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

…, KK Lewis, V Kathardekar, H Mazdiyasni…

Index: Jones, Terence R.; Webber, Stephen E.; Varney, Michael D.; Reddy, M. Rami; Lewis, Kathleen K.; Kathardekar, Vinit; Mazdiyasni, Hormoz; Deal, Judith; Nguyen, Dzuy; Welsh, Katharine M.; Webber, Stephanie; Johnston, Amanda; Matthews, David A.; Smith, Ward W.; Janson, Cheryl A.; Bacquet, Russell J.; Howland, Eleanor F.; Booth, Carol L. J.; Herrmann, Steven M.; Ward, Robert W.; White, Jennifer; Bartlett, Charlotte A.; Morse, Cathy A. Journal of Medicinal Chemistry, 1997 , vol. 40, # 5 p. 677 - 683

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Citation Number: 38

Abstract

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 K i of 27 nM. No sulfone improved on TS inhibition by the previously ...