title: Quinazoline antifolate thymidylate synthase inhibitors: bridge modifications and conformationally restricted analogues in the C2-methyl series.
abstract: Several C2-methylquinazoline-based antifolates have been prepared in which the C9,N10 bridge has been replaced by the reversed N9,C10 unit. This series was extensively studied by incorporating further substituents at N9 and C10 as well as by modifications to the p-aminobenzoate ring. The C2-methylquinazoline analogues 29, 30, and 31 containing the methyleneoxa, methylenethia, and thia bridge units were also synthesized. In general these isosteric replacements of the bridge unit in the parent C2-methyl-N10-propargylquinazoline antifolate 2 were much less potent as inhibitors of isolated thymidylate synthase (TS) but several were at least as potent as inhibitors of L1210 cell growth in culture. The fusion of the p-aminobenzoate ring into the bicyclic systems 75 and 76 also reduced activity against TS but again gave highly cytotoxic compounds. The cytotoxicities were largely prevented by thymidine, confirming that TS is the major locus.
authors.affiliation: ICI Pharmaceuticals, Cheshire, England.
authors.forename: P R
authors.initials: PR
authors.lastname: Marsham
authors.forename: A L
authors.initials: AL
authors.lastname: Jackman
authors.forename: A J
authors.initials: AJ
authors.lastname: Hayter
authors.forename: M R
authors.initials: MR
authors.lastname: Daw
authors.forename: J L
authors.initials: JL
authors.lastname: Snowden
authors.forename: B M
authors.initials: BM
authors.lastname: O'Connor
authors.forename: J A
authors.initials: JA
authors.lastname: Bishop
authors.forename: A H
authors.initials: AH
authors.lastname: Calvert
authors.forename: L R
authors.initials: LR
authors.lastname: Hughes
mesh_terms: D000818:Animals; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D001952:Bridged-Ring Compounds; D005493:Folic Acid Antagonists; D011799:Quinazolines; D013940:Thymidylate Synthase