Lignans Enterolactone

Enterolactone] (lignan) Mammalian lignan derived from intestinal bacterial modification of lignans from ingested Secale cereale (rye) (Poaceae) AROM [14]... 

The most useful of the insertion processes is the intramolecular reactions that occur with high selectivity for the formation of five-membered ring products. The electrophilic nature of the process is suggested by C-H bond reactivity in competitive experiments (3°>20 >1°) [76, 77]. Asymmetric catalysis with Rh2(MPPIM)4 has been used to prepare a wide variety of lignans that include (-)-enterolactone (3) [8], as well as (R)-(-)-baclofen (2) [7],2-deoxyxylolactone (31) [80,81],and (S)-(+)-imperanane (32) [82].Enantioselectivities are 91-96%... 

DMA) and equol, while for lignans enterodiol and enterolactone should be used. 

Recently, some of the specific faecal bacteria involved in the metabolism of dietary isoflavonoids were isolated (Hur et al., 2000). They have been shown to selectively convert genistin and daidzin to their respective aglycones. One of the isolated bacteria, under anoxic conditions, was further shown to metabolise genistein and daidzein to their respective dihydroxy-genistein and dihydroxy-daidzein. In the case of lignans, enterodiol and enterolactone were shown to be excreted in vivo only in rats harbouring a gut microflora (Rowland et al, 1999). 

Substantial individual differences were observed in the response to study breads and the ranges of enterolactone concentration changes in the groups were as follows -54.5-60.0 nmol/1 (placebo), -26.2-101.3 nmol/1 (LP), -19.6-81.8 nmol/1 (HP). This was something that could have been expected as in several studies dietary factors have explained only 10% of the variation in serum enterolactone (Vanharanta et al, 2002b Kilkkinen et al., 2001). This gives further support to the major role of intestinal bacteria in the synthesis of enterolactone. Decreased concentrations of enterolactone may occur due to an increased fiber intake, which may shorten the retention time in the colon and lead to incomplete metabolism of plant lignans. Constipation was earlier shown to be associated with an increased level of serum enterolactone (Kilkkinen et al., 2001). 

Asymmetric catalysis with Rh2(4Y-MPPIM)4 has been used to prepare a wide variety of lignans such as (+)-isodeoxypodophyllotoxin 70 (Equation (62))202,203 and (—)-enterolactone 71 (Equation (63)).194 The chemistry has also been utilized in the synthesis of (A)-(+)-imperanene 72 (Equation (64))197 and (R)-(—)-baclofen 73 (Equation (65)).198 Enantioselectivities of 91-96% ee have been obtained for a broad range of applications. 

Fig. 2.86. Chemical structures of the iosflavones daidzein, genistein, O-desmethylangolensin, equol, and the lignans enterolactone and enterodiol. Reprinted with permission from Z. Kuklenyik el al. [209].

Gut microflora metabolites may also be important. As discussed above, the mammalian lignan aglycones, enterodiol and enterolactone, are estrogenic, and equol is more estrogenic than its dietary precursor, the isoflavone daidzein. ... 

Wang, L.Q., Meselhy, M.R., Li, Y., Qin, G.W., and Hattori, M., Human intestinal bacteria capable of transforming secoisolariciresinol diglucoside to mammalian lignans, enterodiol and enterolactone, Chem. Pharm. Bull, 48, 1606, 2000. 

Jacobs, E., Kulling, S.E., and Metzler, M., Novel metabolites of the mammalian lignans enterolactone and enterodiol in human urine, J. Steroid Biochem. Mol Biol, 68, 211, 1999. 

Heinonen, S., Nurmi, T., Liukkonen, K., Poutanen, K., Wahala, K., Deyama, T., Nishibe, S., and Adlercreutz, H., In vitro metabolism of plant lignans new precursors of mammalian lignans enterolactone and enterodiol, J. Agric. Food Chem., 49, 3178, 2001. 

Oxidative coupling of dianions (12, 278). The oxidative coupling of dianions of carboxylic acids has been used for synthesis of enterolactone (6), a lignan urinary metabolite.1 Thus the dianion 2, generated from 1 with LDA, when treated with I2 (0.5 equiv.) couples to 3, obtained as a mixture of two isomers in a 4.5 1 ratio. This product is converted in 89% overall yield to the dimethyl ether (5) of enterolactone (6). 

As a result of these developments, Doyle and co-workers have synthesized several lignans, among which are (-)-enterolactone, (+)-isodeoxypodophyllotoxin, and (-)-arctigenin [126], Selected examples have been reported of impressive results from C-H insertion reactions of diazoacetamides that result in [3-lactams. For example, [3-lactam formation was the sole C-H insertion process to occur with 51 (Eq. 5.33) [128] or other seven-membered ring diazoacetamides. 

Bannwart C, Adlercreutz H, Fotsis T, Wahala K, Hase T, Brunow G. 1984. Identification of o-desmethylangolensin, a metabolite of daidzein and of matairesinol, one likely plant precursor of the animal lignan enterolactone in human urine. Finn Chem Lett 4-5 120-125. 

Adlercreutz H, Fotsis T, Heikkinen R, Dwyer JT, Woods M, Goldin BR, Gorbach SL. 1982. Excretion of the lignans enterolactone and enterodiol and of equol in omnivorous and vegetarian postmenopausal women and in women with breast cancer. Lancet 2 1295-1299. 

The presence of the oxidized metabolites is unique and may provide additional reasons for the health benefits of lignans. Classical antioxidant mechanisms show that the addition of an ortho hydroxyl group to a monophenol enhances the antioxidant activity of the original monophenol. Thus, some of the mammalian lignan metabolites may actually have greater or different activity than the parent lignan. Kitts et al (1999) reported that enterolactone and enterodiol had greater antioxidant activity than the parent... 

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