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  • Hybrid fluorescent conjugates of COX-2 inhibitors: search for a COX-2 isozyme imaging cancer biomarker.

Hybrid fluorescent conjugates of COX-2 inhibitors: search for a COX-2 isozyme imaging cancer biomarker.

Bioorganic & medicinal chemistry letters (2012-12-04)
Atul Bhardwaj, Jatinder Kaur, Sai Kiran Sharma, Zhangjian Huang, Frank Wuest, Edward E Knaus
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Rhodamine B, for fluorescence
Supelco
Rhodamine B solution, 0.2% in isopropanol, for TLC derivatization
Sigma-Aldrich
Rhodamine B, Dye content 90 %
Sigma-Aldrich
9(10H)-Acridanone, 99%
Sigma-Aldrich
Rhodamine B, ≥95% (HPLC)
Supelco
Rhodamine B, analytical standard