title: Quinazoline antifolates inhibiting thymidylate synthase: 4-thio-substituted analogues.
abstract: We report the synthesis of four new 4-thio-5,8-dideazafolic acid analogues and a 4-(methylthio) analogue structurally related to the thymidylate synthase (TS) inhibitor N10-propargyl-5,8-dideazafolic acid. Three N10-propargyl-4-thio-5,8-dideazafolic acid analogues had C2 amino, hydrogen, and methyl substituents. A 4-thio and a 4-(methylthio) compound each with hydrogen at C2 and ethyl at N10 were also synthesized. In general, the synthetic route involved thionation of the appropriate 4-oxoquinazoline; the sulfur thus introduced was then protected by methylation. Further protection with a pivaloyl group was required for the quinazoline bearing a 2-amino substituent. The protected quinazolines were treated with N-bromosuccinimide and the resulting 6-(bromomethyl) compounds were then coupled to the appropriate N-monoalkylated diethyl N-(4-aminobenzoyl)-L-glutamate in N,N-dimethylacetamide with calcium carbonate as base. The 4-thio-5,8-dideazafolic acids were obtained by removal of the methylthio group with sodium hydrosulfide, followed by deprotection of the carboxyl groups with cold dilute alkali. For the compound containing a pivaloyl protecting group, hot dilute alkali was used. To obtain the 5,8-dideazafolic acid containing a 4-(methylthio) substituent, the corresponding diester was treated with lithium hydroxide which selectively deprotected the carboxyl groups. The five compounds were tested as inhibitors of L1210 TS. It was found that replacement of the 4-oxygen of the quinazoline moiety by sulfur did not alter the TS inhibition. However, the introduction of a methylthio substituent at position 4 severely impaired TS inhibition. All 4-thio compounds were less cytotoxic to L1210 cells in culture than their 4-oxo counterparts.
authors.affiliation: Drug Development Section, Institute of Cancer Research, Sutton, Surrey, England.
authors.forename: T J
authors.initials: TJ
authors.lastname: Thornton
authors.forename: T R
authors.initials: TR
authors.lastname: Jones
authors.forename: A L
authors.initials: AL
authors.lastname: Jackman
authors.forename: A
authors.initials: A
authors.lastname: Flinn
authors.forename: B M
authors.initials: BM
authors.lastname: O'Connor
authors.forename: P
authors.initials: P
authors.lastname: Warner
authors.forename: A H
authors.initials: AH
authors.lastname: Calvert
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D007939:Leukemia L1210 / Q000473:pathology; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D005493:Folic Acid Antagonists; D011799:Quinazolines; D005492:Folic Acid; D013940:Thymidylate Synthase