Podophyllum hexandrum Podophyllotoxin

The plant. Podophyllum hexandrum (Podophyllaceae Berberidaceae), produces podophyllotoxin (3) and its glycoside, both of which are effective anticancer agents. Commercial production of podophyllotoxin from... 

Synthesis of podophyllotoxin (3.86) in cell culture of Linum album results in yields comparable to those of the most efficient tissue cultures of Podophyllum hexandrum. In order to further improve L. album cultures, Seidel et al. (2002) investigated the biosynthesis of podophyllotoxin (3.86). They fed a number of labeled compounds that to L. album cell cultures to identify which of these compounds could be used as precursors to podophyllotoxin. They determined that the substitution pattern on the benzene ring is critical. The substitution has to be either 3-methoxy, 4-hydroxy, as in ferulic acid (3.33), or, alternatively, 3,4-methylenedioxycinnamic acid (3.90) can serve as precursor. The precursor of podophyllotoxin in L. album appears to be deoxypodophyllotoxin (3.83), based on the higher level of isotope incorporation in the latter compound. This means that 7-hydroxymatairesinol, the precursors of 5-methoxypodophyllotoxin in L. flavum (Xia et al., 2000), is not a precursor of podophyllotoxin in L. album. 

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). 

Van Uden, W., Pras, N. and Malingre, T.M. (1990) On the improvement of the podophyllotoxin production by phenylpropanoid precursor feeding to cell cultures of Podophyllum hexandrum Royle. Plant Cell Tiss. Org. Cult., 23, 217-24. 

The broad-band decoupled and DEPT spectra of podophyllotoxin, C22H22OS, isolated from Podophyllum hexandrum, are shown. Although the molecule contains 22 carbons, only 18 signals are visible in the broad-band C-NMR spectrum. This would obviously mean that some of these signals represent more than one carbon. Pairs of C-lO/C-14, C-ll/C-13, and ll-OCHs/lS-OCHj are magnetically equivalent while C-6 and C-7 could show accidental overlap. With this information, assign chemical shifts to various carbon atoms in the molecule. 

Jackson, D. E. and P. M. Dewick, Cinnamic acid precursors of podophyllotoxin in Podophyllum hexandrum, Phytochemistry, 23. 1029-1035 (1984). 

Very recently Dewick has begun a thorough investigation of podophyllotoxin biosynthesis in Podophyllum hexandrum. Cinnamic and ferulic acids are each incorporated equally into both halves of the molecule, the carbon of the 0-methyl group of ferulic acid being retained by both ring A and ring C (Scheme 4). ... 

---