Luzopeptins consist of two identical, substituted quinolines linked to a cyclic decadepsipeptide, with a 2-fold symmetry. Luzopeptin A, with two acetylated sites in its peptide ring, is active against several experimental animal tumor systems. Luzopeptin B (one acetylated site) is less active, and luzopeptin C (no acetylation) is inactive. Our studies showed that all three luzopeptins and a half-molecule of luzopeptin C exhibited similar fluorescence (400 to 700 nm, with a peak at 490 to 496 nm) with an excitation spectrum in the 200 to 450 nm range (with a peak at 250 to 252, 337, and 385 nm). The half-molecule had the strongest fluorescence, followed in order by luzopeptins A, B, and C. DNA binding quenched both fluorescence and absorption of luzopeptins. Studies of the DNA-induced fluorescence and absorption quenching and the drug-induced viscosity and gel electrophoretic mobility changes of DNA suggested that luzopeptin C was slightly more effective than luzopeptins B and A in both the bifunctional DNA intercalation and the drug-induced DNA-DNA intermolecular cross-linking. Thus, the lack of antitumor activity of luzopeptin C is not the result of the lack of interactions with DNA. The half-molecule of luzopeptin C (quinoline with a pentapeptide) and smaller fragments (quinoline alone or with one to four peptide residues) did not react with DNA. Thus, the planar quinoline chromophore alone is unable to intercalate with DNA. The peptidic cyclic structure of luzopeptins is essential for the bifunctional intercalation of the twin chromophores, probably by providing proper conformational orientations of the chromophores.
This work was supported by Grant CA 10893-P12 from the National Cancer Institute and a grant from the Bristol Laboratories.