title: Folate analogues. 30. Synthesis and biological evaluation of N10-propargyl-5,8-dideaza-5,6,7,8-tetrahydrofolic acid and related compounds.
abstract: The 5,6,7,8-tetrahydro derivative (1) of the powerful thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (PDDF) has been synthesized and evaluated for its antifolate activity. A convenient method for the preparation of the key intermediate 2-amino-6-(bromomethyl)-4-hydroxy-5,6,7,8-tetrahydroquinazoline (18) is described. Two closely related analogues of 1 were also synthesized and evaluated for their antifolate activity and thymidylate synthase inhibition. N10-Propargyl-5,8-dideaza-5,6,7,8-tetrahydrofolate (1) and N10-methyl and N10-hydrogen analogues 2 and 3 were weaker inhibitors of Lactobacillus casei thymidylate synthase compared to PDDF. N10-Methyl-5,8-dideaza-5,6,7,8-tetrahydrofolate (2) exhibited the most potent antifolate activity against L. casei (IC50 = 2.8 nM) and Streptococcus faecium (IC50 = 0.57 nM). In intact and permeabilized murine leukemia L1210 cells, the replacement of the quinazoline moiety with its tetrahydro derivative resulted in a marked decrease in potency and a loss of the contribution of the propargyl substituent to enzyme inhibition, indicating an altered binding mode to thymidylate synthase.
mesh_terms: D005492:Folic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013763:Tetrahydrofolates / Q000138:chemical synthesis* / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D005493:Folic Acid Antagonists; D011799:Quinazolines; D013763:Tetrahydrofolates; C053114:N(10)-propargyl-5,8-dideaza-5,6,7,8-tetrahydrofolic acid; C031662:CB 3717; D005492:Folic Acid; D013940:Thymidylate Synthase