7.8.1.4 DNA Topoisomerase Inhibitors
DNA is a topologically constrained molecule because the ends of the circular double
helix are fixed in space, allowing the formation of higher-order structures called “super-
coils.” During replication, the double helix must unwind, and unwinding introduces
additional positive “supertwist.”Topoisomerase I removes this supertwist by breaking
and resealing single strands to produce a “relaxed” DNA. Since the reaction is thermo-
dynamically favorable, no ATP is needed. Topoisomerase II (“gyrase”) catalyzes the
passing of two DNA strands through breaks, and thus produces a “negative supertwist”
which further promotes parental strand separation at the replication fork; ATP is needed
for this reaction. Since the replicating fork rotates at a speed of about 100 revolutions
per second, interference with these enzymes rapidly stops DNA replication. Several
natural products have demonstrated efficacy in inhibiting topoisomerase enzymes.
Camptothecin Topoisomerase Inhibitors.The camptothecins (e.g., topotecan,7.84,
irinotecan,7.85) are natural products that function as topoisomerase I enzyme inhibitors.
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