Synthetic modification of the 2-oxypropionic acid moiety in 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (XK469), and consequent antitumor effects. Part 4.

Abstract

The criteria for the activity of 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (XK469) and 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid (SH80) against transplanted tumors in mice established in previous studies, require a (7-halo-2-quinoxalinoxy)- or a (7-halo-2-quinolinoxyl)-residue, respectively, bridged via a 1,4-OC(6)H(4)O-linker to C(2) of propionic acid. The present work demonstrates that substitution of fluorine at the 3-position of the 1,4-OC(6)H(4)O-linker of XK469 leads to a 10-fold reduction in activity, whereas the corresponding 2-fluoro analog proved to be 100-fold less active than XK469. Moreover, the latter tolerated substitution of but a single, additional methyl group to the 2-position of the propionic acid moiety, that is, the isobutyric acid analog, without loss of significant in vivo activity. Indeed, an intact 2-oxypropionic acid moiety is a prerequisite for maximum antitumor activity of 1a.

• Authors: Stuart T Hazeldine, Lisa Polin, Juiwanna Kushner, Kathryn White, Thomas H Corbett, Jerome P Horwitz
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 13 Issue 12 Pg. 3910-20 (Jun 02 2005) ISSN: 0968-0896 [Print] England
• PMID: 15911307 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Propionates
• Quinoxalines
• XK 469
• Fluorine
• propionic acid

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Fluorine
• Humans
• Methylation
• Mice
• Propionates
• Quinoxalines (chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays