M. Cushman et al., Synthesis of new indeno[1,2-c]isoquinolines: Cytotoxic non-camptothecin topoisomerase I inhibitors, J MED CHEM, 43(20), 2000, pp. 3688-3698
In an attempt to design and synthesize potential anticancer agents acting b
y inhibition of topoisomerase I (top1), a new series of indenoisoquinolines
was prepared and tested for cytotoxicity in human cancer cell cultures and
for activity against top1. The synthesis relied on the condensation of sub
stituted Schiff bases with homophthalic anhydrides to produce cis-3-aryl-4-
carboxyisoquinolones that were cyclized to indenoisoquinolines in the prese
nce of thionyl chloride, Both top1 inhibitory activity and cytotoxicity max
imized in a single compound, 6-[3-(2-hydroxyethyl)aminopropyl]-5,6-dihydro-
2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline h
ydrochloride (19a), which proved to be a very potent top1 inhibitor having
a 110 nM mean graph midpoint (MGM) when tested for cytotoxicity in 55 human
cancer cell cultures. A number of structurally related indenoisoquinolines
were also obtained that had both potent cytotoxicity as well as top1 inhib
itory activity. The key feature of the more potent compounds was the presen
ce of an aminoalkyl side chain on the indenoisoquinoline nitrogen atom. The
DNA cleavage patterns induced by top1 in the presence of the indenoisoquin
olines were different from those-seen with camptothecin. Some of the cleava
ge sites induced by the indenoisoquinolines were different from those seen
with camptothecin, and conversely, camptothecin induced unique cleavage sit
es not apparent with the indenoisoquinolines. However, both camptothecin an
d the indenoisoquinolines also induced DNA cleavage sites that were the sam
e in both series but varied in intensity. In addition, some of the DNA clea
vages seen with the free base of 19a (compound 18c) in the presence of top
1 were inhibited at higher drug concentrations, suggesting either a direct
inhibition of the enzyme or an alternative mechanism involving DNA intercal
ation. Consistent with intercalation, compound 18c did unwind DNA.