Pinophilins A and B, Inhibitors of Mammalian A-, B-, and Y-Family DNA Polymerases and Human Cancer Cell Proliferation

Pinophilins A (1) and B (2), new hydrogenated azaphilones, and Sch 725680 (3) were isolated from cultures of a fungus (Penicillium pinophilum Hedgcok) derived from a seaweed, and their structures were determined using spectroscopic analyses. These compounds selectively inhibited the activities of mammalian DNA polymerases (pols), A (pol gamma), B (pots alpha, delta, and epsilon), and Y (pols eta, iota, and kappa) families, but did not influence the activities of the four X-family pols (pols beta, lambda, mu, and terminal deoxynucleotidyl transferase). Compound I was the strongest inhibitor, with IC50 values of 48.6 to 55.6 mu M. Kinetic analysis showed that compound 1 is a noncompetitive inhibitor of both pol alpha and kappa activities with the DNA template-primer substrate, and a competitive inhibitor with the nucleotide substrate. In contrast, compounds 1-3 showed no effect on the activities of plant and prokaryotic pols or any other DNA metabolic enzymes tested. The compounds suppressed cell proliferation and growth in five human cancer cell lines, but had no effect on the viability of normal human cell lines.