Structural considerations of NK109, an antitumor benzo[c]phenanthridine alkaloid

The antitumor activities of a synthetic benzo[c]phenanthridine, NK109 (7-hydroxy-2, 3-methylenedioxy-5-methyl-8-methoxybenzo[c]phenanthridinium hydrogensulfate dihydrate), and of natural benzo[c]phenanthridines were tested in vitro and in vivo. NK109 (3) had the highest activity among them. NK109 is similar in structure to fagaronine and fagaridine; however, it has a phenolic-OH at C-7. NK109 exists as a resonance hybrid, the keto-amine and zwitterionic forms in neutral media. The resonance hybrid is cationic and has molecular planarity; these have been considered to be essential for the antitumor activity of the benzo[c]phenanthridinium salts. On the other hand, the structurally similar benzo[c]phenthridine alkaloids, chelerythrine and sanguinarine, exist as pseudobases under the same conditions. The latter do not exhibit antitumor activity in vivo, probably because they lose both the immonium region and molecular planarity. Thus, 3 may be considered to be novel category of benzo[c]phenanthridinium salt from the viewpoint of its structure under biological conditions.