Structure-Based Design of Substituted Diphenyl Sulfones and Sulfoxides as Lipophilic Inhibitors of Thymidylate Synthase
| Autor: | Dzuy T. Nguyen, Eleanor F. Howland, S. M. Herrmann, C. A. Morse, Russell J. Bacquet, Jones Terence R, Ward W. Smith, Charlotte A. Bartlett, Stephanie Webber, K. M. Welsh, Cheryl Ann Janson, Kathardekar, M. R. Reddy, Carol L. J. Booth, H. Mazdiyasni, Lewis Kk, J. White, A. Johnston, J. Deal, Stephen E. Webber, David A. Matthews, Robert William Ward, Varney |
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| Rok vydání: | 1997 |
| Předmět: |
Models
Molecular Magnetic Resonance Spectroscopy Molecular Conformation Antineoplastic Agents Crystallography X-Ray Medicinal chemistry Chemical synthesis Thymidylate synthase Sulfone Mice Structure-Activity Relationship chemistry.chemical_compound Aniline Drug Discovery Escherichia coli Tumor Cells Cultured Animals Humans heterocyclic compounds Sulfones Enzyme Inhibitors Sulfonyl chemistry.chemical_classification Molecular Structure biology Sulfoxide Neoplasms Experimental Thymidylate Synthase chemistry Enzyme inhibitor Sulfoxides Quinazolines biology.protein Molecular Medicine Drug Screening Assays Antitumor Thymidine Cell Division |
| Zdroj: | Journal of Medicinal Chemistry. 40:677-683 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Six new diphenyl sulfoxide and five new diphenyl sulfones were designed, synthesized, and tested for their inhibition of human and Escherichia coli thymidylate synthase (TS) and of the growth of cells in tissue culture. The best sulfoxide inhibitor of human TS was 3-chloro-N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-4- (phenylsulfinyl)-N-(prop-2-ynyl)-aniline (7c) that had a Ki of 27 nM. No sulfone improved on TS inhibition by the previously reported 4-(N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2- ynylamino)phenyl phenyl sulfone (Ki = 12 nM). Nevertheless, one sulfone, 4-((2-chlorophenyl)sulfonyl)-N-((3,4-dihydro-2-methyl-4-oxo-6- quinazolinyl)methyl)-N-(prop-2-ynyl)aniline, was selected, on the basis of its inhibition of both TS and cell growth, for antitumor testing; it gave a 61% increase in life span to mice bearing the thymidino kinase-deficient L5178Y (TK-) lymphoma. A crystal structure of N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-4-((2- methylphenyl)sulfinyl)-N-(prop-2-ynyl)aniline complexed with E. coli TS was solved and revealed selective binding of one sulfoxide enantiomer. AMBER calculations showed that the enantioselection was due to asymmetric electrostatic effects at the mouth of the active site. In contrast, a similar crystal structure of the sulfoxide 7c, along with AMBER calculations, indicated that both enantiomers bound, but with different affinities. The side chain of Phe176 shifted in order to structurally accommodate the chlorine of the more weakly bound enantiomer. |
| Databáze: | OpenAIRE |
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