Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/06—Free radical scavengers or antioxidants

Definitions

• the present invention relates to the use of hydroxyl-2 , 3- diarylxanthones (DAX) as therapeutic agents of pathologies due to reactive oxygen species.
• DAX 3- diarylxanthones
• Xanthones are natural oxygen heterocyclic compounds found in higher plants, lichens and fungi. Members of this class of compounds have, among other, antiallergic, anti ⁇ inflammatory, antitumor activities.
• Edavarone a novel radical scavenger, inhibits oxidative modification of low-density lipoprotein (LDL) and reverses oxidized LDL-mediated reduction in the expression of endothelial nitric oxide synthase, Atherosclerosis, 2005, 179, 97-102] is approximately forty times superior with that of edavarone for the CS9, the "least" powerful of DAX.
• a novel radical scavenger inhibits oxidative modification of low-density lipoprotein (LDL) and reverses oxidized LDL-mediated reduction in the expression of endothelial nitric oxide synthase, Atherosclerosis, 2005, 179, 97-102] is approximately forty times superior with that of edavarone for the CS9, the "least" powerful of DAX.
• porcine LDL L. Belguendouz, L. Fremont, A. Linard. Resveratrol inhibits metal ion- dependent and independent per
• the present invention relates to a composition
• a composition comprising polyhydroxy-2 , 3-diaryl-9H-xanthen-9-ones that are antioxidant agents and acting as therapeutic agents.
• polyhydroxy-2 , 3-diaryl-9H- xanthen-9-ones react with reactive oxygen species, organic radicals and peroxyl radicals.
• composition is used to produce a drug: to protect against cutaneous aging and cancers induced by the oxidative stress in human skin.
• the antioxidant therapy can have beneficial effects such as carcinogenesis, diabetes-related vascular disorders, acute inflammatory and ischemia-reperfusion phases of pathologies related to neurology, cardiology and rheumatology and in chronic preventive therapy in cancer and inherited and acquired neurodegenerative diseases .
• Xanthones are natural oxygen heterocyclic compounds found in higher plants, lichens and fungi. Members of this class of compounds have, among other, antiallergic, anti ⁇ inflammatory, antitumor activities. One of the most interesting properties is their strong antioxidant activity due to the presence in some key positions of hydroxyl groups and / or a catechol moiety.
• mango There are currently on the market two formulations with a complex composition of oxygenated and prenylated xanthones extracted from mango [J. N. Selles, H. T. V. Castro, J. Aguero-Aguero, J. Gonzalez-Gonzalez, F. Naddeo, F. De Simone, L. Rastrelli.
• the chemical structures of the evaluated five more active synthetic compounds are represented by the following formulas (1), (2), (3), (4) e (5) .
• the novel and efficient route developed allows the synthesis of these polyhydroxydiarylxanthones (DAX) in good yields (40 to 60%) [C. M. M. Santos, A. M. S. Silva, J. A. S. Cavaleiro.
• DAX polyhydroxydiarylxanthones
• the present invention is also related to the use of polyhydroxy-2 , 3-diaryl-9H-xanthen-9-ones as medicines against cancer and cutaneous ageing and for treatment of cardiovascular diseases and diabetes-related vascular disorders, acute inflammatory and ischemia-reperfusion phases of pathologies related to neurology, cardiology and rheumatology and chronic preventive therapy in cancer and inherited and acquired neurodegenerative diseases.
• polyhydroxy-2 , 3-diaryl-9H-xanthen-9-ones as medicines against cancer and cutaneous ageing and for treatment of cardiovascular diseases and diabetes-related vascular disorders, acute inflammatory and ischemia-reperfusion phases of pathologies related to neurology, cardiology and rheumatology and chronic preventive therapy in cancer and inherited and acquired neurodegenerative diseases.
• Fig. 1 shows the kinetics of conjugated dienes formation during LDL oxidation induced by 5 ⁇ Cu 2+ .
• the LDL phosphate buffer solutions at pH 7.4 contain 0.12 mg protein/ml (240 nM) and were incubated during 15 min at 37°C in the presence or absence of 0.75 ⁇ of antioxidant.
• the absorbance is read at 234 mm. The points are the average of 4 independent experiments. The error bars are not indicated for clarity of presentation of the results.
• the vertical axis denotes the absorbance and the horizontal axis the time in minutes.
• Fig. 2 shows the kinetics of carotenoids consumption under the same conditions as those of figure 1.
• the points are the average of 4 independent experiments.
• the error bars are not indicated for clarity of presentation of the results.
• the vertical axis denotes the percentage of carotenoids consumed and the horizontal axis the time in minutes .
• Fig. 3 shows the effect of polyhydroxyxanthones and quercetin on the survival of human NCTC 2544 keratinocytes .
• the cells are incubated in absence or in presence of antioxidant at concentrations of 0.5 ⁇ , 2 ⁇ and 5 ⁇ .
• the viability test to the Neutral Red was used according to the recommendations of the "Commission Directive 2000/33/EC" published in the Journal of the European Community of 8.6.2000: L136/90-L/07.
• the vertical axis shows all the samples tested with the concentration defined and the horizontal axis shows the percentage of human NCTC 2544 keratinocytes survival.
• Fig.4 shows the transient absorbance spectra of radicals •CS3 and *CS8 observed in pH 7 aqueous solutions, saturated with oxygen containing 10 mM of CTAB, 0,1 M of formate ions and 200 ⁇ of CS after production of 4,5 ⁇ (CS3) and 3.2 ⁇ (CS8) of superoxide anion radical ( ⁇ 02 ⁇ ) by a radiolytic pulse dose : 7 Gy for CS3 and 5 Gy for CS8) .
• the vertical axis shows the absorbance of the samples and the horizontal axis shows the wavelength in nanometers .
• LDLs are natural carriers of important antioxidants such as vitamin E and carotenoids. Because antioxidants compete with LDL lipids for the propagation of the radical chain reactions, a lag time, due to the antioxidant consumption, is observed between the start of the oxidation by Cu(II) ions and the appearance of lipid peroxidation products. The duration of this induction period depends on the constitutive antioxidant content of the LDLs which may vary among blood donors [H. Esterbauer, G. Striegl, H. Puhl, M. Rotheneder . Continuous monitoring of in vivo oxidation of human low density lipoprotein, Free Rad. Res. Commun . 1989; 6, 67-75] .
• the LDL peroxidation results in the formation of conjugated dienes.
• the kinetics represented in Fig. 1 are performed at 37°C by measuring the absorbance of the LDL solutions at 234 nm, after the addition of Cu(II) . It is important to notice that for the native LDL without other additives than Cu(II) ions, the formation of conjugated dienes requires a latency time that increases according to a sigmoid curve as shown in Fig.l. Latency time translates the inhibition of lipid peroxidation by natural antioxidants (vitamin E and carotenoids) transported by native LDLs.
• the consumption of antioxidants is highlighted by the disappearance of carotenoids, as shown in Fig.2, following the kinetics of the characteristic absorbance decreasing at 400-500 nm, after the addition of Cu(II) ions.
• the protective capacity of the antioxidants DAX with respect to the consumption of the carotenoids parallels that observed with the production of dienes. The error bars are not indicated for clarity of presentation of the results.
• the lipid membrane peroxidation is a key-process in many cutaneous lesions [D. R. Bickers, M. Athar . Oxidative stress in the pathogenesis of skin disease, J Invest. Dermatol. 2006, 126, 2565-2575] . At the molecular level, it leads not only to the modification of the lipid double- layers but the free radicals produced by the chain reactions of lipid peroxidation oxidize certain amino acids residues of proteins like Trp, His or Cys causing their inactivation .
• the oxidative stress of human NCTC 2544 keratinocytes culture was generated by 5 mM of t-BuOOH a membrane-permeant oxidant extensively used to induce oxidative stress in different systems.
• Example 3 Mechanistic stage : Reactivity of CS with superoxide anion radical and peroxo-trichloromethyl radicals
• the tryptophan (Trp) residues are particularly sensitive targets of apolipoprotein-B (Apo-B) during copper (II) induced LDL oxidation
• Hydroxy-2 , 3-diarylxanthones are excellent/promising therapeutic agents of pathologies due to reactive oxygen species especially in the treatment of cancer and cutaneous ageing in treatment of cardiovascular diseases and diabetes-related vascular disorders, acute inflammatory and ischemia-reperfusion phases of pathologies related to neurology, cardiology and rheumatology and chronic preventive therapy in cancer and inherited and acquired neurodegenerative diseases.
• N-formylkynurenine suggests the involvement of apolipoprotein B-100 centered tryptophan radicals in the initiation of lipid peroxidation, FEBS Lett. 1996, 389, 136-140.
• D. K. Das, N. Maulik. Resveratrol in cardioprotection a therapeutic promise of alternative medicine, Mol. Interv. 2006, 6, 36-47.

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