Submitted to: Elsevier
Publication Type: Book / Chapter
Publication Acceptance Date: 1/1/2000
Publication Date: 1/24/2002
Citation: Interpretive Summary: Over fifty years after the first medicinal application of the antimitotic activity of podophyllotoxin was proposed, the aryltetralin lignans of Podophyllum continue to be subjects of intense interest and research. Derivatization of podophyllotoxin has produced the potent and widely used antineoplastic drugs etoposide and teniposide. Numerous other analogs have been synthesized in the hope of increasing the usefulness of these drugs, but little improvement has been achieved. These efforts, nevertheless, have generated large amounts of data that may facilitate the design of podophyllotoxin-derived drugs having novel and improved pharmacological properties. On the other hand, significant progress has been made towards securing a reliable source of podophyllotoxin. This compound is, still today, primarily obtained from wild-harvested rhizomes of P. emodi, a species considered in danger of extinction due to over-collection and loss of habitat. The discovery that the leaves of P. peltatum, a North American species, produce large amounts of podophyllotoxin not only promises to make this plant the preferred source of the compound, but also offers the possibility to establish it as a new high value cash crop.
Technical Abstract: Lignans are a widely distributed class of dimeric phenylpropanoid derivatives, many of which have strong antimicrobial, antiviral, or antifeedant activity and thus play important roles in plant defense. Of more restricted taxonomic distribution, the aryltetralin lignans have been found in highest abundance in plants of the genus Podophyllum (Berberidaceae). Foremost among these lignans, podophyllotoxin is a particularly cytotoxic inhibitor of microtubule assembly and a strong antiviral agent. Semisynthetic epimeric derivatives of podophyllotoxin having inhibitory activity against DNA-topoisomerase II have been developed as effective antineoplastic drugs. Current work on Podophyllum lignans is focused on two fronts: 1) Structure optimization to generate derivatives with superior pharmacological profiles and broader therapeutic use, and 2) Development of alternative sources of podophyllotoxin. Numerous variations of the basic aryltetralin structure have been created. Some of the new compounds have shown promising activity profiles, but practically little has been achieved besides improvement in solubility. Interest in new derivatives remains strong, which, along with the formulation of existing drugs for new indications, is increasing the demand for podophyllotoxin. While intense collection has severely reduced the natural stocks of Indian Podophyllum, the preferred source of podophyllotoxin, a North American species has emerged as a rich and renewable source of this compound.