Lignan podophyllotoxin

Etoposide is an effective anticancer drug used in the treatment of small-cell lung cancer, testicular cancer and lymphomas. It is a semi-synthetic modification of the natural lignan podophyllotoxin, and contains three acetal linkages. Can you identify them ... 

Lignans represent an extremely diverse group of compounds. This is the result of both structural diversity and stereo-selective biosynthesis. One particular plant species generally makes only one enantiomer of a particular compound. The other enantiomer may be synthesized by a different species. As a consequence, it is virtually impossible to summarize the biosynthesis of lignans in general. Instead, the focus here will be on the biosynthesis of the lignan podophyllotoxin in a number of different plant species, as an illustration of the different biosynthetic routes that can be used to synthesize the same compound. 

From Taxus baccata (Taxaceae) the alkaloid taxol has been isolated. Taxol also affects the architecture of microtubules in inhibiting their disassembly (312). Nonalkaloidal compounds to be mentioned in this context include the lignan podophyllotoxin (312). In conclusion, any alkaloid which impairs the function of microtubules is likely to be toxic, because of their importance for a cell, and, from the point of view of defense, a well-working and well-shaped molecule. 

Dayan, F.E., Kuhajek, J.M., Canel, G., Watson, S.B. and Moraes, R.M. (2003) Podophyllum peltatum possesses a p-glucosidase with high substrate specificity for the aryl-tetralin lignan podophyllotoxin. Biochim. Biophys. Acta, 1646,157-63. 

Yoo and Porter [67] developed a sensitive immunoassay for the natural Podophyllum lignan, podophyllotoxin. Reverse-phase HPLC separation followed by radioimmunoassay (RIA) for human plasma samples and immunoaffinity extraction (IAE) followed by RIA for human urine samples were used to investigate a lignan-related hypocholesterolemic agent. This analysis proved to be very useful in quantifying extremely low drug concentrations in body fluids [68],... 

Interest in lignans and neolignans has risen sharply in the last few years. This is due chiefly to their powerful, varied biological activities (Table 7.3.1) exemplified by three of the most noteworthy representatives. First, the lignan podophyllotoxin (1), in the form of several semisynthetic derivatives, is one of the very few natural products from higher plants used clinically in cancer chemotherapy (30). Next kadsurenone (2), also isolated from an angiosperm species has been described as... 

Medicinal Properties. In terms of medicinal properties, plants containing lignans have been used as folk medicines by many different cultures. For instance, both the North American Indians and the Native of the Himalayas have utilized, for about 400-600 years, alcoholic extracts of Podophyllum rhizomes (rich in the lignan podophyllotoxin 87) as a cathartic and a poison (90),... 

Podophyllotoxin, a plant lignan, is a potent antimitotic agent (Figure 6.61). An enantioselective synthesis of (—)-podophyllotoxin was achieved via the enzymatic desymmetrization of an advanced meso-diacetate, through PPL-mediated diester hydrolysis [157]. 

Another group of natural products, namely the biologically active lignans of the aryltetralin series - for example, isopodophyllotoxone (2-59), picropodophyllone (2-60), and podophyllotoxin (2-61) (Scheme 2.13) [19] - have also been synthesized using a domino Michael/aldol process. 

Another anti-cancer agent in clinical use is podophyllotoxin (3-59) this has an aryl tetrahydronaphthalene lignan lactone skeleton, and demonstrates potent tubulin-binding, anti-mitotic properties (Scheme 3.16) [30]. The Sherburn group [31] prepared this molecule by a tris(trimethylsilyl)silane promoted conversion of thionocarbonate 3-55 into the lactone 3-58, which proceeded with a yield of 38 %. As intermediates, the radicals 3-56 and 3-57 can be assumed. 

Podophyllotoxin (Fig. 4), a non-alkaloid toxin lignan, is a laxative, anti-tumor and antirheumatic agent. Cell cultures of Linum flavum were shown to be able to convert deoxypodophyllotoxin, a lignan isolated from Anthriscus sylvestris, into podophyllotoxin. ... 

Partially hydrogenated quinoline cores are also present in some important bioactive compounds. For example, the 4-aza-analogs of Podophyllotoxin, a plant lignan that inhibits microtubule assembly, revealed to be more potent and less toxic anticancer agents. In 2006, Ji s group reported a green multicomponent approach to a new series of these derivatives, consisting of the reaction of either tetronic acid or 1,3-indanedione with various aldehydes and substituted anilines in water under microwave irradiation conditions (Scheme 26) [107]. For this efficient and eco-friendly transformation, the authors proposed a mechanism quite similar to the one that was postulated for the synthesis of tetrahydroquinolines in the precedent section. 

Podophyllotoxin is an aryltetralin lignan which has been isoiated from severai plants of the Podophyllum species, it is a potent cytotoxic agent against various cancer celi iines, stopping the cell cycle in metaphase through the inhibition of microtubules assembly by binding the colchicine site of the tubulin [112]. Because of numerous side effects, podophyllotoxin cannot be used as a drug. 

The lignans are a large group of plant phenolics, biosynthesized from the union of two phenylpropane molecules e.g., both matairesinol (Centaurea species, family Asteraceae) and podophyllotoxin Podophyllum peltatum, family Berberidaceae) are formed from the phenylpropane coniferyl alcohol. Lignans are essentially cinnamoyl alcohol dimers, though further cyclization and other structural modifications result in various structural types, e.g. dibenzylbutyrolactone and epoxy lignan. 

The lignan constituents of the two roots are the same, but the proportions are markedly different. The Indian root contains chiefly podophyllotoxin (Figure 4.21) (about 4%) and 4 -demethylpodophyllotoxin (about 0.45%). The main components in the American root are podophyllotoxin (about 0.25%), p-peltatin (about 0.33%) and a-peltatin (about 0.25%). Desoxypodophyllotoxin and podophyllotoxone are also present in both plants, as are the glucosides of podophyllotoxin, 4-demethylpodophyllotoxin, and the peltatins, though preparation of the resin results in considerable losses of the water-soluble glucosides. 

The best example of a lignan used as a lead compound is podophyllotoxin, an antimitotic compound that binds to tubulin, although podophyllotoxin has not been isolated from Taxus species,. Etoposide and teniposide are well-known compounds derived from podophyllotoxin, and their antitumor activity is due to the inhibition of topoisomerase II. 

Lignans 1 Podophyllotoxin 2 Arctnn, phillyrin cpipinorcsinol-4 -/i-D-glucoside matairesomde, and pinoresinol 4 ft D glucoside Buchardt et al 1986 Nishibe et al 1988... 

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