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

Citations Over TimeTop 15% of 1997 papers

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 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.

Related Papers

• → Sulfoxide and Sulfone Synthesis via Electrochemical Oxidation of Sulfides(2021)57 cited
• → Racemic and chiral sulfoxides as potential prodrugs of 4-pyrone COX-2 inhibitors(2006)17 cited
• → Stereoelectronic effects in conformations of sulfide, sulfoxide, and sulfone α-carbanions(2015)7 cited
• → CONFORMATIONS OF MUSTARD SULFOXIDE AND MUSTARD SULFONE(1998)3 cited
• → The enzymatic conversion of sulfoxide to sulfone : The oxidation of methyl tetrahydrofurfuryl sulfoxide to the corresponding sulfone by rat liver microsomes(1967)5 cited