Part 3: synthesis and biological evaluation of some analogs of the antitumor agents, 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid, and 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid.
2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (X469) and 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic Acid (SH80) are among the most highly and broadly active antitumor agents to have been developed in our laboratories. However, the mechanism(s) of action of these agents remain to be elucidated, which prompted our continued endeavor to delineate a pharmacophoric pattern, from which a putative target might be deduced. Herein, we provide additional evidence that intact quinoxaline and quinoline rings in XK469 and SH80, respectively, are fundamental to the activities of these structures against transplanted tumors in mice. The consequence of further modification of the heterocyclic ring system in XK469 and SH80, leading to [1,8]naphthyridine; pyrrolo[1,2-a]; imidazo[1,2-a]; and imidazo[1,5-a] derivatives, all deprive the parent structures of antitumor activity. Introduction of CH3, CF3, CH3O, CO2H, or C6H5 substituents at C4 of the quinoline ring of SH80 led to weakly active antitumor agents. Similarly, the phenanthridine analog of SH80 manifested only modest cytotoxicity. Lastly, XK469 and SH80 are both significantly more active than the corresponding regioisomeric structures, 2-{4-[(7-halo-4-quinolinyl)oxy]phenoxy)propionic acids.
Hazeldine
Stuart T
ST
Department of Internal Medicine, Division of Hematology and Oncology, Wayne State University, School of Medicine, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA.
Polin
Lisa
L
Kushner
Juiwanna
J
White
Kathryn
K
Corbett
Thomas H
TH
Biehl
Jason
J
Horwitz
Jerome P
JP
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D011422:Propionates / Q000138:chemical synthesis* / Q000494:pharmacology*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology*
C502473:2-(4-((7-bromo-2-quinolinyl)oxy)phenoxy)propionic Acid; C502474:2-(4-((7-chloro-2-quinoxalinyl)oxy)phenoxy)propionic acid; D000970:Antineoplastic Agents; D011422:Propionates; D011810:Quinoxalines