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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
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  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the invention relates to pyrrolo [2,3-e] pyridine compounds as well as azaindole compounds useful in the synthesis of these pyrrolo [2,3- ⁇ ] pyridine compounds. It also relates to a process for the manufacture of these pyrrolo [2,3- ⁇ ] pyridine compounds as well as the use of these pyrrolo [2,3-6] pyridine compounds.
• Protein phosphorylation is the mechanism most used by the cell to modulate the activity of its structural proteins and enzymes. Phosphorylation of serine, threonine or tyrosine residues is catalyzed by a large family of enzymes, protein kinases. There is no significant physiological event that does not involve changes in protein phosphorylation. Similarly, the vast majority of human pathologies involve phosphorylation abnormalities often associated with abnormalities in the regulation of certain protein kinases.
• CDKs are attracting considerable interest because of their involvement in many essential physiological processes and multiple human diseases, especially cancers, polycystic kidney disease and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and accidents. cerebrovascular diseases.
• CDKs have been described and demonstrated to have promising anti-tumor, and / or antiproliferative, and / or neuroprotective activities.
• CDK inhibitors All the CDK inhibitors identified so far act in competition with ATP for binding to the catalytic site of their target kinase. Many have been co-crystallized with a CDK target.
• the selectivity of these pharmacological inhibitors is the subject of intensive research using a wide variety of methods, such as the search for selectivity on a large sample of kinases, affinity chromatography on an immobilized inhibitor and the triple hybrid technique. in yeast. While some kinase inhibitors are rather non-selective, such as staurosporine, many have a defined specificity profile. But all inhibit several kinases.
• the protein kinase gene DYRX1A is located in a specific region of chromosome 21, the "Down syndrome critical region", which covers about twenty genes responsible for the trisomic phenotype. Numerous arguments support the hypothesis of an essential contribution of the even modest overexpression (X 1.5) of DYRKlA in the abnormal brain development observed during trisomy 21. Moreover, DYRKlA also seems to be very involved in Alzheimer's disease. 'Alzheimer's disease (which, moreover, appears in Down Syndrome 21 in a systematic and precocious way beyond forty). DYRK1A belongs to a small family of 5 membered kinases (DYRKIa, IB, 2, 3, 4).
• DYRKlA acts as a "priming kinase" for GSK-3, it phosphorylates proteins of Alzheimer's disease such as Tau and CRMP. Joint inhibition of CDKs, GSK-3, CK1 and DYRK could be a major benefit in the treatment of neurodegenerative diseases.
• Meridians a family of 3- (2-aminopyrimidine) indoles, have recently been identified as promising kinase inhibitory structures.
• Meridianines are natural products originally extracted from Aplidium meridianum, an ascidian from the South Atlantic. Meridianine derivatives have been synthesized by various groups of researchers.
• meridianines inhibit various kinases such as CDKs, synthase kinase-3 (GSK-3), cyclic nucleotide-dependent kinases, and casein kinases 1 (CK1), they exhibit significant but modest anti-proliferative effects.
• the patent application WO 2006/124863 also discloses numerous meriolins compounds presented as being usable for treating or preventing diseases or disorders associated with abnormal or deregulated kinase activity, more particularly diseases or disorders which involve abnormal activation, in particular, CDKs.
• Patent application WO 2005/095400 discloses a very large number of azaindole compounds which are presented as inhibitors of protein kinases.
• meriolins of which meriolin, hereinafter meriolin 12, in which the substituent on the pyrimidine ring is a 2 -SMe radical, of formula:
• - Ri is selected from halogen or alkyl Ci-C 10 substituted or unsubstituted group, a (Ci-Cio alkyl) cycloalkyl, C 5 -C 8 alkyl, a group (C
• R 2 represents a hydrogen or halogen atom, or independently of Ri, a group as defined for R 1,
• R 3 represents H or a group -SO 2 R 3 or -COR 3 , or C 1 -C 0 alkyl
• R 4 represents a hydrogen atom or an NH 2 group
• R 3 and R b are each independently of the other a hydrogen atom, or an optionally substituted group selected from alkyl, -C Ci 0 alkenyl, C 2 -C] 0 alkynyl C 2 -C 0, a cycloalkyl C 5 -C 8 cycloalkyl (C 5 -C 8) alkyl-C] 0, a (cycloalkyl C 5 -C 8) alkenyl, C 2 -C 0 a cycloalkyl (C 5 -C 8) alkynyl, C 2 -C 0, a (C 5 -C heterocycle 2) Cl-Clo alkyl, a (C 5 -C heterocycloalkyl 2) alkenyl, C 2 - Ci 0, a (C 5 -C heterocycloalkyl 2) alkynyl, C 2 -C 0, or R 3 and R b are linked together to form, with the nitrogen atom to which they are attached, a heterocycle optional
• R 1 is selected from halogen or C 1 -C 10 alkyl, unsubstituted or substituted C 1 -C 10 alkoxy, C 1 -C 10 fluoroalkoxy, C 1 -C 10 alkoxy-C 1 -C 10 alkoxy, C 5 cycloalkoxy 5 -C 8 , -OH, -OCOR 3 , -CN, -NO 2 , -SR 3 , -NR a R b , -NHCOR 3 , -NHSO 2 R 3 , -NHCONR a R b , NHCO 2 R 3 , phenyl, aryl, heteroaryl, R 2 represents a hydrogen atom or independently of R 1, a halogen or a group as defined for R 1 ,
• R 3 represents H or a group -SO 2 R 3 or -COR 3 , or alkyl
• R 4 represents a hydrogen atom or an NH 2 group
• - R 3 and R b each independently represent a hydrogen atom, or an optionally substituted group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkenyl, or R 3 and R b are linked together to form, with the nitrogen atom to which they are bonded, an optionally substituted heterocycle selected from a grouping pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
• R 3 should be H or a group -SO 2 R 3 or -COR 3 , or alkyl.
• R 3 is H or an alkyl group.
• R 3 is H.
• R 1 is selected from OH, Cl, methoxy, ethoxy, propoxy, butyloxy, isopropoxy, benzyloxy, cyclohexylmethoxy, cyclohexyloxy, 2-propylethynyl, 2-butylethynyl, 2-cyclohexylethynyl, phenethyl-1-ynyl, phenyl, pentyl. or phenylethyl.
• R 1 is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, cyclohexylmethyloxy, cyclohexyloxy, 2-propylethynyl, pentyl, phenyl and phenylethyl.
• the effect of the compounds tested on the protein kinases CK1 and CDK9 demonstrates their exceptional antiproliferative effect resulting in cell death, in particular tumor cells, and the effect of meriolins tested on the protein kinases CDK5, GSK3 and CDK1 demonstrates their neuroprotective effect, as will be shown in the following examples.
• the compounds of the invention were obtained by four methods which all use as starting compounds the compounds of the following formula II:
• substituents R 1, R 2 and R 3 are those defined for the compounds of formula I, as being preferred.
• the meriolins of the invention can be used as a medicament, particularly for all disorders related to abnormal activity of cyclin-dependent kinases.
• the meriolins of the invention can be used for the manufacture of a medicament for the treatment of disorders related to abnormal proliferation of cells, whether or not cancerous, or as a neuroprotector, that is to say, for treat especially tumors, neurodegenerative diseases such as Alzheimer's disease and trisomy 21, leukemias, kidney diseases
• FIG. 1 represents the decrease in cell survival induced by different concentrations of meriolins according to the invention, compared to that induced by varioline B at the same concentrations.
• FIG. 2 represents the percentage of cell death induced by different concentrations of meriolins according to the invention, in comparison with that induced by varioline B, at the same concentrations, and
• FIG. 3 represents the average tumor volume of a tumor exposed to a meriolin according to the invention, compared to that of a tumor exposed to a control compound, that is to say, untreated.
• CDK cyclin-dependent kinase
• CK1 casein kinase
• DYRK1A dual specificity kinase activated by tyrosine phosphorylation (dual-specific tyrosine phosphorylation activated kinase)
• FCS fetal calf serum
• GSK3 glycogen synthase kinase-3
• PBS saline buffered sulfate
• diethyl azodicarboxylate (520 ⁇ L, 3.3 mmol) is added dropwise to a solution of PPh 3 (1.04 g, 3.96 mmol) in THF anhydrous (13 mL). Under an inert atmosphere, this solution is canulated in a flask containing a solution of 4-hydroxy-7-azaindole (222 mg, 1.65 mmol), ethanol (115 ⁇ L, 1.98 mmol) in tetrahydrofuran (THF). anhydrous (41 mL). The solution is stirred at ambient temperature for 2 hours. The solvent is evaporated.
• DEAD diethyl azodicarboxylate
• 4-propoxy-1H-pyrrolo [2,3-d] pyridine Following the procedure described for the preparation of 4-ethoxy-1H-pyrrolo [2,3- ⁇ ] pyridine, 4-propoxy-1H-pyrrolo [ 2,3- ⁇ ] pyridine is obtained in 78% yield from 4-hydroxy-7-azaindole and propanol.
• the first process for obtaining the meriolins of the invention consists in carrying out an acylation reaction in the presence of aluminum chloride (AlCl 3 ), of CH 3 COCl as described in J. Org . Chem. 2002, 67, 6226-6227 or Ac 2 O, and trifluoroacetic acid on the compounds of formula II substituted on the 4-position and / or the 6-position, which leads to obtaining the compound denoted 1 in scheme 1 .
• AlCl 3 aluminum chloride
• 67, 6226-6227 or Ac 2 O trifluoroacetic acid
• trifluoroacetic acid on the compounds of formula II substituted on the 4-position and / or the 6-position
• the formation of the substituted pyrimidine ring is carried out, for its part, by treating compound 3 in the presence of guanidinium hydrochloride or its derivatives.
• the second process for obtaining the meriolins of the invention differs from the method 1 by the step of obtaining the compounds 2.
• the iodination on the 3-position of the compounds of the formula II substituted on the 4-position and or at position 6 is carried out in the presence of diiod in basic medium to give the derivatives noted in scheme 1.
• the benzenesulfonylation reaction on the NI indole nitrogen of the derivatives gives the compounds denoted 6 in scheme 1.
• These are engaged in a palladium catalyzed coupling reaction (Stille reaction) in the presence of tri-n-butyl (1-ethoxyvinyl) stannane to give compounds 2.
• the third method makes it possible to obtain the meriolins in which the substituent at R 4 on the pyrimidine ring is H.
• the compound denoted 7 in scheme 1 is obtained directly from the compounds of formula II by treatment with CuO and formamide.
• the fourth method for obtaining the meriolins of the invention differs from the processes 1 and 2 by the step of obtaining the compounds 2.
• the functionalization of the 4-position of the 7-azaindole is carried out from 7 This step is carried out by palladium catalyzed reactions (Sonogashira reaction, Stille reaction, Suzuki-Myaura reaction, Heck reaction, etc.) to conduct to Compounds 2. Then from these compounds 2, compounds 4 are obtained by the same steps as for the first method described.
• the compound Ib is obtained in a yield of 55% from 4-methoxy-7-azaindole. Mp> 210 ° C
• Another method for synthesizing the meriolins of the invention via the N-alkylation (NaH, EX) or the arylation (ArX, Cu 2 O, K 2 CO 3 ) of the compounds 1 leads to obtaining the products 12.
• Enaninones 13 are prepared by treatment of 12 in the presence of DMF-DMA (Tetrahedron 2001, 57, 2355-2363).
• the final compounds 14 are obtained by heating 13 in the presence of guanidinium hydrochloride or derivatives.
• Example 17 Synthesis of 3 - [(2-amino) pyrimidin-4-yl] -4-methoxy-l-methyl-l / - f-pyrrolo [2.3-6] pyridine (14b): procedurerioline 9a ) 3-Acetyl-4-methoxy-1-methyl-1H-pyrrolo [2,3-d] pyridine (12b)
• Meriolin 1 was synthesized according to the procedure described in Tetrahedron 2001, 57, 2355-2363.
• Variolin B was synthesized according to the procedure described by Anderson RJ & ai, in 2005 in "Concise total syntheses of variolin B and deoxyvariolin B", J. Org. Chem. 2005, 70, 6204-6212. II) TESTS OF THE INHIBITION ACTIVITY OF THE PROTEINS KINASES OF THE MERIOLINES OF THE INVENTION
• Biochemical reagents Sodium ortho-vanadate, EGTA, EDTA, Mops, ⁇ -glycerophosphate, phenylphosphate, sodium fluoride, dithiothreitol (DTT), glutathione-agarose, glutathione, albumin Bovine serum (BSA), nitrophenylphosphate, leupeptin, aprotinin, pepstatin, soybean trypsin inhibitor, benzamidine, histone H1 (type III-S) were obtained from Sigma Chemicals. [ ⁇ - 33 P] ATP has' been obtained from Amersham.
• the GS-I peptide (YRRAAVPPSPSLSRHSSPHQSpEDEEE) was synthesized by the Peptide Synthesis Unit, Institute of Biomolecular Sciences, University of Southampton, Southampton SO 16 7PX, United Kingdom.
• the CK1 specific peptide substrate (RRKHAAIGSpAYSITA) was a generous donation from Drs F. Meggio and L. Pinna (Marin et al., 1994). Buffers.
• Homogenization Buffers 60 mM ⁇ -glycerophosphate, 15 mM p-nitrophenylphosphate, 25 mM Mops (pH 7.2), 15 mM EGTA, 15 mM MgCl 2 , 1 mM DTT, 1 mM sodium vanadate, 1 mM NaF, 1 mM phenylphosphate , 10 ⁇ g leupeptin / ml, 10 ⁇ g aprotinin / ml, 10 ⁇ g of soy trypsin inhibitor / ml and 100 ⁇ M benzamidine.
• Buffer A 10 mM MgCl 2 , 1 mM EGTA, 1 mM DTT, 25 mM Tris-HCl pH 7.5, 50 ⁇ g heparin / ml.
• Buffer C homogenization buffer but 5 mM EGTA, no NaF and no protease inhibitors.
• kinases were assayed in buffer A or buffer C at 30 ° C at a final concentration of ATP of 15 ⁇ M.
• the blank values were subtracted and the activities calculated as pmoles of phosphate incorporated for 10 minutes of incubation. The activities are usually expressed in% (percentage) of maximal activity, that is, in the absence of inhibitors. Controls were carried out with appropriate dilutions of dimethylsulfoxide.
• CDK1 / cyclin B was extracted in a homogenization buffer from purified chromatography of phase M starfish oocytes (Marthaste ⁇ as glacialis) on p19 CKShsl- labeled sepharose beads of which it was eluted by free p9 CKShsl as previously described in Meijer et al, (1997) "Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5", Eur. J. Biochem. 1997, 243, 527-536.
• the kinase activity was assayed in buffer C, with 1 mg of histone H1 / ml, in the presence of 15 ⁇ M of [ ⁇ - 33 P] ATP (3000 Ci / mmol, 10 mCi / ml) in a final volume. of 30 ⁇ l. After 30 minutes of incubation at 30 ° C., 25 ⁇ l aliquots of the supernatant were stained on Whatman P81 phosphocellulose paper filters, and, 20 seconds later, the filters were washed five times. minus five (five) minutes each) in a solution of 10 ml of phosphoric acid / liter of water. The wet filters were counted in the presence of Amersham ACS scintillation fluid.
• CDK2 / cyclin A human, recombinant, expressed in insect cells was assayed as described for CDK1 / cyclin B.
• CDK5 / p25 was reconstituted by mixing equal amounts of recombinant mammalian CDK5 and p25 expressed in E. coli as a GST (glutathione-S-transferase) fusion protein and purified by glutathione-agarose affinity chromatography (vectors provided by Dr. LH Tsai) (p25 is a truncated version of p35, the 35 kDa CDK5 enhancer). Its activity was assayed with histone H1 in buffer C as described for CDK1 / cyclin B.
• CDK1 / cyclin H human, recombinant, expressed in insect cells
• MBP basic myelin protein
• CDK9 / cyclin T human, recombinant, expressed in insect cells
• aa773-9228 3.5 ⁇ g / assay
• GSK-S a / ⁇ was purified from porcine brain by affinity chromatography on immobilized axin (Primot et al, 2003). It was determined following a 1/100 dilution in 1 mg BSA / ml and 10 mM DTT, with 5 ⁇ l of 4 ⁇ M GS-peptide substrate in buffer A, in the presence of 15 ⁇ M [ ⁇ ].
• CK1 ⁇ / ⁇ was purified from porcine brain by affinity chromatography on an immobilized axin fragment. It was assayed as described for CDK1 but using a CK1 specific peptide substrate.
• Recombinant rat derived DYRK1A kinase expressed in E. coli as a GST fusion protein, was purified by glutathione-agarose bead affinity chromatography and assayed as described for CDK1 / cyclin B with myelin basic protein. (1 mg / ml) as substrate.
• a CeIl Titer 96 ® kit containing MTS reagent was purchased from Promega (Madison, WI, USA).
• the protease inhibitor cocktail originated from Roche and the fetal calf serum (FCS) originated from Invitrogen. Unlisted reagents were from Sigma unless otherwise indicated.
• the human neuroblastoma cell line SH-SY5Y was grown in DMEM medium with L-glutamine from Invitrogen (Cergy Pontoise, France), antibiotics and 10% by volume of FCS from Invitrogen.
• HEK293 cells were grown in MEM medium with Glutamax from Invitrogen, antibiotics and 10% by volume of FCS.
• the general culture conditions were an atmosphere of 5% CO 2 and a temperature of 37 ° C.
• control experiments were carried out using also appropriate dilutions of DMSO.
• IC 50 values were calculated from the dose-response curves and are plotted in Table 1 below in micromoles.
• meriolins 3 to 6, 15 to 18 and 22 to 23 exhibit an effect of inhibition of CDK1, CDK2 and CDK9 protein kinases much higher than varioline B and merionol 1, which indicates their antiproliferative effect causing cell death.
• meriolins 3 to 6, and 15 to 19 and 22 to 23 exhibit an inhibitory effect on the protein kinases CDK5, GSK3, CK1 and DYRK1A which is also much greater than that of varioline B, meriolin 1 and meriolin 12, indicating a potent neuroprotective effect.
• the apoptotic effect of meriolins 3 to 6, 15 to 18 and 22 to 23 is demonstrated by the results obtained on the survival of SH-SY5Y and HEK293 neuroblastoma cells, which are reported in Table 2 below.
• merion 19 exhibits a particularly effective effect on the protein kinase DYKR1A with a moderate effect on the other protein kinases, which shows not only its efficiency but also its selectivity on this kinase and the makes it particularly suitable for the treatment of neurodegenerative diseases such as Alzheimer's disease and trisomy 21.
• SH-SY5Y cells were exposed for 24 hours to increasing concentrations of each meriolin, and as a comparison of varioline B.
• the survival of the cells was estimated by the determination of the rate of reduction of MTS induced by this exposure.
• FIG. 1 represents the results obtained for merionol 3 and merionol 4. These results are expressed in% of survival relative to untreated cells. As seen from Table 2 and Figure 1, the meriolins of the invention have an antiproliferative effect far superior to that of varioline B.
• mice Athymic nude male mice (5-6 weeks old) were obtained from the National Cancer Institute. The mice were housed in the pet store division of the University of Comparative Medicine Georgetown. All animal work was done under protocols approved by the Georgetown University Animal Care Use Committee. The mice were inoculated by subcutaneous injection into the right posterior flank with 4 ⁇ 10 6 A4573 cells in 100 ⁇ l Matrigel base membrane matrix (Becton Dickinson). Xenografts were grown at an average tumor volume of 129 ⁇ 30 mm 3 . The compounds tested were first dissolved in either absolute methanol or DMSL (1 volume).
• a carrier solution was produced using a diluent containing 10% Tween 80, 20% NN-dimethylacetamide, and 70% polyethylene glycol 400 (Fisher Scientific, Pittsburgh, PA). Mice were randomly divided into two groups (six animals per group) and treatment initiated. One group was treated with merionol 3, administered by intraperitoneal injection once a day and at a dose of 50 mg / kg, for either five days or two five-day series with a two-day break between each set of five. days. The control group received intraperitoneal injections of the carrier solution following identical programs. All mice were sacrificed by CO 2 asphyxiation. Mericol 3-treated mice were euthanized either 7 days after the first injection or up to four weeks after the end of the treatment.
• the mean tumor volume, in mm 3 increases only slightly with time when the tumor is exposed to merionol 3, as compared to exposure to a control, DMSO.
• the meriolins of the invention cause the cell death of cell lines involved in different cancers.
• the meriolins of the invention induce the death of cell lines particularly involved in cancer processes by apoptosis.
• this process is not the only one involved in the process of inducing cell death by meriolins, meriolins also acting as potent inhibitors of proliferation of these cells.
• kidney diseases including glomerulonephritis, polycystic kidney disease, inflammation, type II diabetes and even neurodegenerative diseases such as Alzheimer's disease.

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