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Patent Issued for Synthetic Flavonoids and Pharmaceutical Compositions and Therapeutic Methods of Treatment of HIV Infection and Other Pathologies

Staff Writer


December 3, 2012



2012 DEC 3 (NewsRx) -- By a News Reporter-Staff News Editor at AIDS Weekly -- A patent by the inventors Redda, Kinfe (Tallahassee, FL); Mills, Chavonda Janeebra (Decatur, GA); Mateeva, Nelly (Tallahassee, FL), filed on December 31, 2007, was cleared and issued on November 20, 2012, according to news reporting originating from Alexandria, Virginia, by NewsRx correspondents (see also Florida A&M University).

Patent number 8314143 is assigned to Florida A&M University (Tallahassee, FL).

The following quote was obtained by the news editors from the background information supplied by the inventors: "The entire disclosure and content of each reference and patent referred to herein is incorporated by reference.

"Flavonoids (benzo-y-pyrones), as shown in Scheme 1 are a class of about 4,000 natural compounds present in all vascular plants. They appear to exhibit a wide range of biological activities including anti-oxidative [H. Bao et al, Food Chemistry, 86, 517 (2004); T. Miura et al, Food and Chemical Toxicology 41, 759 (2003)], anti-inflammatory [J. J. A. Hendricks et al, Journal of Experimental Medicine, 200,1667 (2004); H. Y. Lin et al, Journal of Cellular Physiology, 202. 579 (2005); Y. S. Chi et al, Biochem. Pharmacol, 62, 1185 (2001)], cancer suppressing [T. Zhang et al, Biorganic & Medicinal Chemistry, 12, 6097 (2004); C. A. Rowe et al, Journal of Medicinal Food, 7,402 (2004). X. Zheng et al, Bioorganic and Medicinal Chemistry Letters, 13, 3423 (2003; X. Zheng et al, Bioorganic and Medicinal Chemisty Letters, 13, 881 (2003)] and antiviral (anti-HIV) [W. Wang et al, Antiviral Research, 64, 189 (2004); T. B. Ng, et al, Life Sei., 61, 933 (1997); A. J. Vlietnick et al, Plant Flavonoids in Biol. And Medicine II: Biochem. Cell. and Medicinal Properties, 283 (1988).]. The average human diet contains about 1 g of flavonoids per day, assimilated through fruits, vegetables, red wine, tea etc. [G. Di Carlo et al, Life Sciences, 65, 337 (1999)].

"##STR00002##

"A family of flavonoids are known to be selectively toxic to multidrug resistant cancer cells. Several recent studies have linked the regulation of P-glycoprotein (Pgp) gene expression to the expression of the drug-metabolizing P450 genes, with the speculation that, in normal cells, P-glycoprotein may function in conjunction with the P450 enzymes in the detoxication of xenobiotics. Indeed, benzo[a]pyrene, an inducer and a substrate for cytochrome P4501a1, is also a substrate for P-glycoprotein. While investigating the coordinated regulation of these genes following exposure of multidrug resistant (MDR) cells to inducers of P450 gene expression, it was observed that one of these inducers, .beta.-naphthoflavone (.beta.NF), was considerably more toxic to multidrug resistant cells than to their drug-sensitive counterparts. This collateral sensitivity to .beta.NF and other flavonoid compounds has now been further investigated in several multidrug resistant cell lines. For a further discussion of the anti-cancer properties of flavonoids, see US. H1,427; U.S. Pat. Nos. 5,336,685; 6,706,865 and 6,528,042.

"Plant flavonoids usually occur in plants as glycosides, although in some circumstances they may occur as free aglycones. Most glycosides are O-glycosides, with the most common monoglycoside being at the 7-position. Diglycosides usually have sugars at the -7 and -3 positions and occasionally the -7 and -4' positions. Other combinations and mono-glycosides exist but are less abundant. C-glycosides also occur in a more restricted distribution with C-6 and C-8 glycosides being the most common.

"Plant flavonoids have antioxidative properties, cytostatic effects in tumorigenesis, and the ability to inhibit a broad spectrum of enzymes, such as angiotensin converting enzyme (ACE), protein kinase C, tyrosine protein kinase, and topoisomerase II. They are regarded as potential cancer preventatives and cardioprotective agents. Their potential use as anti-inflammatory or antiviral agents has also been examined. It is also disclosed in the literature that bioflavonoids, especially rutin, citrin, quercetin, hesperidin or derivatives are responsible for the inactivation of protein-cleaving enzymes (such as hyaluronidase and/or collagenase), which promote skin-aging processes. These compounds are used for general skin care or cosmetic surgery. It is reported that rutin, quercetin, isoquercitrin, catechin and other compounds also prevent and ameliorate the aging phenomena of the skin. It is also said that, together, quercetin glycoside, divalent metal ion, and extract of liquorice prevent intoxication by promoting alcohol metabolism in the human liver.

"Rutin is a flavonoid glycoside comprised of quercetin and the sugar, rutinose. Many beneficial health effects of rutin have been demonstrated. Such effects have been attributed to anti-inflammatory, anti-mutagenic, anti-tumor, anticarcinogenic, smooth muscle relaxation, and estrogen receptor binding activities of rutin. Rutin is also being used in the treatment of capillary fragility, cerebral thrombosis, retinitis and rheumatic-fever-associated hemorrhagic conditions. Under conditions of low dietary fat intake, rutin and quercetin have been reported to considerably suppress colon tumor incidence. Backhaus (Use of bioflavonoid, especially rutin for retrovirus inactivation. Germany Patent DE4340438) claimed that rutin and its derivatives, in an oral dosage form, and injection or infusion solution, or a suppository, would inactivate retroviruses (e.g., HIV).

"Most of the flavonoids have been isolated from plants in order to test their biological properties; others have been synthetically produced in search of more potent drug candidates.

"The structure-activity relationship (SAR) in flavonoids is empirical, i.e., based on numerous data from testing different compounds. Although there are a lot of data in the literature, it is very difficult to outline a clear tendency that will lead to an optimized structure of high activity and low toxicity.

"Among the most studied compounds, quercetin and baicalin are polyhydroxylated flavones [L. M. Larocca et al, J. Ural., 152, 1029 (1994) 1417; K. Ono et al, Biochem. Biophys. Res. Commun., 160, 982 (1989); B. Q. Li et al, Cell And Mol. Biol. Res., 39, 119 (1993)]. It is believed that the important structural features leading to high biological activities are the presence of 5-OH and 3-OH groups. The latter, however, is considered to be responsible for some mutagenic properties observed in quercetin, which disappeared after this group was methylated. Their solubilities can be modified through selective introduction of lipophilic and hydrophilic substituents. The most popular approach is to balance the number of the alkyl substituents and free hydroxyl groups.

"The incorporation of electronegative elements, such as halogens and nitro groups in the flavonoid structure, introduce new patterns of biological properties. 4',6-dichloroflavan has been reported to be a potent antirhinovirus compound. Halogenated and nitro-substituted flavones exhibit structure-dependent aryl hydrocarbon receptor (AhR) agonist and antagonist activities comparable to that observed for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [Y. F. Lu et al, Biochemical Pharmacology. 51. 1077 (1996)]. 8-lodo, 8-bromo, and 8-trifluoromethyl derivatives of chrysin exhibit strong activities against human gastric adenocarcinoma cell lines (SGC-7901) and colorectal adenocarcinoma (HT-29) cells. One of the most recent studies reports the effect of some flavonoids on the central nervous system.

"Halogenated flavanones and flavones are considered potential benzodiazepine receptor ligands. Indeed, 6-bromoflavone and 6-bromo-3'-nitroflavone showed activities close or higher than that of diazepam [P. Bovichelli et al, Tetrahedron Letters, 43, 5563 (2002)].

"It is an object of the present invention to provide novel chalcones and flavones substituted with electronegative groups useful for the treatment of mammals (man or animal), in particular, mammals afflicted with viral and retroviral, in particular, HIV infections and methods for their synthesis."

In addition to the background information obtained for this patent, NewsRx journalists also obtained the inventors' summary information for this patent: "The above and other objects are realized by the present invention, one embodiment of which relates to novel compounds having the structure:

"##STR00003##

"wherein:

"R.sub.1 is an electronegative substituent,

"R.sub.2 is R.sub.1 or alkyl,

"R.sub.3 is H or O-alkyl,

"R.sub.4 and R.sub.5 are the same or different and are alkyl, and

"R.sub.6 is H or OH.

"A further embodiment of the invention concerns methods for the syntheses of the above described compounds comprising synthesizing the chalcones by the Claisen condensation of appropriately substituted acetophenones and benzaldehydes, preferably in ethanol and synthesizing the flavones by a three step Baker-Venkataraman rearrangement.

"An additional embodiment are pharmaceutical compositions comprising therapeutically effective amounts for the treatment of viral and retroviral, in particular, HIV infections of a compound or mixture of compounds as described above and pharmaceutically acceptable carriers or excipients thereof.

"A further embodiment of the invention comprises methods for the treatment of viral and retroviral, in particular, HIV infections in mammals in need thereof comprising administering thereto a therapeutically effective amount of a compound or mixture of compounds as described above.

"Still further embodiments of the invention relate to (1) articles comprising packaging material which contains at least one biologically active agent contained within the packaging material, wherein the at least one therapeutic agent is effective for the treatment of a subject requiring treatment for viral and retroviral, in particular, HIV infections, and wherein the packaging material comprises a label which indicates that the therapeutic agent can be used for at least ameliorating the symptoms with which the subject is afflicted, and wherein the at least one biologically active agent is a compound or mixture of compounds as described above and (2) kits comprising, in separate packages: (A) a therapeutically effective amount of a compound or mixture of compounds as described above and (B) a carrier or excipient therefore or a biologically active agent different from the compound or mixture of compounds."

URL and more information on this patent, see: Redda, Kinfe; Mills, Chavonda Janeebra; Mateeva, Nelly. Synthetic Flavonoids and Pharmaceutical Compositions and Therapeutic Methods of Treatment of HIV Infection and Other Pathologies. U.S. Patent Number 8314143, filed December 31, 2007, and issued November 20, 2012. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=56&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=2763&f=G&l=50&co1=AND&d=PTXT&s1=20121120.PD.&OS=ISD/20121120&RS=ISD/20121120

Keywords for this news article include: Cancer, Therapy, Genetics, HIV/AIDS, Oncology, Chemicals, Chemistry, Ion Pumps, RNA Viruses, Retroviridae, HIV Infections, Glycoconjugates, P-Glycoproteins, Carrier Proteins, Membrane Proteins, Vertebrate Viruses, Primate Lentiviruses, Enzymes and Coenzymes, Florida A&M University, Membrane Glycoproteins.

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