5-methoxypodophyllotoxin

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. 

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. 

Van Uden, W., Bos, J.A., Bocke, G.M., Woerdenbag, H.J. and Pras, N. (1997) The large-scale isolation of deoxypodophyliotoxin from rhizomes of Anthriscus sylvestris followed by its bioconversion into 5-methoxypodophyllotoxin p-D-glucoside by cell cultures of Linum flavum.. Nat. Prod., 60,401-3. 

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). 

Figure 4.11 Proposed biosynthetic steps involved in the biosynthesis of podophyllotoxin(-glucoside) and 6-methoxypodophyllotoxin(-glucoside). Steps catalyzed by yet unidentified enzymes are shown with dashed arrows. Enzymes involved are as follows (1) deoxypodophyllotoxin 7-hydroxylase, (2) deoxypodophyllotoxin...

Federolf, K., Alfermann, A.W. and Fuss, E. (2007) Aryltetralin-lignan formation in two different cell suspension cultures of Linum album Deoxypodophyllotoxin 6-hydroxylase, a key enzyme for the formation of 6-methoxypodophyllotoxin. Phytochemistry, 68,1397-A06. 

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