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Introduction
Since the prehistoric period, human beings have treated various diseases with natural products, from plants, marine materials, and animals. The earliest recorded medical text, which came from ancient Egypt, described several plant-derived medicinal substances. Today, plants are the main resource for modern pharmacological research and the development of new drugs, including anticancer agents. The first plant-derived anticancer drugs were the vinca alkaloids, vinblastine and vincristine. They come from the Madagascar periwinkle, Catharanthus roseus G. Don, which was traditionally used to treat diabetes (1).
Podophyllotoxin was isolated as an active ingredient of a plant used for the traditional treatment of skin cancer and warts. Podophyllotoxin acetate (PA), which is a naturally occurring derivative of podophyllotoxin, is obtained as an abundant lignan from podophyllin, which is a type of resin produced by Podophyllum peltatum Linnaeus. The lignans are a family of abundant natural products and secondary metabolites that are manufactured through the shikimic acid pathway, and consist of two bound phenylpropane units. Podophyllotoxin exhibits the aryltetralin structure of a cyclolignan, which is a lignin in which the two phenylpropane units are joined by a carbocycle that consists of two single carbon-carbon bonds that occur between the side chains (one at the β-β′ positions). In terms of biological effects, podophyllotoxin is known to have immunosuppressive activity and antiviral effects against herpes, measles, influenza and venereal warts (2).
It is also considered to be a candidate anticancer agent, as it reversibly binds tubulin and interrupts its polymerization, thereby preventing the formation of mitotic spindles to trigger cell cycle arrest and inhibit cell proliferation (2). Many investigators have synthesized various derivatives in an effort to improve the antitumor effects of podophyllotoxin. Three kinds of representative semi-synthetic epipodophyllotoxin derivatives have been developed: etoposide, teniposide and etopophos. These drugs do not inhibit microtubule polymerization due to the presence of a bulky glucoside moiety in their chemical structure. Instead, their anticancer activity arises from their ability to bind DNA topoisomerases, which are ubiquitous enzymes that control the topological state of DNA in cells. There are two forms of DNA topoisomerase: type I enzymes cleave a single strand of DNA, while type II enzymes cleave both strands. Together, they decide the topology of DNA in actively proliferating cancer cells. Thus, DNA topoisomerases are...