title: Quinazoline antifolates inhibiting thymidylate synthase: synthesis of four oligo(L-gamma-glutamyl) conjugates of N10-propargyl-5,8-dideazafolic acid and their enzyme inhibition.
abstract: The synthesis is described of four oligo(gamma-glutamyl) conjugates of N10-propargyl-5,8-dideazafolic acid containing a total of two, three, four, and five L-glutamic acid residues. The tert-butyl group was chosen as the carboxyl protecting group in order to obviate the use of alkali and thus the possibility of gamma----alpha transpeptidation. The starting material, di-tert-butyl glutamate, was coupled to N-(benzyloxycarbonyl)-L-glutamic acid alpha-tert-butyl ester via a mixed anhydride with isobutyl chloroformate. Hydrogenolysis of the benzyloxycarbonyl group in the product gave a carboxyl-protected diglutamate, which either was acylated with 4-[(benzyloxycarbonyl)amino] benzoyl chloride to give a protected aminobenzamide or was cycled further by using the above mixed anhydride/hydrogenolysis sequence into tri-, tetra-, and pentaglutamates. Each of the last named was also acylated, as above, to give a benzamide. The benzyloxycarbonyl group in the benzamides was removed by hydrogenolysis and the amino groups thus exposed were N-alkylated with propargyl bromide. The resulting proparglyamines were further alkylated with 2-amino-6-(bromomethyl)-4-hydroxyquinazoline hydrobromide to give the antifolate poly(t-Bu) esters. Deprotection with trifluoroacetic acid in the final step delivered the desired antifolates as their trifluoroacetate salts. The di- to pentaglutamates were, respectively, 31-, 97-, 171-, and 167-fold more inhibitory to WI-L2 human thymidylate synthase than the parent compound.
authors.affiliation: Institute of Chemistry, Pedagogical University, Opole, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Pawelczak
authors.forename: T R
authors.initials: TR
authors.lastname: Jones
authors.forename: M
authors.initials: M
authors.lastname: Kempny
authors.forename: A L
authors.initials: AL
authors.lastname: Jackman
authors.forename: D R
authors.initials: DR
authors.lastname: Newell
authors.forename: L
authors.initials: L
authors.lastname: Krzyzanowski
authors.forename: B
authors.initials: B
authors.lastname: Rzeszotarska
mesh_terms: D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D011624:Pteroylpolyglutamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D011624:Pteroylpolyglutamic Acids; D011799:Quinazolines; C031662:CB 3717; D005492:Folic Acid; D013940:Thymidylate Synthase