Synthesis and antiproliferative activity of 2,6-diamino-9-benzyl-9-deazapurine and related compounds

Abstract

Treatment of 6-bromomethyl- or 6-dibromomethyl-5-nitropyrimidine-2,4-diamine with KCN gave the same product––(2,6-diamino-5-nitropyrimidinyl)acetonitrile. Benzylation of the nitrile took place on the α-carbon to the cyano group preferentially affording the corresponding mono- and dibenzyl derivative, whose reductive cyclization resulted in 7-benzyl-5 H-pyrrolo[3,2- d]pyrimidine-2,4-diamine and 7,7-dibenzyl-7 H-pyrrolo[3,2- d]pyrimidine-2,4,6-triamine, respectively. Suitability of the protection of N 2 and N 4 atoms with benzyl, acetyl, or benzoyl groups was also investigated. The in vitro evaluation of cell growth inhibition on CCRF-CEM, HL-60, HeLa S3, and L1210 cell lines showed significant activity in 8 new compounds. The most potent compounds were the above mentioned 6-dibromomethyl derivative (IC 50=0.54, 1.7, 5.0, and 1.9 mol L −1) and 7, N 2, N 4-tribenzyl-5 H-pyrrolo[3,2- d]pyrimidine-2,4-diamine (IC 50=1.9, 2.7, 7.3, and 1.0 mol L −1).