Taxonomically close to the Annonaceae, the Lauraceae family abounds with apor-phinoid alkaloids. A remarkable advance in the search for topoisomerase inhibitors from Lauraceae has been provided by Woo et al. (6). Using DNA-unwinding assay and structural modeling, they showed that dicentrine can attain a relatively planar conformation and molecular bulk which allow it to occupy the active site of topoisomerase II which becomes inactive. The requirement of a suboptimal conformation to achieve DNA binding appears to make dicentrine less potent against topoisomerase II than the
very planar oxoaporphine alkaloid liriodenine (7). Other inhibitors of topoisomerase present in Lauraceae are diaryldimethylbutane lignans. Such compounds are found in Persea thunbergii (Sieb. & Zucc.) Kosterm.
P. thunbergii (Sieb. & Zucc.) Kosterm. (Machilus thunbergii Sieb.& Zucc.), or common machilus, tabunoki (Japanese), is a tree native to Korea and Japan and is also found in Taiwan. The bark is smooth, fawn, and lenticelled. The leaves are spiral, simple, exstipulate-elliptic, glossy, and somewhat fleshy. In Japan and Korea, the plant affords a remedy for eczema, diseases of the spleen and stomach, and asthma.
Li et al. using bioassay-guided fractionation, isolated a number of diaryldimethyl-butane lignans, of which meso-dihydroguaiaretic acid, which inhibited the enzymatic activity of topoisomerase I and II by 93.6 and 82.1%, respectively, and nectandrin B showed 79.1 and 34.3% inhibition, respectively, in vitro at a concentration of 100 mM (8). Note that such lignans are present in the Myristicaceae, and one might set the hypothesis that lignans with potent topoisomerase inhibitors await discovery in the Laurales-Magnoliales group.
Lindera tzumu Hemsl. (Sassafras tzumu [Hemsl.]) Hemsl, Pseudosassafras tzumu (Hemsl.) Lecte., Pseudosassafras laxiflora (Hemsl.) Nakai, Lindera camphorata Levi., or cha mu, mu wang (Chinese), is a tree that grows in China. The plant grows to 35 m tall and 2-5 m in diameter. The bark is yellow-green, smooth, and irregularly and longitudinally fissured. The wood is yellowish, finely grained, durable, and used for boat and furniture making. Leaves are simple, alternate, aggregate at apex of stems, and exstipulate. The blade is ovate or obovate and 9-18 X 6-10 cm. The fruits are subglobose, up to 10 mm in diameter, blackish-blue, and seated on a cup-shaped perianth. The wood of this tree is highly esteemed by the Chinese, who believe that a house built of this timber is never struck by lightning. The drug consists of the white inner bark, which is used as an anthelmintic, parasiticidal, antiseptic, anti-emetic, and antipyretic. The pharmacological potential of this plant is unexplored yet. Note that D-dicentrine, from the root of Lindera megaphylla Hemsl. abrogated the survival of a number of cancer cell lines cultured in vitro including esophageal carcinoma HCE-6, lymphoma cell lines Molt-4 and CESS, leukemia cell lines HL60 and K562, and hepatoma cell line MS-G2, and significantly inhibited the tumor incidence of leukemia cell line K562 in severe combined immunodeficient mice (9). The cytotoxic activity of dicentrine is mediated via inhibition of topoisomerase II (6,7). Dicentrinone from Ocotea leucoxylon is closely related to dicentrine, and even more planar has shown potent topoisomerase I activity (9).
Cassytha filiformis L., mentioned earlier, contains aporphine alkaloids such as actin-odaphnine, cassythine, and dicentrine, which effectively bind to DNA and behave as typical intercalating agents and interfere with the catalytic activity of topoisomerases (3,10,11).
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