title: Hybrid fluorescent conjugates of COX-2 inhibitors: search for a COX-2 isozyme imaging cancer biomarker.
abstract: The observation that the cyclooxygenase-2 (COX-2) isozyme is over-expressed in multiple types of cancer, relative to that in adjacent non-cancerous tissue, prompted this investigation to prepare a group of hybrid fluorescent conjugates wherein the COX inhibitors ibuprofen, (S)-naproxen, acetyl salicylic acid, a chlororofecoxib analog and celecoxib were coupled via a linker group to an acridone, dansyl or rhodamine B fluorophore. Within this group of compounds, the ibuprofen-acridone conjugate (10) showed potent and selective COX-2 inhibition (COX-2 IC(50)=0.67 μM; SI=110.6), but its fluorescence emission (λ(em)=417, 440 nm) was not suitable for fluorescent imaging of cancer cells that over-express the COX-2 isozyme. In comparison, the celecoxib-dansyl conjugate (25) showed a slightly lower COX-2 potency and selectivity (COX-2 IC(50)=1.1 μM; SI>90) than the conjugate 10, and it possesses a better fluorescence emission (λ(em)=500 nm). Ultimately, a celecoxib-rhodamine B conjugate (28) that exhibited moderate COX-2 potency and selectivity (COX-2 IC(50)=3.9 μM; SI>25) having the best fluorescence emission (λ(em)=580 nm) emerged as the most promising biomarker for fluorescence imaging using a colon cancer cell line that over-expresses the COX-2 isozyme.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Atul
authors.initials: A
authors.lastname: Bhardwaj
authors.forename: Jatinder
authors.initials: J
authors.lastname: Kaur
authors.forename: Sai Kiran
authors.initials: SK
authors.lastname: Sharma
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.forename: Frank
authors.initials: F
authors.lastname: Wuest
authors.forename: Edward E
authors.initials: EE
authors.lastname: Knaus
mesh_terms: D000166:Acridines / Q000737:chemistry; D054831:Acridones; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D005456:Fluorescent Dyes / Q000737:chemistry*; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry; D018613:Microscopy, Confocal; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry; D012235:Rhodamines / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D000166:Acridines; D054831:Acridones; D014408:Biomarkers, Tumor; D052246:Cyclooxygenase 2 Inhibitors; D005456:Fluorescent Dyes; D011720:Pyrazoles; D012235:Rhodamines; D013449:Sulfonamides; C041300:acridone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000068579:Celecoxib; C029773:rhodamine B; D007052:Ibuprofen