title: 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.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Stuart T
authors.initials: ST
authors.lastname: Hazeldine
authors.forename: Lisa
authors.initials: L
authors.lastname: Polin
authors.forename: Juiwanna
authors.initials: J
authors.lastname: Kushner
authors.forename: Kathryn
authors.initials: K
authors.lastname: White
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Corbett
authors.forename: Jerome P
authors.initials: JP
authors.lastname: Horwitz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005461:Fluorine; D006801:Humans; D008745:Methylation; D051379:Mice; D011422:Propionates; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011422:Propionates; D011810:Quinoxalines; C118180:XK 469; D005461:Fluorine; C029658:propionic acid