title: Towards aspirin-inspired self-immolating molecules which target the cyclooxygenases.
abstract: Cyclooxygenases (COXs) are enzymes that play a vital role in the inflammatory cascade through the generation of prostaglandins. Their over-expression has been implicated in numerous diseases. In particular, over-expression of COX-2 has been shown to be a predictive biomarker for progression of pre-malignant lesions towards invasive cancer in various tissues. This makes the early detection of COX-2 expressing lesions of high clinical relevance. Herein we describe the development of the first self-immolating trigger which targets COXs. We incorporated our trigger design into 2 activatable fluorogenic probes and demonstrated COX-specific activation in vitro. Experimental data revealed probe activation was likely caused by solvent-exposed amino acids on the surface of the COXs. Overall, the probes reported here mark the first step towards developing self-immolating imaging/therapeutic agents targeted to specific COXs.
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94107, USA. chris.drake@ucsf.edu.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Drake
authors.forename: Luis
authors.initials: L
authors.lastname: Estévez-Salmerón
authors.forename: Philippe
authors.initials: P
authors.lastname: Gascard
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.forename: Thea D
authors.initials: TD
authors.lastname: Tlsty
authors.forename: Ella F
authors.initials: EF
authors.lastname: Jones
mesh_terms: D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives* / Q000378:metabolism*; D002460:Cell Line; D051545:Cyclooxygenase 1 / Q000032:analysis / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D061848:Optical Imaging; D012756:Sheep; D013050:Spectrometry, Fluorescence; D013552:Swine
chemical_list: D005456:Fluorescent Dyes; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D001241:Aspirin