Structure-based design of substituted diphenyl sulfones and sulfoxides as lipophilic inhibitors of thymidylate synthase

Journal of Medicinal Chemistry

Volumn 40, Issue 5, 1997, Pages 677-683

  Jones, Terence R ^a,b   Webber, Stephen E ^a   Varney, Michael D ^a   Reddy, M Rami ^a,c   Lewis, Kathleen K ^a   Kathardekar, Vinit ^a   Mazdiyasni, Hormoz ^a   Deal, Judith ^a   Nguyen, Dzuy ^a   Welsh, Katharine M ^a   Webber, Stephanie ^a   Johnston, Amanda ^a   Matthews, David A ^a   Smith, Ward W ^a   Janson, Cheryl A ^a   Bacquet, Russell J ^a   Howland, Eleanor F ^a   Booth, Carol L J ^a   Herrmann, Steven M ^a   Ward, Robert W ^a   White, Jennifer ^a   Bartlett, Charlotte A ^a   Morse, Cathy A ^a   more..

^a AGOURON PHARMACEUTICALS INC   (United States)

^b Angstrom Pharmaceuticals   (United States)

^c Gensia Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 CHLORO N [(3,4 DIHYDRO 2 METHYL 4 OXO 6 QUINAZOLINYL)METHYL] 4 (PHENYLSULFINYL) N (PROP 2 YNYL)ANILINE; THYMIDYLATE SYNTHASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CELL GROWTH; CONTROLLED STUDY; CRYSTAL STRUCTURE; CYTOTOXICITY; DNA SYNTHESIS INHIBITION; DRUG SYNTHESIS; ENZYME INHIBITION; ESCHERICHIA COLI; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL DIVISION; CRYSTALLOGRAPHY, X-RAY; DRUG SCREENING ASSAYS, ANTITUMOR; ENZYME INHIBITORS; ESCHERICHIA COLI; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MICE; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR STRUCTURE; NEOPLASMS, EXPERIMENTAL; QUINAZOLINES; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONES; SULFOXIDES; THYMIDYLATE SYNTHASE; TUMOR CELLS, CULTURED;

EID: 15444349896     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960613f     Document Type: Article

References (13)

1. Appelt, K.; Bacquet, R. J.; Bartlett, C. A.; Booth, C. L. J.; Freer, S. T.; Fuhry M. A. M.; Gehring, M. R.; Herrmann, S. M.; Howland, E. F.; Janson, C. A.; Jones, T. R.; Kan, C.-C.; Kathardekar, V.; Lewis, K. K.; Marzoni, G. P.; Matthews, D. A.; Mohr, C.; Moomaw, E. W.; Morse, C. A.; Oatley, S. J.; Ogden, R. C.; Reddy, M. R.; Reich, S. H.; Schoettlin, W. S.; Smith, W. W.; Varney, M. D.; Villafranca, J. E.; Ward, R. W.; Webber, S.; Webber, S. E.; Welsh, K. M.; White, J. Design of enzyme inhibitors using iterative protein crystallography analysis. J. Med. Chem. 1991, 34, 1925-1934.
2. Jones, T. R.; Varney, M. D.; Webber, S. E.; Lewis, K. K.; Marzoni, G. P.; Palmer, C. L.; Kathardekar, V.; Welsh, K. M.; Webber, S.; Matthews, D. A.; Appelt, K.; Smith, W. W.; Janson, C. A.; Villafranca, J. E.; Bacquet, R. J.; Howland, E. F.; Booth, C. L. J.; Herrmann, S. M.; Ward, R. W.; White, J.; Moomaw, E. W.; Bartlett, C. A.; Morse, C. A. Structure-based design of lipophilic quinazoline inhibitors of thymidylate synthase. J. Med. Chem. 1996, 39, 904-917.
3. Matthews, D. A.; Appelt, K.; Oatley, S. J.; Xuong, Ng. H. Crystal structure of Escherichia coli thymidylate synthase containing bound 5-fluoro-2′-deoxyuridylate and 10-propargyl-5,8-dideazafolate. J. Mol. Biol. 1990, 214, 923-936.
4. Hughes L. R.; Jackman, A. L.; Oldfield, J.; Smith, R. C.; Burrows, K. D.; Marsham, P. R.; Bishop, J. A. M.; Jones, T. R.; O'Connor, B. M.; Calvert, A. H. Quinazoline antifolate thymidylate synthase inhibitors: Alkyl, substituted alkyl, and aryl substituents in the C2 position. J. Med. Chem. 1990, 33, 3060-3067.
5. Weiner, S. J.; Kollman, P. A.; Case, D. A.; Singh, U. C.; Ghio, C.; Alagona, G.; Profeta, S., Jr.; Weiner, P. A new force field for moecular mechanical simulation of nucleic acids and proteins. J. Am. Chem. Soc. 1984, 106, 765-784.
6. Singh, U. C.; Weiner, P. K.; Caldwell, J. K.; Kollman, P. A. AMBER (Version 3.3); University of California: San Francisco, 1986.
7. Reddy, M. R.; Bacquet, R. J.; Zichi, D.; Matthews, D. A.; Welsh, K. M.; Jones, T. R.; Freer, S. Calculation of solvation and binding free energy differences for folate-based inhibitors of the enzyme thymidylate synthase. J. Am. Chem. Soc. 1992, 114, 10117-10122.
8. Hamada, Y.; Matsuoka, H., Hayashi, M. Yakugashi Zasshi 1970, 90, 644-646.
9. Stacy, G. W.; Bresson, C. R.; Harmon, R. E.; Thamm, R. C. Preparation of some aminotrifluoromethyldiphenyl sulfones as possible antibacterial agents. J. Org. Chem. 1957, 22, 298-302.
10. Gilman, H.; Broadbent, H. S. Some basically substituted diaryl sulfides and sulfones. J. Am. Chem. Soc. 1947, 69, 2053-2057.
11. Singhal, G. P. U.S. Patent 3,576,872, April 27, 1971.
12. Loeffler, R. S. T.; Woodcock, D.; Carter, G. A.; Johnson, D. M. Structure-activity relationships in fungitoxicants related to triforine and chloraniformethan. Part IV. Evaluation of the predictive power of the Hansch analysis by the preparation and testing of further chloraniformethan analogs. Pestic. Sci. 1981, 12, 627-637.
13. Heiduschka, A.; Langkammerer, H. Über p-und o-toluolsulfinsäure. J. Prakt. Chem., Ser. 2. 1913, 88, 425-442.