Mode of action of the schistosomicide hycanthone: site of DNA alkylation

Abstract

Condensation of hycanthone N-methylcarbamate (HNMC) with deoxyguanosine (dG) furnished a mixture of the N-1 and N2 adducts which were purified and characterized as their acetates. Condensation of HNMC with thymidine (T) gave the N-3 adduct in poor yield. Adenosine (A) and cytidine (C) did not react with HNMC. Incubation of schistosomes with either [3H]hycanthone (HC) or [3H]HNMC furnished DNA to which [3H]HC was covalently bound. The alkylated DNA was degraded enzymically and the radiolabeled nucleosides were separated using HPLC. Two major peaks were observed which coincided in retention time with the synthetic N-1 and N2 alkylated dG. Alkylated T was absent. Thus, the site of alkylation of DNA by either HC or HNMC is dG.