Linum flavum

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. ... 

Van Uden W, Bos JA, Boeke GM, Woerdenbag HI, Pras N. (1997) The large scale isolation of deoxypodophyUotoxin from rhizomes of Anthriscus sylvestris followed by its bioconversion into 5-methoxypodophyUotoxin P-D-glucoside by cell cultures of Linum flavum. J Nat Prod 60 401 403. 

In addition to podophyllotoxin itself, closely related compounds, such as 5-methoxypodophyllotoxin (3.89), can be used as a precursor for anti-cancer drugs. Linum species (flax, linseed) can produce podophyllotoxin or substituted podophyllotoxins in tissue culture with yields of up to 0.35% of dry weight. The biosynthesis of 5-methoxypodophyllotoxin in Linum flavum was investigated by Xia et al. (2000), whereas Seidel et al. (2002) investigated podophyllotoxin (3.86) production in cell cultures of Linum album. 

Figure 3-12. Biosynthesis of 5-methoxypodophyllotoxinin in Linum flavum, according to Xia et al. (2000). (a) pinoresinol/lariciresionol reductase, and (b) secoisolariciresinol...

Broomhead, A.J. and Dewick, P.M. (1990) Aryltetralin lignans from Linum flavum and Linum capitatum. Phytochemistry, 29, 3839-44. 

Molog, G.A., Empt, U., Kuhlmann, S., Van Uden, W., Eras, N., Alfermann, A.W. and Petersen, M. (2001) Deoxypodophyllotoxin 6-hydroxylase, a cytochrome P450 monooxygenase from cell cultures of Linum flavum involved in the biosynthesis of cytotoxic lignans. Planta, 214, 288-94. 

Van Uden, W, Holidi Oeij, K., Woerdenbag, H.J. and Pras, N. (1993) Glucosylation of cyclodextrin-complexed podophyllotoxin by cell cultures of Linum flavum (L.). Plant Cell Tiss. Org. Cult., 34,169-75. 

Van Uden, W., Pras, N., Batterman, S., Visser, J.F. and Malingre, T.M. (1991) The accumulation and isolation of coniferin from a high-producing cell suspension of Linum flavum. Planta, 183, 25-30. 

Wichers, H.J., Versluis-De Haan, G., Marsman, J.W. and Harkes, M.P. (1991) Podophyllotoxin-related Ugnans in plants and cell cultures of Linum flavum. Phytochemistry, 30, 3601. ... 

Xia, Z.Q., Costa, M.A., Proctor, J., Davin, L.B. and Lewis, N.G. (2000) Dirigent-mediated podophyllotoxin biosynthesis in Linum flavum and Podophyllum peltatum. Phytochemistry, 55, 537-49. 

The in vitro cytotoxicity of 5-methoxypodophyllotoxin, obtained from a root culture derived from Linum flavum, against EAT and HeLa cells was determined and compared with those of podophyllotoxin, etoposide, teniposide and 5-methoxypodophyllotoxin-4- 3-D-glucoside [106]. The tested lignans had about the same cytotoxic potency as podophyllotoxin (ED50 of 32 and 22 pg/mL versus 42.8 and 20.5 pg/mL, respectively against EAT and HeLa cells). However, in comparison with etoposide and teniposide they were clearly less potent (1.1 and 7.9 pg/mL, and 0.06 and 0.3 pg/mL, respectively). 

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. 

---