Stability and DNA alkylation rates of the simplest functional analogues ofCC-1065, para-hydroxy and para-amino phenethyl bromides

We have recently synthesised a series of compounds based on the simplest fu nctional unit of CC-1065 containing a para substituted phenethyl halide moi ety. These compounds alkylate N3 of adenines in a similar fashion to CC-106 5, as well as N7 of guanines to a limited extent [9]. In this work we compa red the para amino substituted derivative (2) with the published hydroxyl c ompound (1) in terms of stability, DNA reactivity and pH dependence using g el electrophoresis techniques. The results show that 2 has a shorter lifeti me and is at least 2.5 times more reactive with DNA than 1. It is completel y hydrolysed between 30 and 60 min in buffer and its reaction with DNA is c omplete within 5 min. In contrast, only a fraction of 1 is hydrolysed after 60 min and retains reactivity towards DNA even after 3 h. The reactivities of both 1 and 2 with DNA are pH dependent and reaction rates rapidly decre ase in the range pH 5.8-8.8. Preliminary molecular modelling studies sugges t that the p-amino group on 2 enables the drug to bind to the AT-rich minor groove more effectively, thus stabilising the orientation of the substrate in the groove such that the reactive cyclopropyl ring is located close to the nucleophilic centre N3 of adenine. A possible mechanism of action of th ese drugs is presented based on these findings. (C) 1999 Elsevier Science I reland Ltd. All rights reserved.