Design, Synthesis, and Structure–Activity Relationship Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted Optical Imaging Agents
Open Access
- 28 March 2013
- journal article
- research article
- Published by American Chemical Society (ACS) in Bioconjugate Chemistry
- Vol. 24 (4), 712-723
- https://doi.org/10.1021/bc300693w
Abstract
Cycloxygenase-2 (COX-2) is an attractive target for molecular imaging because it is an inducible enzyme that is expressed in response to inflammatory and proliferative stimuli. Recently, we reported that conjugation of indomethacin with carboxy-X-rhodamine dyes results in the formation of effective, targeted, optical imaging agents able to detect COX-2 in inflammatory tissues and premalignant and malignant tumors (Uddin et al. Cancer Res. 2010, 70, 3618-3627). The present paper summarizes the details of the structure-activity relationship (SAR) studies performed for lead optimization of these dyes. A wide range of fluorescent conjugates were designed and synthesized, and each of them was tested for the ability to selectively inhibit COX-2 as the purified protein and in human cancer cells. The SAR study revealed that indomethacin conjugates are the best COX-2-targeted agents compared to the other carboxylic acid-containing nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors (COXIBs). An n-butyldiamide linker is optimal for tethering bulky fluorescent functionalities onto the NSAID or COXIB cores. The activity of conjugates also depends on the size, shape, and electronic properties of the organic fluorophores. These reagents are taken up by COX-2-expressing cells in culture, and the uptake is blocked by pretreatment with a COX inhibitor. In in vivo settings, these reagents become highly enriched in COX-2-expressing tumors compared to surrounding normal tissue, and they accumulate selectively in COX-2-expressing tumors as compared with COX-2-negative tumors grown in mice. Thus, COX-2-targeted fluorescent inhibitors are useful for preclinical and clinical detection of lesions containing elevated levels of COX-2.Keywords
Funding Information
- National Institutes of Health
This publication has 35 references indexed in Scilit:
- Fluorinated COX-2 Inhibitors as Agents in PET Imaging of Inflammation and CancerCancer Prevention Research, 2011
- [123I]-Celecoxib Analogues as SPECT Tracers of Cyclooxygenase-2 in InflammationACS Medicinal Chemistry Letters, 2010
- Selective Visualization of Cyclooxygenase-2 in Inflammation and Cancer by Targeted Fluorescent Imaging AgentsCancer Research, 2010
- Detection of Overexpressed COX‐2 in Precancerous Lesions of Hamster Pancreas and Lungs by Molecular Imaging: Implications for Early Diagnosis and PreventionChemMedChem, 2006
- Dynamic imaging of protease activity with fluorescently quenched activity-based probesNature Chemical Biology, 2005
- Gastrin-Induced Cyclooxygenase-2 Expression in Barrett’s CarcinogenesisClinical Cancer Research, 2004
- Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2.JCI Insight, 1997
- Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agentsNature, 1996
- Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2Nature Structural & Molecular Biology, 1996
- The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1Nature, 1994