both normal physiological processes and those pertaining to disease state onset. Thus, it is important to elucidate the details of interactions at the molecular level, such as lipid-binding specificities and affinities, the location of receptor binding domains and multivalency in binding. For this purpose, we have designed and developed azido-tagged lipid analogues as conveniently functionalizable lipid probe scaffolds. Herein, we report the design and synthesis of the initial structure of this type, diacylglycerol analogue 2, which contains an azide tag at the sn-1 position of the lipid headgroup. Direct functionalization of this compound with a range of reporter groups has been performed to illustrate the facile access to probes of use for characterizing binding. Quantitative lipid-binding studies using protein kinase C, a known DAG-binding receptor, demonstrate that these probes are active mimetics of natural DAG. Thus, these DAG probes will serve as robust sensors for studies aimed at understanding binding interactions and as precursors for the development of analogous probes of more complex phospholipids and glycolipids.

Original languageEnglish (US)
Pages (from-to)1855-1863
Number of pages9
JournalBioconjugate Chemistry
Volume19
Issue number9
DOIs
StatePublished - Sep 1 2008

Fingerprint

Azides
Diglycerides
Lipids
Proteins
Physiological Phenomena
Cell signaling
Membranes
Glycolipids
Phospholipids
Membrane Lipids
Protein Binding
Scaffolds
Protein Kinase C
Membrane Proteins
Ligands
Sensors

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

Cite this

Synthesis and convenient functionalization of azide-labeled diacylglycerol analogues for modular access to biologically active lipid probes. / Smith, Matthew D.; Gong, Denghuang; Sudhahar, Christopher G.; Reno, Justin C.; Stahelin, Robert V.; Best, Michael D.

In: Bioconjugate Chemistry, Vol. 19, No. 9, 01.09.2008, p. 1855-1863.

Research output: Contribution to journalArticle

Smith, Matthew D. ; Gong, Denghuang ; Sudhahar, Christopher G. ; Reno, Justin C. ; Stahelin, Robert V. ; Best, Michael D. / Synthesis and convenient functionalization of azide-labeled diacylglycerol analogues for modular access to biologically active lipid probes. In: Bioconjugate Chemistry. 2008 ; Vol. 19, No. 9. pp. 1855-1863.
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