Design, Synthesis, and Biological Evaluation of Potential Prodrugs Related to the Experimental Anticancer Agent Indotecan (LMP400)

Indenoisoquinoline
topoisomerase I (Top1) inhibitors are a novel
class of anticancer agents with two compounds in clinical trials.
Recent metabolism studies of indotecan (LMP400) led to the discovery
of the biologically active 2-hydroxylated analogue and 3-hydroxylated
metabolite, thus providing strategically placed functional groups
for the preparation of a variety of potential ester prodrugs of these
two compounds. The current study details the design and synthesis
of two series of indenoisoquinoline prodrugs, and it also reveals
how substituents on the O-2 and O-3 positions of the A ring, which
are next to the cleaved DNA strand in the drug-DNA-Top1 ternary cleavage
complex, affect Top1 inhibitory activity and cytotoxicity. Many of
the indenoisoquinoline prodrugs were very potent antiproliferative
agents with GI50 values below 10 nM in a variety of human
cancer cell lines.