Podophyllotoxins

The rhizome of Podophyllum species is known to contain several lignans. Lignans possess antitumour activity and are highly toxic for the treatment of neoplastic diseases in humans. These are dimerisation products of phenylpropanoid pathway intermediates linked by the central carbons of their side chain, podophyllotoxin being the most active cytotoxic compound. Therefore, two semisynthetic glycosides of the isomeric natural product epipodophyllotoxin, called etoposide and teniposide, have been developed by Sandoz (now part of Novartis). They show less cytotoxicity and act as inhibitors of microtubule assemblies, and are commercially used as therapeutic agents against several human neoplasms, including small cell carcinomas of the lung, testis neuroblastoma, Hodgkin's disease, diffuse histocytic lymphoma, and others [9, 62, 67]. Much recent synthetic work on podophyllotoxins has concentrated on the design of more water-soluble analogues. Although podophyllotoxin

binds to tubulin at a site different from that for Catharanthus alkaloids, the drug has no effect on microtubular structure or function but inhibits topoisomerase II [67].

American podophyllum (P. peltatum) contains 4 to 5% podophyllum resin, whereas the Indian species (P. hexandrum) contains 7 to 16%. The variation in percentage of resin is attributed to seasonal differences, age of the plant and altitude [68-70]. The resin of P. hexandrum contains approx. 40% podophyllotoxin and low amounts of peltatin [71]. Unfortunately, the Indian species, P. hexandrum Royle (Berberidaceae), has become a critically endangered species. A recent study aimed at the domestication of the plant in the Himalayan region [72] reported that the plants grown at high altitude contain high podophyllotoxin content [69], and content increases with the age of the plant [70]. One of the major problems associated with the utilisation of P. hexandrum is its long juvenile phase and poor trait setting ability of the plants resulting in selection problems. Moreover, its seeds take a long time to germinate [72].

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