Stability and DNA alkylation rates of the simplest functional analogues of CC-1065, para-hydroxy and para-amino phenethyl bromides.
We have recently synthesised a series of compounds based on the simplest functional unit of CC-1065 containing a para substituted phenethyl halide moiety. These compounds alkylate N3 of adenines in a similar fashion to CC-1065, as well as N7 of guanines to a limited extent. In this work we compared the para amino substituted derivative (2) with the published hydroxyl compound (1) in terms of stability, DNA reactivity and pH dependence using gel electrophoresis techniques. The results show that 2 has a shorter lifetime and is at least 2.5 times more reactive with DNA than 1. It is completely hydrolysed between 30 and 60 min in buffer and its reaction with DNA is complete 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 decrease in the range pH 5.8-8.8. Preliminary molecular modelling studies suggest 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 these drugs is presented based on these findings.
Shalders
R L
RL
National Research Centre for Environmental Toxicology, Coopers Plains, QLD, Australia.
Blanch
G
G
Brown
C L
CL
Young
D J
DJ
Prakash
A S
AS
D000225:Adenine / Q000378:metabolism; D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D001483:Base Sequence; D003198:Computer Simulation; D004247:DNA / Q000378:metabolism*; D000080890:Duocarmycins; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000378:metabolism*; D062385:Hydroxybenzoates / Q000378:metabolism*; D007211:Indoles; D007933:Leucomycins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D008956:Models, Chemical; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D006842:Hydrocarbons, Brominated; D062385:Hydroxybenzoates; D007211:Indoles; D007933:Leucomycins; C018782:CC 1065; D004247:DNA; D000225:Adenine