Quinazoline antifolates inhibiting thymidylate synthase: synthesis of four oligo(L-gamma-glutamyl) conjugates of N10-propargyl-5,8-dideazafolic acid and their enzyme inhibition.
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.
Pawelczak
K
K
Institute of Chemistry, Pedagogical University, Opole, Poland.
Jones
T R
TR
Kempny
M
M
Jackman
A L
AL
Newell
D R
DR
Krzyzanowski
L
L
Rzeszotarska
B
B
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*
D011624:Pteroylpolyglutamic Acids; D011799:Quinazolines; C031662:CB 3717; D005492:Folic Acid; D013940:Thymidylate Synthase