Podophyllotoxin Lignans

hexandrum (in India and Nepal) and P peltatum (in America) are the two main Podophyllum species that produce PTOX. The rhizome of P. hexandrum yields the highest amount of PTOX (4.3% of total dry weight), while the rhizome of P. peltatum contains 0.3-1.0% PTOX by mass. 

The approaches that are commonly used to improve the in vitro production of PTOX in plant organ cultures include optimization of cultivation, precursor feeding, and elicitation [96]. The highest amount of PTOX (2.26% DW) was achieved in the coculture of L. album suspension cells with the live fungus Sebacina ver-mifera [97]. In addition, several endophytic fungi cultures have the capacity to produce PTOX, such as Fusarium solani from P hexandrum [98], Phialocephala fortinii from P. peltatum [99], Trametes hirsuta from P. hexandrum [100], and 

2-oxoglutarate/Fe(ll)-dependent dioxygenase. The double arrows indicate multiple reactions the dashed arrow represents uncharacterized reactions, and the dashed box encloses a bypass of the podophyllotoxin biosynthetic pathway. 

E oxysporum from Juniperus recurva [101]. The accumulation of PTOX in these fungi is approximately 30 pgg DW. 

Presently, no metabolic engineering effort of PTOX biosynthesis has been reported. Rajesh et al. [24] developed an efficient transformation protocol into P. hexandrum embryogenic cells, providing a basis for future gene transfer into PTOX-producing plants to optimize the production systems. 

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The stegane lignans are thought to originate biogenetically from the same pathway as the podophyllotoxin lignans, a common precursor being the dibenzylbutyrolactone yatein, Fig. (6) [35]. 

In recent decades, a number of antitumor lignans have been synthesized, and their structure-activity correlations have been reported. Ring-A-opened podophyllotoxin lignans were synthesized by Michael Initiated Ring Closure (MIRC). Compound 67 showed the strongest inhibition of DNA topoisomerase II like 65 [55]. Naturally... 

Recent unpublished work by W.M. Kamil and P.M. Dewick, who I thank for permission to use these results, yields fascinating information about the ring closure process (Scheme 5). Whereas yatein and its cis-isomer are precursors of podophyllotoxin, most surprisingly the functionalized compounds anhydropodorhizol and podorhizol are not. This suggests a quinone methide intermediate with a central function. It is tempting to see matairesinol, not yet tested, as a possible precursor and branching point for all of the podophyllotoxin lignans. 

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. ... 

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 ... 

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. 

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. 

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... 

Podophyllotoxin 1-0-glucoside (= Podophyllinic acid lactone 1-0-glucoside) (lignan)... 

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. 

Coniferin (the (3-D-glucoside of coniferyl alcohol) is accumulated prior to lignin formation as well as in lignan-s)mthesizing cell cultures (e.g. Berlin et al, 1986 Van Uden et al., 1991 Smollny et al, 1998). Coniferin and lignan contents were found to be inversely correlated in cell cultures. However, there is no direct proof for a transformation of stored coniferin to lignans. Feeding of coniferin resulted in an enhanced podophyllotoxin accumulation in cell cultures of Podophyllum hexandrum (Van Uden et al, 1990). 

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