title: Quinazoline antifolate thymidylate synthase inhibitors: nitrogen, oxygen, sulfur, and chlorine substituents in the C2 position.
abstract: The synthesis of 16 new N10-propargylquinazoline antifolates with methylamino, ethylamino, (2-aminoethyl)amino, [2-(dimethylamino)ethyl]amino, (2-hydroxyethyl)amino, (carboxymethyl)amino, dimethylamino, imidazol-1-yl, methoxy, ethoxy, phenoxy, 2-methoxyethoxy, 2-hydroxyethoxy, mercapto, methylthio, and chloro substituents at C2 is described. In general, the synthetic route involved the coupling of diethyl N-[4-(prop-2-ynylamino)benzoyl]-L-glutamate (5a) with 6-(bromomethyl)-2-chloro-3,4-dihydro-4-oxoquinazoline in N,N-dimethylformamide with calcium carbonate as the base, displacement of the C2-chloro substituent with nitrogen and sulfur nucleophiles, and deprotection using mild alkali. The C2-ether analogues were most conveniently prepared by coupling 5a with 6-(bromomethyl)-2,4-diakoxy(or diphenoxy)quinazolines. In this series the final deprotection step with aqueous alkali gave simultaneous selective hydrolysis of the C4-alkoxy or C4-phenoxy substituent. The compounds were tested as inhibitors of partially purified L1210 thymidylate synthase (TS). As a measure of cytotoxicity, they were examined for their inhibition of the growth of L1210 cells in culture. The C2-methoxy analogue 11a was equivalent to the previously described tight binding TS inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717, ICI 155387, 1a) against the TS enzyme and exhibited enhanced potency in culture. The C2-methoxy substituent also gave a 110-fold enhancement in aqueous solubility relative to the C2-amine. These results suggest that 11a will be an interesting compound for further study as a potential antitumor agent in vivo. A further series of 2-methoxyquinazoline antifolates with modified alkyl substituents at N10 is also described. None of these analogues equalled the activity of 11a. Thus the propargyl group appears to be the optimum N10 substituent in both 2-amino- and 2-methoxyquinazoline antifolates.
authors.affiliation: ICI Pharmaceuticals, Macclesfield, Cheshire, England.
authors.forename: P R
authors.initials: PR
authors.lastname: Marsham
authors.forename: P
authors.initials: P
authors.lastname: Chambers
authors.forename: A J
authors.initials: AJ
authors.lastname: Hayter
authors.forename: L R
authors.initials: LR
authors.lastname: Hughes
authors.forename: A L
authors.initials: AL
authors.lastname: Jackman
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
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002713:Chlorine; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D009584:Nitrogen; D010100:Oxygen; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013455:Sulfur; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D005493:Folic Acid Antagonists; D011799:Quinazolines; D002713:Chlorine; D013455:Sulfur; D013940:Thymidylate Synthase; D009584:Nitrogen; D010100:Oxygen