Synthesis and biological evaluation of conformationally constrained analogs of the antitumor agents XK469 and SH80. Part 5

• Published in: Bioorganic & medicinal chemistry 2006-04, Vol.14 (7), p.2462-2467
• Main Authors: Hazeldine, Stuart T., Polin, Lisa, Kushner, Juiwanna, White, Kathryn, Corbett, Thomas H., Horwitz, Jerome P.
• Format: Article
• Language: English
• Subjects: Analogs; Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor; Benzofurans - chemical synthesis; Benzofurans - chemistry; Benzofurans - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Conformational restriction; Crystallography, X-Ray; Drug Screening Assays, Antitumor; General aspects; Humans; In Vitro Techniques; Medical sciences; Mice; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Propionates - chemical synthesis; Propionates - chemistry; Propionates - pharmacology; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Quinoxalines - chemical synthesis; Quinoxalines - chemistry; Quinoxalines - pharmacology; SH80; Structure-Activity Relationship; XK469
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.11.036

Conformational restriction of bioactive molecules offers the possibility of generating structures of increased potency. To this end, a synthesis has been achieved of ( R, S)-2-[(8-chlorobenzofurano[2,3- b]quinolinyl)oxy]propionic acid ( 12a), a highly rigidified, polycyclic analog of 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid ( 2a, XK469). Efforts to effect the same synthesis of the corresponding 8-bromo-derivative led to a mixture of intermediate, 8-chloro ( 9a), and 8-bromo-2-hydroxybenzofurano[2,3- b]quinoline ( 9b), generated by halogen-exchange, via an aromatic S RN 1(A RN 1) reaction of precursor, 8b, with pyridine hydrochloride. The presumption that conformational restriction of 1b– 12a might enhance the antitumor potency of the latter has not been sustained. In fact, 12a proved to be significantly less active than 1b. However, it is apparent that virtually all of the spatial and steric properties of 12a, necessary for improved activity, including the disposition of the 2-oxypropionic acid side chain remain to be identified.