Department of Applied Biological Science, Science University of Tokyo, Noda, Chiba 278-8510, Japan.
J Nat Prod. 2012 Feb 24;75(2):135-41. doi: 10.1021/np200523b. Epub 2012 Jan 20.
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 γ), B (pols α, δ, and ε), and Y (pols η, ι, and κ) families, but did not influence the activities of the four X-family pols (pols β, λ, μ, and terminal deoxynucleotidyl transferase). Compound 1 was the strongest inhibitor, with IC₅₀ values of 48.6 to 55.6 μM. Kinetic analysis showed that compound 1 is a noncompetitive inhibitor of both pol α and κ 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.
从一种来源于海藻的真菌（Penicillium pinophilum Hedgcok）的培养物中分离得到了新的氢化氮杂菲酮类化合物 pinophilins A（1）和 B（2）以及 Sch 725680（3），并通过光谱分析确定了它们的结构。这些化合物选择性地抑制了哺乳动物 DNA 聚合酶（pols）家族 A（pol γ）、B（pols α、δ 和 ε）和 Y（pols η、ι 和 κ）的活性，但不影响四个 X 家族 pols（pols β、λ、μ 和末端脱氧核苷酸转移酶）的活性。化合物 1 是最强的抑制剂，其 IC₅₀ 值为 48.6 至 55.6 μM。动力学分析表明，化合物 1 是非竞争性抑制剂，对 pol α 和 κ 活性与 DNA 模板-引物底物结合，以及对核苷酸底物具有竞争性抑制作用。相比之下，化合物 1-3 对植物和原核 pols 或任何其他测试的 DNA 代谢酶的活性均无影响。这些化合物抑制了五种人类癌细胞系的增殖和生长，但对正常人类细胞系的活力没有影响。
