Structure-Based Design of Substituted Diphenyl Sulfones and Sulfoxides as Lipophilic Inhibitors of Thymidylate Synthase

J. Med. Chem., 40 (5), 677 -683, 1997. jm960613f S0022-2623(96)00613-9

Structure-Based Design of Substituted Diphenyl Sulfones and Sulfoxides as Lipophilic Inhibitors of Thymidylate Synthase

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

Agouron Pharmaceuticals, Inc., 3565 General Atomics Court, San Diego, California 92121

Received August 26, 1996

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 reported 4-(N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2-ynylamino)phenyl phenyl sulfone (K_i = 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 thymidine 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.

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