United States Patent 6,433,187
Clark , et al. August 13, 2002
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Certain polycyclic compounds useful as tubulin-binding agents
Abstract
Derivatives of known tubulin-binding compounds are provided in which a (poly)fluorobenzene, a fluoropyridine, or a fluoronitrobenzene moiety is incorporated or added to the structure. These derivatives can be used as antimitotic agents and can be considered covalent modifiers of tubulin. The strategy developed for each of the compounds is to i) append a fluorinated electrophile (e.g., pentafluorophenylsulfonamido, 2-fluoropyridyl, or 3,5-dinitro-4-fluorophenyl) to an existing functional group in a natural product, ii) replace an aromatic ring in a natural product with a fluorinated electrophile, or iii) attach a fluorinated electrophile to an open valence in a portion of the molecule that will not interfere with recognition and binding to the tubulin site. Derivatives are provided based on colchicine, steganacin, podophyllotoxin, nocodazole, combretastatin, curacin A, vinblastine, vincristine, dolastatin, 2-methoxyestradiol, dihydroxy-pentamethoxyflavanone and others.
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Inventors: Clark; David (Albany, CA); Frankmoelle; Walter (South San Francisco, CA); Houze; Jonathan (San Mateo, CA); Jaen; Juan C. (Burlingame, CA); Medina; Julio C. (San Carlos, CA)
Assignee: Tularik Inc. (So. San Francisco, CA)
Appl. No.: 464217
Filed: December 15, 1999 |
