Inhibition of topoisomerases by fatty acids

The inhibitory effects of various fatty acids on topoisomerases were examin ed, and their structure-activity relationships and mechanism of action were studied. Saturated fatty acids (C-6:0 to C-22:0) did not inhibit topoisome rase I, but cis-unsaturated fatty acids (C-16:1 to C-22:1) with one double bond showed strong inhibition of the enzyme. The inhibitory potency depende d on the carbon chain length and the position of the double bond in the fat ty acid molecule. The trans-isomer, methyl ester and hydroxyl derivative of oleic acid had no or little inhibitory effect on topoisomerases I and II. Among the compounds studied petroselinic al:id and vaccenic acid (C-18:1) w ith a cis-double bond were the potent inhibitors. Petroselinic acid was a t opoisomerase inhibitor of the cleavable complex-nonforming type and acted d irectly on the enzyme molecule in a noncompetitive manner without DNA inter calation.