Irreversible enzyme inhibitors. XCIV. inhibition of dihydrofolic reductase with derivatives of 2,6-diaminopurines

In order to gain additional information on the hydrophobic bonding region of dihydrofolic reductase, some derivatives of 2, 6-diaminopurine with aryl or aralkyl groups at the N⁶, C⁸ and N⁹-positions were investigated as inhibitors. Since none of the six compounds gave an increment in binding over the parent 2, 6-diaminopurine, hydrophobic bonding to dihydrofolic reductase could not be detected with this ring system. Furthermore, 2, 6-diaminopurine bridged from its 8-position with methylene groups to the amino group of p-aminobenzoic acid also failed to show an increment in binding. The 8-substituted 2, 6-diaminopurines were synthesized by base-catalyzed cyclodehydration of the appropriate 5-acylamido-2, 4, 6-triaminopyrimidines; the latter compounds were readily prepared by selective acylation of tetraaminopyrimidine.