Design of Fluorine-Containing 3,4-Diarylfuran-2(5H)-ones as Selective COX-1 Inhibitors

详细信息    查看全文

• 作者：Md. Jashim Uddin ; Anna V. Elleman ; Kebreab Ghebreselasie ; Cristina K. Daniel ; Brenda C. Crews ; Kellie D. Nance ; Tamanna Huda ; Lawrence J. Marnett
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：November 13, 2014
• 年：2014
• 卷：5
• 期：11
• 页码：1254-1258
• 全文大小：208K
• ISSN：1948-5875

文摘

We report the design and synthesis of fluorine-containing cyclooxygenase-1 (COX-1)-selective inhibitors to serve as prototypes for the development of a COX-1-targeted imaging agent. Deletion of the SO₂CH₃ group of rofecoxib switches the compound from a COX-2- to a COX-1-selective inhibitor, providing a 3,4-diarylfuran-2(5H)-one scaffold for structure鈥揳ctivity relationship studies of COX-1 inhibition. A wide range of fluorine-containing 3,4-diarylfuran-2(5H)-ones were designed, synthesized, and tested for their ability to selectively inhibit COX-1 in purified protein and human cancer cell assays. Compounds containing a fluoro-substituent on the C-3 phenyl ring and a methoxy-substituent on the C-4 phenyl ring of the 3,4-diarylfuran-2(5H)-one scaffold were the best COX-1-selective agents of those evaluated, exhibiting IC₅₀s in the submicromolar range. These compounds provide the foundation for development of an agent to facilitate radiologic imaging of ovarian cancer expressing elevated levels of COX-1.

Keywords:

Cyclooxygenase-1 (COX-1); rofecoxib; furanone; structure鈭抋ctivity relationship; imaging