Cargando…
Design, Synthesis, and Structure–Activity Relationship Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted Optical Imaging Agents
[Image: see text] 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 forma...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2013
|
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3630741/ https://www.ncbi.nlm.nih.gov/pubmed/23488616 http://dx.doi.org/10.1021/bc300693w |
_version_ | 1782266722837856256 |
---|---|
author | Uddin, Md. Jashim Crews, Brenda C. Ghebreselasie, Kebreab Marnett, Lawrence J. |
author_facet | Uddin, Md. Jashim Crews, Brenda C. Ghebreselasie, Kebreab Marnett, Lawrence J. |
author_sort | Uddin, Md. Jashim |
collection | PubMed |
description | [Image: see text] 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. |
format | Online Article Text |
id | pubmed-3630741 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-36307412013-04-19 Design, Synthesis, and Structure–Activity Relationship Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted Optical Imaging Agents Uddin, Md. Jashim Crews, Brenda C. Ghebreselasie, Kebreab Marnett, Lawrence J. Bioconjug Chem [Image: see text] 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. American Chemical Society 2013-03-15 2013-04-17 /pmc/articles/PMC3630741/ /pubmed/23488616 http://dx.doi.org/10.1021/bc300693w Text en Copyright © 2013 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) |
spellingShingle | Uddin, Md. Jashim Crews, Brenda C. Ghebreselasie, Kebreab Marnett, Lawrence J. Design, Synthesis, and Structure–Activity Relationship Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted Optical Imaging Agents |
title | Design, Synthesis, and Structure–Activity Relationship
Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted
Optical Imaging Agents |
title_full | Design, Synthesis, and Structure–Activity Relationship
Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted
Optical Imaging Agents |
title_fullStr | Design, Synthesis, and Structure–Activity Relationship
Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted
Optical Imaging Agents |
title_full_unstemmed | Design, Synthesis, and Structure–Activity Relationship
Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted
Optical Imaging Agents |
title_short | Design, Synthesis, and Structure–Activity Relationship
Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted
Optical Imaging Agents |
title_sort | design, synthesis, and structure–activity relationship
studies of fluorescent inhibitors of cycloxygenase-2 as targeted
optical imaging agents |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3630741/ https://www.ncbi.nlm.nih.gov/pubmed/23488616 http://dx.doi.org/10.1021/bc300693w |
work_keys_str_mv | AT uddinmdjashim designsynthesisandstructureactivityrelationshipstudiesoffluorescentinhibitorsofcycloxygenase2astargetedopticalimagingagents AT crewsbrendac designsynthesisandstructureactivityrelationshipstudiesoffluorescentinhibitorsofcycloxygenase2astargetedopticalimagingagents AT ghebreselasiekebreab designsynthesisandstructureactivityrelationshipstudiesoffluorescentinhibitorsofcycloxygenase2astargetedopticalimagingagents AT marnettlawrencej designsynthesisandstructureactivityrelationshipstudiesoffluorescentinhibitorsofcycloxygenase2astargetedopticalimagingagents |