Isoflavone derivatives

Details Isoflavone derivatives Isoflavone derivatives

2000-12-15

2003-04-01

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C549S402000, C549S403000, C549S220000

Reexamination Certificate

active

06541613

ABSTRACT:

FIELD OF THE INVENTION
The field of the invention is isoflavones.
BACKGROUND OF THE INVENTION
The isoflavones are a group of naturally occurring plant compounds having the aromatic heterocyclic skeleton of flavan. Soybeans are the most common and well known source of isoflavones, reported to contain the isoflavones, daidzin, genistin, glycitin, 6″-dadidzin-O-acetyl, 6″-O-acetyl genistin, 6″-O-malonyl daidzin, and 6″-O-malonyl genistin. (see U.S. Pat. No. 5,679,806 to Zheng et al., (October 1997) incorporated herein by reference). Isoflavones are present in processed soy foods as well, including miso and soy sauce. Legumes, lupine, fava bean, kudzu and psoralea may also be important sources. The existence of isoflavones in Pueraria has long been known, with the roots of Pueraria containing several isoflavone compounds, such as daidzin, and puerarin.
Isoflavones are known in aglucone forms, as well as 7-acetylated and 7-substituted glycosides. Especially important isoflavones in aglucone form include daidzein, genistein, and glycitein. Especially important isoflavones in 7-glycoside form include daidzin, genistin, and glycitin. Genistein is also known to occur naturally as a 4′-glucoside (sophoricoside), and a 4′-methyl ether (biochanin A).
Isoflavones in general, and genistein in particular, have structural similarities to that of certain human estrogens, and such compounds are said to have estrogenic activity. Isoflavones are also said to have other useful biological and pharmacological activities, including antiangiogenic, antihemolytic, antiischemic, antileukemic, antimitogenic, antimutagenic, antioxidant, fungicidal, pesticidal, MAO-inhibition, phytoalexin, and tyrosine kinase inhibition activities (1).
The anticancer effects of genistein are of particular interest. Genistein may exert antitumor effects in part by inhibiting angiogenesis, i.e., reducing formation of vasulature and blood flow to the tumor. Its affinity to estrogenic sites in the vicinity of cancer cells may also inhibit tumor growth. As a well-known inhibitor of the enzyme tyrosine kinase, genistein may also inhibit energy and signaling pathways in tumors. Examples of research are described in references
4
and
5
.
Genistein and other isoflavones are also said to be important contributors to bone health, resulting at least in part from the ability of these compounds to inhibit protein kinase activity, and thereby inhibit osteoclast cell activity. The isoflavones are especially attractive in this regard because they generally have a low toxicity relative to many other known protein kinase inhibitors. Examples of research along these lines are described in references
6
and
7
. Citations for still other research articles describing beneficial effects of isoflavonoids are set forth as references.
Because of its many beneficial effects, enriched sources of genistein are marketed to consumers around the world in a wide variety of nutritional supplements. Many of the health benefits of soy products are ascribed to the presence of genistein.
Unfortunately genistein and other isoflavones are very insoluble in water. See, for example, descriptions of genistein, genistin, biochanin A, and sophoricoside in the Merck Index (3). The insolubility of the isoflavones complicates their formulation into foodstuffs and cosmetics, many of which are aqueous-based systems. Low solubility is also frequently an impediment to efficient bioavailability in orally administered products. Low solubility is a particularly serious impediment to formulation of intravenous medications, which are most often delivered in aqueous media.
Thus, there is a continuing need to provide isoflavones in forms which have increased bioavailability, especially enhanced aqueous solubility relative to the unmodified compounds, while retaining the active properties of such unmodified compounds.
SUMMARY OF THE INVENTION
Methods and compositions of the present invention provide increased bioavailability of isoflavones by converting a starting isoflavone into a pro-compound. This is preferably accomplished by attaching a polar (solubilizing) leaving group which can be readily hydrolyzed under physiologic conditions to produce the starting isoflavone.
In preferred embodiments, an alcohol functionality of an isoflavone is esterified using a carboxylic acid group or a phosphoric acid group. This yields a carboxylic acid hemiester or a phosphate ester. In general, fluids of the digestive and absorptive gastrointestinal tract, other acids, and various enzymes are capable of hydrolyzing the esterified isoflavone to the starting isoflavone.
In another aspect of the invention, the starting isoflavone preferably comprises a natural isoflavone, more preferably comprises genistin or daidzin, and still more preferably comprises an aglycone form such as genistein or daidzein.
In still other aspects of the invention, the pro-compounds may advantageously be employed therapeutically or prophylactically for a variety of conditions, provided as a dietary supplement, or added to natural or processed food-stuffs. Thus, the pro-compounds may be used as pro-drugs or pro-nutrients.
Various objects, features, aspects and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the invention.


REFERENCES:
patent: 5550152 (1996-08-01), Koch et al.
patent: 5679806 (1997-10-01), Zheng et al.

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