title: Structure-based design of substituted diphenyl sulfones and sulfoxides as lipophilic inhibitors of thymidylate synthase.
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.
authors.affiliation: Agouron Pharmaceuticals, Inc., San Diego, California 92121, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Jones
authors.forename: S E
authors.initials: SE
authors.lastname: Webber
authors.forename: M D
authors.initials: MD
authors.lastname: Varney
authors.forename: M R
authors.initials: MR
authors.lastname: Reddy
authors.forename: K K
authors.initials: KK
authors.lastname: Lewis
authors.forename: V
authors.initials: V
authors.lastname: Kathardekar
authors.forename: H
authors.initials: H
authors.lastname: Mazdiyasni
authors.forename: J
authors.initials: J
authors.lastname: Deal
authors.forename: D
authors.initials: D
authors.lastname: Nguyen
authors.forename: K M
authors.initials: KM
authors.lastname: Welsh
authors.forename: S
authors.initials: S
authors.lastname: Webber
authors.forename: A
authors.initials: A
authors.lastname: Johnston
authors.forename: D A
authors.initials: DA
authors.lastname: Matthews
authors.forename: W W
authors.initials: WW
authors.lastname: Smith
authors.forename: C A
authors.initials: CA
authors.lastname: Janson
authors.forename: R J
authors.initials: RJ
authors.lastname: Bacquet
authors.forename: E F
authors.initials: EF
authors.lastname: Howland
authors.forename: C L
authors.initials: CL
authors.lastname: Booth
authors.forename: S M
authors.initials: SM
authors.lastname: Herrmann
authors.forename: R W
authors.initials: RW
authors.lastname: Ward
authors.forename: J
authors.initials: J
authors.lastname: White
authors.forename: C A
authors.initials: CA
authors.lastname: Bartlett
authors.forename: C A
authors.initials: CA
authors.lastname: Morse
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013454:Sulfoxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: C105121:3-chloro-N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-4-(phenylsulfinyl)-N-(prop-2-ynyl)aniline; C105122:4-((2-chlorophenyl)sulfonyl)-N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-N-(prop-2-ynyl)aniline; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011799:Quinazolines; D013450:Sulfones; D013454:Sulfoxides; D013940:Thymidylate Synthase