WO1996041800A1 - Isolement de l'isoflavanone naturelle et quelques emplois cliniques de cette substance - Google Patents

Isolement de l'isoflavanone naturelle et quelques emplois cliniques de cette substance Download PDF

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Publication number
WO1996041800A1
WO1996041800A1 PCT/AP1996/000002 AP9600002W WO9641800A1 WO 1996041800 A1 WO1996041800 A1 WO 1996041800A1 AP 9600002 W AP9600002 W AP 9600002W WO 9641800 A1 WO9641800 A1 WO 9641800A1
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Prior art keywords
pmz
compound
hiv
prenylation
substituted
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PCT/AP1996/000002
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English (en)
Inventor
Peter Mashava
Original Assignee
Chavunduka, Gordon, Lloyd
University Of Zimbabwe
Zimbabwe National Traditional Healers Association (Zinatha)
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Chavunduka, Gordon, Lloyd, University Of Zimbabwe, Zimbabwe National Traditional Healers Association (Zinatha) filed Critical Chavunduka, Gordon, Lloyd
Priority to APAP/P/1996/000799A priority Critical patent/AP675A/en
Publication of WO1996041800A1 publication Critical patent/WO1996041800A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/38—2,3-Dihydro derivatives, e.g. isoflavanones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/40—Separation, e.g. from natural material; Purification

Definitions

  • the present invention relates to the extraction and purification of a dihydo-isoflavonone from the stem bark, the root and the leaves of Bolusanthus speciosus (Bolus) Harms belonging to the plant family Fabaceae: Fabiodeae. identification of the structure of the dihydro- isoflavonone isolated to the potential clinical applications of the pure dihydo-isoflavonone as anti-HIV and anti-cancer chemotherapeutic compound among other applications still under evaluation.
  • the crude extract (19.51 gm) was redissolved in 100 ml of methylene chloride : methanol (4:1) and 47 gm of silica gel 60 (0.040-0.063 mm, 230-400 mesh, EM Science); were added.
  • the solvent was removed at reduced pressure at the rotary evaporator with bath temperature maintained at 40°C and further dried under high vacuum (0.01 torr) to give silica gel coated extract.
  • To a short column Kontes 17 x 7 cm, ID, fitted with sintered glass of M porosity
  • the silica gel coated crude extract was added on top.
  • the packed column was wetted with hexane (200 ml).
  • TLC plates were developed with methylene chloride : methanol (97 :3). The spots on the plate are visible in short UV and are orange when sprayed with vanilin/sulphuric acid TLC spray reagent.
  • the dried stem bark (100 gm) was placed into a 400 ml soxlet to which a piece of cotton wool had been placed to serve as a filter.
  • 500 ml of hexane were added to a 1 L round bottomed flask.
  • Two to three boiling anti- bumping chips were also added.
  • the sample was soxleted for 4 hours. This procedure removed most of the lipophillic compounds and most of the chlorophyll.
  • the hexane extract was discarded.
  • the receiver flask was replaced with one containing 500 ml of methylene chloride : ethyl acetate (1 :1). The sample was further soxleted for a further 4 hours.
  • a sample of crude extract (10 gm) was placed into a 500 ml round bottom flask and redissolved in methanol (100 ml). To this solution, 20 ml of water were added. The mixture was partitioned with 3 x 100 ml hexane. The hexane fractions were discarded. The aqueous methanol fraction was evaporated to remove as much of the methanol as possible. To the residual aqueous extract, was added a further 20 ml of water and partitioned with 3 x 100 ml of ethyl acetate. The combined organic layer was partitioned with 1 x 50 ml of brine.
  • PMZ-1 The structure of PMZ-1 was determined using a sample (5.6 mg) in CDCl 3 /DMSOd 6 ( ⁇ 120 ⁇ l) by one and two dimensional (I D and 2D) nuclear magnetic resonance (NMR) at 1 1.75 Tesla (500 Mhz for 1 H and
  • the 1 3 C NMR, Table 4 contained 21 peaks, and gave the following structural data.
  • the 61.05 ppm peak was connected in the hmbc to the OCH 3 protons.
  • the final three carbons connected to the CH 2 and two CH 3 's in the pentenyl group.
  • the pentenyl group C 1 " to C5" has the following hmbc's shown in Figure 7, which confirm not only its point of attachment but its sequence as well.
  • the vicinal coupling constants of 7.2 Hz between H2" and H1" as well as long range J's between H2'and the methyl groups at 4" and 5" are also in agreement.
  • the final piece of information involves the following hmbc's shown in Figure 7, which confirm not only its point of attachment but its sequence as well.
  • the vicinal coupling constants of 7.2 Hz between H2" and H1" as well as long range J's between H2'and the methyl groups at 4" and 5" are also in agreement.
  • the final piece of information involves the following hmbc's shown in Figure 7, which confirm not only its point of attachment but its sequence as well.
  • the compound, PMZ-1 has been shown to be active against various strains of HIV, active in some HIV mutants and against breast cancer.
  • the search for effective chemotherapeutic compounds against the effects of the HIV virus has to be directed at the inhibition of the main viral enzymes responsible for its replication.
  • the three major enzymes are reverse transcriptase, integrase and protease among other viral enzymes.
  • the compound, PMZ-1 has been evaluated for its efficacy to inhibit various viral enzymes.
  • the first point of replication of the virus in the host cells is initiated by the viral attachment and fusion with the CD 4 receptors on the surface of the host's helper T-lymphocytes (white blood cells).
  • the virus uses its receptor glycoprotein to recognize the CD 4 of the host lymphocites.
  • This attachment is then followed by the fusion of the viral and cellular membranes.
  • the virus is able to penetrate the host cell.
  • the virus uses its reverse transcriptase enzyme to copy the double stranded DNA of the viral RNA genome.
  • This process is followed by integration of the double stranded DNA of the virus into the chromosomes of the host nucleus, a process catalyzed by the integrase enzyme.
  • the protease enzyme is initially used to cleave the integrase from the reverse transcriptase enzyme.
  • the compound (PMZ-1) was evaluated in the National Cancer Institute (NCI) of the United States' in vitro anti-AIDS Drug Discovery Program (Weislow, O. W. et al. J. Natl. Cancer Inst., 81:577-586, 1989).
  • NCI National Cancer Institute
  • the compound showed good protection of the CEM-SS when assayed for HIV-1 RF and the results are shown in Figure 14.
  • the data presented in Figure 14 is divided into three sections:
  • the section specifies the sample tested by its NSC #D-675740-J along with the compound code name (COMI : PMZ-1 ), the actual experimental number from which the results were recorded (Plate), the laboratory which performed the experiment (Lab), the date of the experiment (Test date), the date the report was printed (Report date), and the cell line used in the test (Cell line).
  • the solvent used in formulating the compound for testing is indicated (Solvent).
  • the SSPL and Solubility Ind. are used for administrative purposes.
  • This section displays a plot of the log 10 of PMZ-1 in molar concentrations against the measured test values expressed as a percentage of the uninfected, untreated control values.
  • the solid line represent the percentage of surviving HIV-infected cells treated with PMZ-1 , at various concentrations, relative to uninfected, untreated controls. This line expresses the in vitro anti-HIV activity of PMZ-1.
  • the dashed line depicts the percentage of surviving uninfected cells treated with PMZ-1 relative to the same uninfected, untreated controls.
  • This line represent the in vitro growth inhibitory, properties of PMZ-1.
  • the dotted reference line represent the viral cytopathic effect.
  • the line shows the extent of destruction of cells by the virus in the absence of treatment and is used as a quality control parameter.
  • the survival values of this parameter less than 50% are considered acceptable in this protocol.
  • the percent of protection has been calculated from the data and is presented on the left side of the graph.
  • This section provides a listing of the numerical data plotted in the graphics section.
  • the approximate values for 50% effective concentration (EC 50 ) against HIV cytopathic effects, 50% inhibitory concentration (IC 50 ) for cell growth, and Therapeutic Index (TI IC 50 /EC 50 ) have been calculated for each test and are provided.
  • the NCI staff determination of the activity of PMZ-1 is printed in the lower left-hand corner.
  • the compound PMZ-1 was also tested in a range of in vitro activities and the results are summarized in Table 5.
  • the compound showed greatest therapeutic index (TI) against Mono/Mac resistant strain.
  • MOI multiplicity of infection
  • TOA time-of-addition assay
  • Dextran sulfate (100 ⁇ g/ml) and 2',3'-dideoxycytidine (ddC) (10 ⁇ M) served as controls for inhibitors of virus attachment and reverse transcriptase, respectively.
  • the cells were collected by centrifugation, lysed in QuickLyse buffer (10 mM Tris, pH 8.3, 50 mM KCI, 2.5 mM MgCl 2 , 0.1 mg/ml gelatin, 0.45% Nonidet P-40, 0.45% Tween-20 containing 100 ⁇ g/ml proteinase K, incubated at 56°C for two hours and boiled for 20 minutes.
  • QuickLyse buffer 10 mM Tris, pH 8.3, 50 mM KCI, 2.5 mM MgCl 2 , 0.1 mg/ml gelatin, 0.45% Nonidet P-40, 0.45% Tween-20 containing 100 ⁇ g/ml proteinase K
  • the products of viral transcriptase were amplified by polymerase chain reaction (PCR) using LTR/gag primer pairs (M667/M661 , Recombinant DNA Laboratory, Program Resources, Inc., NCI-FCRDC, Frederick, MD, USA) and products of the ⁇ -globin gene were amplified using primer pairs as previously described (Zack et al., Cell, 61, 213-22, 1990). Amplified products were analyzed by electrophoresis in 2% agarose gels and visualized by ethidium bromide staining. The specificity of the products were verified by restriction enzyme cleavage and by Southern blot hybridization. The results of these tests are summarized in Figure 15.
  • PMZ-1 When PMZ-1 is compared with another non-nucleoside HIV inhibitor, Nevirapine, PMZ-1 offers cell protection for more than 48 hours after administration of the drug.
  • the comparative studies are shown in Figure 16. The activity was measured by the production of ⁇ 24 protein.
  • the binding of gp120 to CD 4 was analyzed using an antigen-capture enzyme-linked immonosorbaent assay (ELISA) from DuPont. All steps off the assay were carried out according to the manufacturer's protocols.
  • ELISA antigen-capture enzyme-linked immonosorbaent assay
  • the effect of the drugs on the in vitro activity recombinant reverse transcriptase (RT) was determined by a previously described method (Buckeit and Swanstron, AIDS RES HUMAN RETROVIRUSES, 7, 295-302, 1991).
  • the assay measures the incorporation of ( 3 H)-TTP to the artificial poly (rA): oligo (dT) or poly (rC):oligo (dG) homopolymer primer/template.
  • the HIV protease activity was quantified by a reverse - phase HPLC assay utilizing the Ala - Ser - Glu - Asn - Tyr - Pro - lle - Val -Amide substrate (Multiple Peptide Systems, San Diego, CA) as described (E. M. Wondrak et al., FEBS LETT, 280, 347-350, 1991). The results are shown in figure 21. The results of integrase activity are shown in Figure 21.
  • PMZ-1 is active in the Mo/Mo assays as shown in Figure 24, but has no effect on the attachment of virons on the cell receptors nor effect on the fusion of virons with the cells containing CD 4 receptors with those expressing viral envelop glycoproteins as shown in Figure 23.
  • the results for independent syncytia response for PMZ-1 on Magi cells are shown in Figure 24.
  • PMZ-1 is soluble in ethanol (>1 mg/ml) and in 40% hydroxypropyl betacyclodextrin (HPCD) but poorly soluble in water. It is very soluble in propylene glycol (PG), polyethylene glycol (PEG) 400 and soybean oil. These solvents may be useful in formulating cosolvents suitable for pharmceutiacal applications.
  • the ethanolic solutions has UV absorptions in the 290-300 nm range, useful for analytical work.
  • Aqueous solutions for anlytical work were prepared in HPCD and diluted with water to the required concentrations. The stock solutions were stable when incubated for 48 hours at 37°C and when stored at room temperature.
  • PMZ-1 is stable at room temperature for several months without detectable deterioration by TLC.
  • Stock solutions in ethyl acetate have been used for TLC work over 8 months without decomposition. This observation suggests long shelf life for the compound.
  • PMZ-1 was unstable in 1.0 N hydrochloric acid (HCl) at 37°C, with 20% and 90% loss of parent compound after 3 and 24 hours of incubation, respectively. In 0.1 N HCl, only 10% degradation was observed after 24 hours. Loss of PMZ-1 was associated with the appearance of an earlier eluting peak. The compound was incubated in 1.0 N HCl at 60°C, all but 5% of PMZ-1 had degraded after 3 hours, and converted to a putative metabolite peak which eluded at 4 minutes. The rate of degradation of PMZ-1 was, however, slower when the experiment was repeated in 0.1 N HCl at 60°C after 3 hours.
  • HPLC high pressure liquid chromatography
  • Figure 30 shows the traces of processed control mouse plasma (a) and mouse plasma sample seeded with 50 ⁇ M of PMZ-1 (b).
  • the peak at 6.26 minutes is that of an internal standard, acetophenone.
  • PMZ-1 give a good correlation coefficients (>0.99) between concentration and peak heights in the concentration ranges 1-100 ⁇ M both in aqueous and processed mouse plasma.
  • the peak after 4.29 minutes in Figure 31c refers to a putative metabolite of PMZ-1. Its height is propotional to the decrease of the peak height of PMZ-1 at 12.39 minute after drug intravenous administration.
  • FIG. 32 shows the HPLC traces for the ultrafiltrates (30 kD norminal cutoff) of an aqueous solution (a) and for a solution in mouse plasma (b) of 10 ⁇ M of PMZ-1.
  • PMZ-1 is present in the urine after parenteral and non-parenteral administration. The drug was also detected readily in liver, kidneys and small intestine tissue samples taken during the first 60 minutes after intraveneous administration at 10 mg/kg body weight of a mouse. An earlier eluting peak representing a possible metabolite was also observed in the urine. The presence of this peak in plasma after oral administration is suggestive of first-pass metabolism.
  • the compound, PMZ-1 is a natural product extracted from stem bark, leaves and root bark of a Vietnamesean medicinal plant, Bolusanthus speciosus.
  • the plant is locally known as mupaka (Shona) and impaca (Ndebele).
  • B. speciosus is a deciduous tree common in all parts of clouds, (A Rhodesian Botanical Dictionary of African and English Plant Names, H. Wild revised by H.M. Biegel and S. Mavi, National Herbarium, Department of Research and Specialist Services, Ministry of Agriculture; Printed by Government Printer, Harare, Moscow). Its distribution is wide spread throughout the country at low to medium altitudes. It grows to the height of about 4 meters attaining its largest size on termite mounts. It is found in woodlands usually on sand clay and on rocky grounds. The wood is very durable and resistant to termite attack.
  • the plant is used as a herbal remedy as bile emesis (leaves), for abdominal pains (root bark) and is used to induce vomiting (root bark).
  • PMZ-1 was isolated from Bolusanthus speciosus (Bolus) Harms collected from the National Herbarium Botanical Garden, Harare, Moscow on June 16, 1993. The voucher specimen can be viewed at this venue. Main Herbarium Accession # 285825 and Collector's # 106. Followup samples were collected from other parts of Moscow.
  • PBMC's peripheral blood mononuclear cells
  • MC's EC 50 ⁇ 1 ⁇ M
  • monocytes/macrophages Monocytes/macrophages
  • SIV simian immunodeficiency virus
  • PMZ-1 exhibit a pattern of activity against mutant HIV viral strains indicating its non- nucleoside reverse transcriptase inhibitory (NNRTI) activity.
  • PMZ-1 is active against azidothymidine sensitive and resistant (AZF sen and AZT res ) as well as 2',3'-dideoxy-inosine (ddl) mutants.
  • AZF sen and AZT res azidothymidine sensitive and resistant
  • ddl 2',3'-dideoxy-inosine
  • the compound shows weak activity against viruses containing mutations in reverse transcriptase (RT) codons affecting nonnucleoside reverse transcriptase inhibitors (NNRTIs).
  • RT reverse transcriptase
  • NRTIs nonnucleoside reverse transcriptase inhibitors
  • the compound shows reasonable activity (EC 50 ⁇ 1.0 ⁇ M) against mutants, Y181 and L1001, which frequently arise during NNRTI clinical treatments and affecting
  • PMZ-1 has demonstrated moderate activities against mutants, isolated by Merck Sharp & Dohme Research Laboratories, which exhibits two mutations in the reverse transcriptase domain at codons 103 and 181. The compound also exhibits some activity against three other mutant viruses containing reverse transcriptase domain at codons 181 , 139 and 100. Although the pattern against mutant viral strains suggests that PMZ-1 is a NNRTI, the compound exhibits some activities against HIV-2 and SIV a property not usually associated with NNRTIs. The fact that PMZ-1 shows activity against double mutant strain and mutant strains 181 , 139, and 100 warrants further studies. Virtually all NNRTIs studied so far are totally inactive against mutant virus 100.
  • PMZ-1 shows no effect on the attachment of virons to cells nor on fusion of cells containing CD 4 receptor with those expressing viral envelope glycoprotein.
  • the interaction of gp120 env protein of the HIV-1 virus and CD 4 at the cell surface is necessary for the viral entry into the host cell.
  • the interaction of gp120 env of infected infected CD 4 with non-infected CD 4 causes cell aggregation leading to the proliferation of the virus.
  • PCR time-course study has confirmed the activity of PMZ-1 against HIV-1 RT in infected cells.
  • PMZ-1 was added at various times after infection up to 28 hours postinfection
  • PMZ-1 exhibits other biological activities in addition to inhibition of RT.
  • PMZ-1 is compared with nevirapine, a typical NNRTI
  • nevirapine is only effective when added to culture within the first 8 hours (before the period in which DNA synthesis occurs) after infection of the cells.
  • PMZ-1 is effective even after DNA synthesis has occurred.
  • the XTT cytoprotection and inhibition of p24 production are observed when PMZ-1 is added after reverse transcriptase has been completed.
  • PMZ-1 is NNRTI with a novel chemical structure and unique properties that acts intracellularly against the reverse transcriptase (RT) viral enzyme and possibly against other viral enzymatic targets.
  • RT reverse transcriptase
  • the possibility of PMZ-1 attacking multiple targets will have important clinical applications. More definitive studies to understand the mechanism(s) of action of PMZ- 1 against HIV- 1 virus are in progress. Better elucidation of the pattern of activity of PMZ-1 against HIV-1 variants with site directed mutations affecting NNRTI's is also in progress. Detailed studies using drug resistant strains are important in order to evaluate the total effect of inhibition against HIV mutants. There is need for better assessment of the role of anti-protease and anti- integrase activities of the HIV-1 production. Preliminary formulation, pharmacokinetics, quantitative assays, bioavailability, and toxicological studies are necessary to assess the clinical potential of PMZ-1 as an anti- HIV-1 chemotherapeutic drug.
  • PMZ-1 is easily extracted from the natural sources but its simple structure suggests that the compound can be synthesized in the laboratory by such persons as skilled in the art. Additionally, structural activity relationships (SAR) studies of PMZ-1 are in progress with the aim of improving both the integrase and protease activities. Table 8 below gives the summary of activities of PMZ-1.
  • PMZ-1 Activity in Cancer Assays PMZ-1 Activity in Cancer Assays:
  • PMZ-1 shows good activity against breast cancer when tested in the 60 cell line panel. PMZ-1 is active and selective for the MCF7 cell line at lower concentration ⁇ 0.025 ⁇ g/ml. The results of these studies are shown in Table 9 and Figures 33, 34 and 35.
  • the cancer data for PMZ-1 in this application were recorded at the National Cancer Institute, USA.
  • Table 9 is the record of the experimental optical densities as a factor of logarithmic concentrations of the sample tested.
  • the table shows 9 major cancer cell lines along with the sub-cell lines for each major cell line.
  • the percent growth (PG) refers to the percentage increase of the mass/numbers of cells being tested as compared to the cells in the control.
  • the response factors GI 50 .
  • Figure 33 shows the dose-response curves for PMZ-1 derived by plotting PG vs log 10 values of the approprieate concentrations for each cell line. The curves are grouped by subpanels of the major group. GI 50 , TGI and LC 50 from the point each curve crosses PG line +50, 0 and -50 respectively.
  • Figure 34 shows all cell line responses combined.
  • Figure 35 shows the mean graphs from the response parameters Gl 50 . TGI and LC 50 .
  • the centre line represent athe average response of all cell lines to the drug. For each group and subpanels, bars extending to the right are more sensitive to the drug than the avereage, and those extending to the left are less sensitive.
  • the compound PMZ-1 shows the greatest sensitivity against brest cancer subpanel MCF7 with Gl 50 and LC 50 at ⁇ 0.025 ⁇ g/ml and 16.8 ⁇ g/ml respectively.
  • PMZ-1 along with its analogs, has a potential to be developed into useful chemotherapeutic compounds against breast and other cancers.

Abstract

Le composé représenté par la formule (II), désigné par 'PMZ-1', a été isolé à partir de Bolusanthus speciosus (Bolus Harms). Le PMZ-1 présente une activité contre le VIH-1RF (EC50 = 0,1 νM) et le VIH-1IIIB (EC50 = 0,2 νM), avec des concentrations cytotoxiques (IC50) de 30 à 50 νM respectivement. LePMZ-1 présente un large indice thérapeutique (IT > 300). Ce composé fait preuve d'une activité satisfaisante quand il est essayé dans les cellules mononucléaires fraîches du sang humain périphérique (PBMC, EC < 1 νM) et dans les dosages monocytes-macrophages (mono-mac, EC50 < 1 νM). Il a inhibé l'activité enzymatique de la protéase (ID50 = 3,8 νM) et de l'intégrase (ID50 = 40 νM). Il manifeste une activité contre le cancer du sein.
PCT/AP1996/000002 1995-06-12 1996-04-24 Isolement de l'isoflavanone naturelle et quelques emplois cliniques de cette substance WO1996041800A1 (fr)

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APAP/P/1996/000799A AP675A (en) 1995-06-12 1996-04-24 Isolation of natirally occuring isoflavanone and some clinical uses thereof.

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ZW8995 1995-06-12

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AP675A (en) * 1995-06-12 1998-09-24 Mashava Peter M Isolation of natirally occuring isoflavanone and some clinical uses thereof.
EP1254132A1 (fr) * 2000-01-21 2002-11-06 Novogen Research Pty. Ltd. Produit et procede alimentaires
US7488494B2 (en) 1999-09-06 2009-02-10 Novogen Research Pty Ltd. Compositions and therapeutic methods involving isoflavones and analogues thereof
US7504401B2 (en) 2003-08-29 2009-03-17 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
CN104829580A (zh) * 2015-04-11 2015-08-12 云南中烟工业有限责任公司 烟草所含的异黄酮类化合物及其制备方法和应用
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AP675A (en) * 1995-06-12 1998-09-24 Mashava Peter M Isolation of natirally occuring isoflavanone and some clinical uses thereof.

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C.P.FALSHAW ET AL: "The extracts of Piscidia erythrina L-III", TETRAHEDRON SUPPLEMENT, vol. 7, 1966, pages 333 - 348, XP000590855 *
J.L.INGHAM ET AL: "Isoflavanoids from the root bark of Piscidia erythrina", Z.NATURFORSCH, vol. 44c, no. 11/12, 1989, pages 905 - 913, XP000577557 *
K ASRES ET AL: "Isoflavanoids from Bolusanthus speciosus (Bolus) Harms Leguminosae", Z.NATURFORSCH, vol. 40c, no. 7/8, 1985, pages 617 - 620, XP000577562 *
M.MAILLARD ET AL: "An Antifungal Isoflavanone and a structure revisiion of a flavanone from Erythrina berteroana", PLANTA MED, vol. 55, no. 3, 1989, pages 281 - 282, XP000577448 *
R.HOFFMAN: "Potent inhibition of Breast cancer cell lines by the isoflavanoid Kievitone: Comparison with Genistein", BIOCHEM. BIOPHYS. RES. COMMUN, vol. 211, no. 2, 15 June 1995 (1995-06-15), pages 600 - 606, XP000590861 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AP675A (en) * 1995-06-12 1998-09-24 Mashava Peter M Isolation of natirally occuring isoflavanone and some clinical uses thereof.
US7488494B2 (en) 1999-09-06 2009-02-10 Novogen Research Pty Ltd. Compositions and therapeutic methods involving isoflavones and analogues thereof
EP1254132A1 (fr) * 2000-01-21 2002-11-06 Novogen Research Pty. Ltd. Produit et procede alimentaires
EP1254132A4 (fr) * 2000-01-21 2003-04-16 Novogen Res Pty Ltd Produit et procede alimentaires
JP2003520794A (ja) * 2000-01-21 2003-07-08 ノボゲン リサーチ ピーティーワイ リミテッド 食品とその製造方法
US7504401B2 (en) 2003-08-29 2009-03-17 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
CN104829580A (zh) * 2015-04-11 2015-08-12 云南中烟工业有限责任公司 烟草所含的异黄酮类化合物及其制备方法和应用
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof

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ZA964981B (en) 1997-01-24
AP675A (en) 1998-09-24

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