Mizushina Yoshiyuki, Akihisa Toshihiro, Ukiya Motohiko, Hamasaki Yusuke, Murakami-Nakai Chikako, Kuriyama Isoko, Takeuchi Toshifumi, Sugawara Fumio, Yoshida Hiromi
Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan.
Life Sci. 2005 Sep 9;77(17):2127-40. doi: 10.1016/j.lfs.2005.03.022.
Isosteviol (ent-16-ketobeyeran-19-oic acid) is a hydrolysis product of stevioside, which is a natural sweetener produced in the leaves of Stevia rebaudiana (Bertoni) Bertoni. In this report, we prepared isosteviol and related compounds from stevioside by microbial transformation and chemical conversion and assayed the inhibitory activities toward DNA metabolic enzymes and human cancer cell growth. Among twelve compounds obtained, only isosteviol (compound 3) potently inhibited both mammalian DNA polymerases (pols) and human DNA topoisomerase II (topo II), and IC50 value for pol alpha was 64.0 microM. This compound had no inhibitory effect on higher plant (cauliflower) pols, prokaryotic pols, human topo I, and DNA metabolic enzymes such as human telomerase, T7 RNA polymerase, and bovine deoxyribonuclease I. With pol alpha, isosteviol acted non-competitively with the DNA template-primer and nucleotide substrate. Isosteviol prevented the growth of human cancer cells, with LD50 values of 84-167 microM, and 500 microg of the compound caused a marked reduction in TPA (12-O-tetradecanoylphorbol-13-acetate)-induced inflammation (inhibitory effect, 53.0%). The relationship between the structure of stevioside-based compounds and these activities were discussed.
异甜菊醇（对映-16-氧代贝壳杉烷-19-酸）是甜菊糖苷的水解产物，甜菊糖苷是一种在甜叶菊（Bertoni）Bertoni叶片中产生的天然甜味剂。在本报告中，我们通过微生物转化和化学转化从甜菊糖苷制备了异甜菊醇及相关化合物，并测定了它们对DNA代谢酶和人类癌细胞生长的抑制活性。在所获得的12种化合物中，只有异甜菊醇（化合物3）能有效抑制哺乳动物DNA聚合酶（pols）和人类DNA拓扑异构酶II（topo II），α-聚合酶的IC50值为64.0微摩尔。该化合物对高等植物（花椰菜）pols、原核生物pols、人类拓扑异构酶I以及DNA代谢酶如人类端粒酶、T7 RNA聚合酶和牛脱氧核糖核酸酶I没有抑制作用。对于α-聚合酶，异甜菊醇与DNA模板引物和核苷酸底物的作用是非竞争性的。异甜菊醇可抑制人类癌细胞的生长，LD50值为84-167微摩尔，500微克该化合物可使佛波酯（12-O-十四烷酰佛波醇-13-乙酸酯）诱导的炎症显著减轻（抑制作用为53.0%）。本文还讨论了基于甜菊糖苷的化合物结构与这些活性之间的关系。
