Synthesis and Antitumor Properties of N1-(Hydroxymethyl Phenylmethyl) Pyrimidine Derivatives and their Intermediates

A series of ortho- meta- and para-N1-[(chloromethylphenyl)methyl]pyrimidines and N1- [(hydroxymethylphenyl)methyl]pyrimidines 4-27 were prepared by the alkylation of various pyrimidine nucleic acid bases with α,α'-dichloroxylenes followed by acid catalyzed hydrolysis. Compounds 4-27 were evaluated for the cytotoxic activity against a panel NCI-H460 (lung), MCF7 (breast) and SF-268 (CNS) cancer cell lines. The ‘active’ compounds which reduced growth of cancer cells to ca. 32% or less have been evaluated in the full panel of 60 human cancer cell lines over a 5-log dose range at the National Cancer Institute. Specifically, the ortho-N1-[(chloromethylphenyl)methyl]pyrimidines in this series (5, 6 and 7) have demonstrated growth inhibitory effects (GI50) on the leukemia (CCRF-CEM, HL-60, K562, MOLT-4, SR) and other cancer cell lines at 10-5 to 10-7 M concentrations.