Synthesis and structure-activity relationships of novel benzofuran farnesyltransferase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 6, 2009, Pages 1753-1757

  Asoh, Kohsuke ^a   Kohchi, Masami ^a   Hyoudoh, Ikumi ^a   Ohtsuka, Tatsuo ^a   Masubuchi, Miyako ^a   Kawasaki, Kenichi ^a   Ebiike, Hirosato ^a   Shiratori, Yasuhiko ^a   Fukami, Takaaki A ^a   Kondoh, Osamu ^a   Tsukaguchi, Toshiyuki ^a   Ishii, Nobuya ^a   Aoki, Yuko ^a   Shimma, Nobuo ^a   Sakaitani, Masahiro ^a  

^a CHUGAI PHARMACEUTICAL CO LTD   (Japan)

Author keywords

Anti cancer; Benzofuran; Farnesyltransferase inhibitors; Tipifarnib

Indexed keywords

ANTINEOPLASTIC AGENT; BENZOFURAN DERIVATIVE; FARNESYLTRANSFERASE; PROTEIN FARNESYLTRANSFERASE INHIBITOR; TIPIFARNIB; TRANSFERASE; UNCLASSIFIED DRUG;

ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG MECHANISM; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; IN VIVO STUDY; LUNG NON SMALL CELL CANCER; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; TUMOR REGRESSION; TUMOR XENOGRAFT;

ANIMALS; ANTINEOPLASTIC AGENTS; BENZOFURANS; CHEMISTRY, PHARMACEUTICAL; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; DRUG SCREENING ASSAYS, ANTITUMOR; ENZYME INHIBITORS; FARNESYLTRANSTRANSFERASE; HUMANS; INHIBITORY CONCENTRATION 50; MICE; NEOPLASM TRANSPLANTATION; QUINOLONES; STRUCTURE-ACTIVITY RELATIONSHIP;

MUS;

EID: 61349125021     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.01.074     Document Type: Article

References (17)

1. Clarke S. Annu. Rev. Biochem. 61 (1992) 355
2. Cox A.D., and Der C.J. Crit. Rev. Oncog. 3 (1992) 365
3. Gibbs J.B. Cell 65 (1991) 1
4. Newman C.M.H., and Magee A.I. Biochim. Biophys. Acta 1155 (1993) 79
5. Schafer W.R., and Rine J. Annu. Rev. Genet. 26 (1992) 209
6. Tamanoi F., Kato-Stankiewicz J., Jiang C., Machado I., and Thapar N. J. Cell. Biochem. Suppl. 37 (2001) 64
7. Leonard D.M. J. Med. Chem. 40 (1997) 2971
8. Sebti S.M., and Hamilton A.D. Drug Discov. Today 3 (1998) 26
9. Jabbour E., Kantarjian H., and Cortes J. Expert Opin. Investig. Drugs 16 (2007) 381
10. Stille J.R., Ward J.A., Leffelman C., and Sullivan K.A. Tetrahedron Lett. 37 (1996) 9353
11. Cogan D.J., Liu G., Kim K., Bradley B.J., Backes J., and Ellman J.A. J. Am. Chem. Soc. 120 (1998) 8011
12. Carpenter A.J., and Chadwick D.J. Tetrahedron 42 (1986) 2358
13. Prepared diastereomers were separated and purified by chiral column chromatography over DAICEL CHIRACEL OD (eluent: hexane/2-propanol 1:1).
14. Assay methods described in: Sakaitani, M.; Masubuchi, K.; Kohchi, M.; Hyoudoh, I,; Asoh, K.; Asai, M. WO Patent 04/037816, 2004.
15. Crystals of rat FTase with compounds were obtained within a week under the crystallization condition of 10% (w/v) PEG 6000, 0.2 M Mg acetate, 0.1 M Na acetate buffer (pH4.5) at 4 °C. The structures in complex with compounds 8 k and 8w were solved at 2.6 and 2.4 Å, respectively, and their coordinates have been deposited in the Protein Data Bank under the access codes 2ZIS and 2ZIR.
16. 2/2, where a and b represent tumor length and width, respectively. Drug administration was initiated on the day of grouping (day 0). 11f was administered orally once a day from days 0 to 4 and days 7 to 11.
17. ® AS (eluent: hexane/ethanol, 4:1) to determine enantiomeric excess.