Matsui Yuki, Takeuchi Toshifumi, Kumamoto-Yonezawa Yuko, Takemura Masaharu, Sugawara Fumio, Yoshida Hiromi, Mizushina Yoshiyuki
Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, and.
Exp Ther Med. 2010 Jan;1(1):19-26. doi: 10.3892/etm_00000004. Epub 2010 Jan 1.
Acetogenins from the Annonaceous plant are a fatty acid-derived natural product. Chemically synthesized natural acetogenins, such as mucocin (compound 1), jimenezin (compound 2), muconin (compound 4), pyranicin (compound 5) and pyragonicin (compound 6) were investigated. Concomitantly, 19-epi jimenezin (compound 3), 10-epi pyragonicin (compound 7) and a γ-lactone (compound 8), which is estimated to be a biosynthetic precursor of acetogenins, were synthesized and investigated. Compounds 5 and 6 strongly inhibited, and compound 7 moderately inhibited the activities of mammalian DNA polymerases (pols), such as replicative pol α and repair/recombination-related pol β and λ, and also inhibited human DNA topoisomerase (topos) I and II activities. On the other hand, compounds 1-4 and 8 did not influence the activities of any pols and topos. Compound 5 was the strongest inhibitor of the pols and topos tested, and the IC(50) values were 5.0-9.6 μM, respectively. These compounds also suppressed human cancer cell growth with almost the same tendency as the inhibition of pols and topos. Compound 5 was the strongest suppressor of the proliferation of the promyelocytic leukemia cell line, HL-60, in human cancer cell lines tested with an LD(50) value of 9.4 μM, and arrested the cells at G1 phases, indicating that it blocks DNA replication by inhibiting the activity of pols rather than topos. This compound also induced cell apoptosis. The relationship between the three-dimensional molecular structure of acetogenins and these inhibitory activities is discussed. The results suggested that compound 5 is a lead compound of potentially useful cancer chemotherapy agents.
番荔枝科植物中的产乙酸素是一种脂肪酸衍生的天然产物。对化学合成的天然产乙酸素，如粘菌素（化合物1）、吉门菌素（化合物2）、木柯宁（化合物4）、吡喃菌素（化合物5）和吡拉戈菌素（化合物6）进行了研究。同时，合成并研究了19-表吉门菌素（化合物3）、10-表吡拉戈菌素（化合物7）以及一种γ-内酯（化合物8），后者据估计是产乙酸素的生物合成前体。化合物5和6强烈抑制，化合物7中度抑制哺乳动物DNA聚合酶（pol）的活性，如复制性polα以及与修复/重组相关的polβ和λ，并且还抑制人DNA拓扑异构酶（topos）I和II的活性。另一方面，化合物1-4和8对任何pol和topos的活性均无影响。化合物5是所测试的pol和topos的最强抑制剂，IC(50)值分别为5.0 - 9.6 μM。这些化合物还以与抑制pol和topos几乎相同的趋势抑制人癌细胞生长。在测试的人癌细胞系中，化合物5是早幼粒细胞白血病细胞系HL-60增殖的最强抑制剂，LD(50)值为9.4 μM，并使细胞停滞在G1期，表明它通过抑制pol的活性而非topos来阻断DNA复制。该化合物还诱导细胞凋亡。讨论了产乙酸素的三维分子结构与这些抑制活性之间的关系。结果表明化合物5是潜在有用的癌症化疗药物的先导化合物。
