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

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• 作者：Yusuke Myobatake ; Toshifumi Takeuchi ; Kouji Kuramochi ; Isoko Kuriyama ; Tomomi Ishido ; Ken Hirano ; Fumio Sugawara ; Hiromi Yoshida ; Yoshiyuki Mizushina
• 刊名：Journal of Natural Products
• 出版年：2012
• 出版时间：February 24, 2012
• 年：2012
• 卷：75
• 期：2
• 页码：135-141
• 全文大小：250K
• 年卷期：v.75,no.2(February 24, 2012)
• ISSN：1520-6025

文摘

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 纬), B (pols 伪, 未, and 蔚), and Y (pols 畏, 喂, and 魏) families, but did not influence the activities of the four X-family pols (pols 尾, 位, 渭, and terminal deoxynucleotidyl transferase). Compound 1 was the strongest inhibitor, with IC₅₀ values of 48.6 to 55.6 渭M. Kinetic analysis showed that compound 1 is a noncompetitive inhibitor of both pol 伪 and 魏 activities with the DNA template-primer substrate, and a competitive inhibitor with the nucleotide substrate. In contrast, compounds 1鈥?b>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.