Total synthesis of photoactivatable or fluorescent anandamide probes: novel bioactive compounds with angiogenic activity.
Endocannabinoids are endogenous polyunsaturated fatty acids involved in a multitude of health and disease processes. Recently, several lines of evidence suggest the presence of a novel non-CB1/CB2 anandamide receptor in endothelial cells. Thus, we synthesized two types of photoaffinity probes that contain either an arylazide group or a diazirin moiety, together with a fluorescent analogue. The key steps rely on selective hydrogenation of skipped tetrayne backbones and on copper-mediated cross-coupling reactions between diynic precursors. Three synthetic routes were investigated. In biological functional assays, we found that both the arylazide and the fluorescent probes induced robust increases in matrix metalloprotease activity and produced positive angiogenic responses in in vitro endothelial cell tube formation assays. Irradiation of the arylazide probe nicely enhanced this effect in both HUVEC and CB1-KO HUVEC. These results suggest that the arylazide and the fluorescent probes can be used to identify "non-CB1/CB2 anandamide receptor" from endothelial cells.
Balas
Laurence
L
Institut des Biomolécules Max Mousseron, UMR 5247 CNRS, Université de Montpellier I, 15, Av. Ch. Flahault, F-34093 Montpellier Cedex 05, France. balas@univ-montp1.fr
Durand
Thierry
T
Saha
Sattyabrata
S
Johnson
Inneke
I
Mukhopadhyay
Somnath
S
D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D001386:Azides; D001389:Azirines; D063385:Cannabinoid Receptor Modulators; D002478:Cells, Cultured; D063388:Endocannabinoids; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology; D005456:Fluorescent Dyes / Q000138:chemical synthesis; D006801:Humans; D020782:Matrix Metalloproteinases / Q000187:drug effects* / Q000378:metabolism; D015335:Molecular Probes / Q000138:chemical synthesis*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019920:Photoaffinity Labels / Q000138:chemical synthesis; D053284:Polyunsaturated Alkamides / Q000138:chemical synthesis* / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2
D001095:Arachidonic Acids; D001386:Azides; D001389:Azirines; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005456:Fluorescent Dyes; D015335:Molecular Probes; D019920:Photoaffinity Labels; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; D020782:Matrix Metalloproteinases; C078814:anandamide