Coralyne and several other synthetic benzo[a,g]quinolizium derivatives related to
protoberberine alkaloids have exhibited activity as topoisomerase
poisons. These compounds are characterized by the presence of a positively charged iminium group, which has been postulated to be associated with their pharmacological properties. The objective of the present study was to devise stable noncharged bioisosteres of these compounds. Several similarly substituted
benz[a]acridine and
benz[c]acridine derivatives were synthesized and their relative activity as topoisomerase
poisons was determined. While the
benz[c]acridine derivatives evaluated as part of this study were devoid of topoisomerase
poisoning activity, several dihydrobenz[a]
acridines were able to enhance DNA cleavage in the presence of
topo I. In contrast to certain
protoberberine derivatives that did exhibit activity as
topo II
poisons, none of the benz[a]
acridines derivatives enhanced DNA cleavage in the presence of
topo II. Among the benz[a]
acridines studied, 5,6-dihydro-3,4-methylenedioxy-9,10-dimethoxybenz[a]
acridine, 13e, was the most potent
topo I
poison, with comparable potency to
coralyne. These data suggest that
heterocyclic compounds structurally related to
coralyne can exhibit potent
topo I
poisoning activity despite the absence of an iminium
cation within their structure. In comparison to
coralyne or other
protoberberine derivatives, these
benz[a]acridine derivatives possess distinctly different physicochemical properties and represent a novel series of
topo I
poisons.