CN104906086A - Application of indole-3-methaol, bis(indoly)methane and derivatives thereof in medicine for treating glomerulonephritis - Google Patents
Application of indole-3-methaol, bis(indoly)methane and derivatives thereof in medicine for treating glomerulonephritis Download PDFInfo
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Abstract
The invention provides application of indole-3-methaol, bis(indolyl)methane and derivatives thereof in a medicine for treating glomerulonephritis. The indole-3-methaol, bis(indoly)methane and derivatives thereof can be used for treating glomerulonephritis by inhibiting mitosis of basal cells. The DIM and I3C and the derivatives thereof can effectively reduce the disease symptom of the glomerulonephritis and gradually cure the glomerulonephritis, and also can become candidate medicine molecules for treating the glomerulonephritis. The micromolecular medicines are easily available, low in price, stable in property and convenient to store and transport, and have a wide application prospect.
Description
Technical field
The invention belongs to biomedicine technical field, be used for the treatment of the application of glomerulonephritis medicine more specifically to Indole-3-carbinol, di-indole methyl hydride and derivant thereof.
Background technology
Glomerulonephritis is the modal renal glomerular disease of China, account for 50% of primary glomerulopathy, its pathological change is proliferation of mesangial cells, secondary mesangial region extracellular matrix is built up and amplification, particularly proliferative glomerulonephritis often has the propagation of mesangial cell, increasing of extracellular matrix, and mesangial cell mostly is polypeptide or the glycoprotein of molecular weight 6 ~ 60KD, there is high bioactivity, under pathological state, the synthesis of these cytokine mesangial cells stimulateds propagation and protein, causes inflammation to be aggravated.Urine protein simultaneously, for mesangial cell, renal tubular cells etc. have direct toxic action, local lipid metabolic disorder can be caused, immune system is exciting, somatomedin and other cytokine-expressings increase, promote that extracellular matrix is assembled, increase the weight of glomerular sclerosis, also indirectly cause mononuclear phagocyte in glomerule interstitial to infiltrate simultaneously, produce a large amount of chemotactic factor, promote the expression of ICAM and unicellularly to move to mesangial region, cause delayed hypersensitivity, cause mesangial cell and stromal proliferation, promote that nephropathy occurs.
Summary of the invention
The object of the present invention is to provide a kind of disease symptom effectively can treating glomerulonephritis animal model, can be used as treatment brightic molecule drug candidate and Indole-3-carbinol, di-indole methyl hydride and derivant thereof treatment brightic medicine application.
Indole-3-carbinol and the application of derivant in preparation treatment glomerulonephritis medicine thereof with structural formula (I) of the present invention, in structural formula (I), R1, R2, R4, R5, R6, R7 are H or halogenic substituent or nitro or C1-C10 alkyl or C1-C10 alkoxyl separately.
Preferably, in described structural formula (I), when R1, R2, R4, R5, R6, R7 are hydrogen, the compound shown in this structural formula is Indole-3-carbinol;
When R5 is halogenic substituent or nitro or C1-C10 alkyl or C1-C10 alkoxyl, R1, R2, R4, R6, R7 are hydrogen, now, the compound shown in this structural formula (I) comprises: the chloro-Indole-3-carbinol of 5-, the bromo-Indole-3-carbinol of 5-, the fluoro-Indole-3-carbinol of 5-; 5-nitro-indole-3-methanol; 5-Methvl-indole-3-methanol, 5-Ethyl-indole-3-methanol, 5-propyl group-Indole-3-carbinol, 5-butyl-Indole-3-carbinol, 5-amyl group-Indole-3-carbinol, 5-Methoxv-indole-3-methanol, 5-ethyoxyl-Indole-3-carbinol, 5-propoxyl group-Indole-3-carbinol, 5-butoxy-Indole-3-carbinol, 5-amoxy-Indole-3-carbinol etc.;
When R1 is C1-C10 alkyl or C1-C10 alkoxyl, R2, R4, R5, R6, R7 are hydrogen, now, the compound shown in this structural formula (I) comprises: N-Methvl-indole-3-methanol, N-Ethyl-indole-3-methanol, N-propyl group-Indole-3-carbinol, N-butyl-Indole-3-carbinol, N-amyl group-Indole-3-carbinol, N-Methoxv-indole-3-methanol, N-ethyoxyl-Indole-3-carbinol, N-propoxyl group-Indole-3-carbinol, N-butoxy-Indole-3-carbinol, N-amoxy-Indole-3-carbinol etc.;
When R2 is C1-C10 alkyl or C1-C10 alkoxyl, R1, R4, R5, R6, R7 are hydrogen, now, the compound shown in this structural formula (I) comprises: 2-Methvl-indole-3-methanol, 2-Ethyl-indole-3-methanol, 2-propyl group-Indole-3-carbinol, 2-butyl-Indole-3-carbinol, 2-amyl group-Indole-3-carbinol, 2-Methoxv-indole-3-methanol, 2-ethyoxyl-Indole-3-carbinol, 2-propoxyl group-Indole-3-carbinol, 2-butoxy-Indole-3-carbinol, 2-amoxy-Indole-3-carbinol etc.;
Di-indole methyl hydride and the application of derivant in preparation treatment glomerulonephritis medicine thereof with structural formula (II) of the present invention,
Wherein, R1, R2, R4, R5, R6, R7, R1 ', R2 ', R4 ', R5 ', R6 ', R7 ' are separately hydrogen or halogen substituent group or nitro or C1-C10 alkyl or C1-C10 alkoxyl.
Preferably, in described structural formula (II), as R1, R2, R4, R5, R6, R7, R1 ', R2 ', R4 ', R5 ', R6 ', R7 ' be when being hydrogen, now the compound shown in this structural formula is di-indole methyl hydride;
When R5 and R5 ' is halogenic substituent or nitro or C1-C10 alkyl or C1-C10 alkoxyl simultaneously, R1, R2, R4, R6, R7, R1 ', R2 ', R4 ', R6 ', R7 ' be hydrogen, now, shown in structural formula (II), compound comprises: 5,5 '-two chloro-di-indole methyl hydride, 5,5 '-two bromo-di-indole methyl hydride or 5,5 '-two fluoro-di-indole methyl hydride; 5,5 '-dinitro-di-indole methyl hydride; 5,5 '-dimethyl-di-indole methyl hydride, 5,5 '-diethyl-di-indole methyl hydride, 5,5 '-dipropyl-di-indole methyl hydride, 5,5 '-dibutyl-di-indole methyl hydride, 5,5 '-diamyl-di-indole methyl hydride, 5,5 '-dimethoxy-di-indole methyl hydride, 5,5 '-diethoxy-di-indole methyl hydride, 5,5 '-dipropoxy-di-indole methyl hydride, 5,5 '-dibutoxy-di-indole methyl hydride or 5,5 '-two amoxy-di-indole methyl hydride etc.
When R1 and R1 ' is C1-C10 alkyl or C1-C10 alkoxyl simultaneously, R2, R4, R5, R6, R7, R2 ', R4 ', R5 ', R6 ', R7 ' be hydrogen, now, shown in structural formula (II), compound comprises: N, N '-dimethyl-di-indole methyl hydride, N, N '-diethyl-di-indole methyl hydride, N, N '-dipropyl-di-indole methyl hydride, N, N '-dibutyl-di-indole methyl hydride, N, N '-diamyl-di-indole methyl hydride.N, N '-dimethoxy-di-indole methyl hydride, N, N '-diethoxy-di-indole methyl hydride, N, N '-dipropoxy-di-indole methyl hydride, N, N '-dibutoxy-di-indole methyl hydride or N, N '-two amoxy-di-indole methyl hydride etc.
When R2 and R2 ' is C1-C10 alkyl or C1-C10 alkoxyl simultaneously, R1, R4, R5, R6, R7, R1 ', R4 ', R5 ', R6 ', R7 ' is hydrogen, now, shown in structural formula (II), compound comprises: 2, 2 '-dimethyl-di-indole methyl hydride, 2, 2 '-diethyl-di-indole methyl hydride, 2, 2 '-dipropyl-di-indole methyl hydride, 2, 2 '-dibutyl-di-indole methyl hydride, 2, 2 '-diamyl-di-indole methyl hydride, 2, 2 '-dimethoxy-di-indole methyl hydride, 2, 2 '-diethoxy-di-indole methyl hydride, 2, 2 '-dipropoxy-di-indole methyl hydride, 2, 2 '-dibutoxy-di-indole methyl hydride or 2, 2 '-two amoxy-di-indole methyl hydride etc.
Indole-3-carbinol of the present invention, di-indole methyl hydride and derivant thereof are in the application for the treatment of glomerulonephritis medicine, single compound Indole-3-carbinol or a kind of use of di-indole methyl hydride or derivatives thereof can treat glomerulonephritis, so obvious, the various forms of mixtures of above-claimed cpd also can reach certain therapeutic effect.
Use commercial available substituted indoles may be obtain these compounds method the most easily to synthesize the substitutive derivative of I3C.The derivant of DIM can be prepared by the method for formaldehyde condensation substituted indoles equally.But the inferior position of the latter is that the formation of by-product makes the DIM derivant required for separation and purification more complicated.
Compound provided by the present invention is the indole-3-acetaldehyde replaced by using dimethyl formamide condensation substituted indoles to synthesize preparation, and the indole-3-acetaldehyde product be substituted reduces its aldehyde radical thus obtain the substitutive derivative of I3C by use methanol and sodium borohydride process.Indole-3-carbinol (I3C) is very unstable in gastric acid environment in vivo, condensation reaction can occur and form oligomer 3,3'-Diindolylmethane.The substitutive derivative of di-indole methyl hydride of the present invention (DIM) is synthesized by the substitution product of condensation Indole-3-carbinol (I3C), and this can realize (the derivant preparation of I3C and DIM is with reference to US Patent No. 5948808) by taking the methods such as the phosphate buffer process of such as pH value about 5.5.
Adopt Indole-3-carbinol of the present invention (I3C), di-indole methyl hydride (DIM) and derivant thereof, combine with multiple pharmaceutically acceptable carrier, by such as oral cavity, vein, nasal cavity, rectum or other any administering modes can carrying the active substance of effective dose, various liquid preparation can be prepared into as injection, oral liquid formulations etc., also can be prepared into various effectively and the solid preparation being easy to administration as capsule, suppository etc.Wherein, for injecting or liquid preparation for oral use, the carrier needed for it can be the carrier as medically acceptable in cyclodextrin, Semen Maydis oil, olive oil, ethyl oleate, glycols etc. of sterilized water, Sterile Saline or water solublity organic carrier; Solid dosage formulation can add the conventional adjuvant of solid preparation as excipient glucose, lactose, cellulose etc. in preparation, also can add lubricant Polyethylene Glycol, magnesium stearate etc., and the adjunct ingredient needed for the solid preparation such as binding agent, correctives, then by operation molding such as mixing, granulations.The effective dose of the active substance in these preparations above-mentioned is the amount that glomerulonephritis symptom can be made obviously to reduce, the research worker with routine techniques can determine that the most effective dosage of the reagent that this invention provides and time consider administering mode, drug metabolism, and some other pharmacokinetic parameter such as drug distribution, clearance rate etc.
The present invention carries out illustration by glomerulonephritis.Animal herein includes, but are not limited to: mice, rat, and performing animal includes, but are not limited to cat, Canis familiaris L., and some other animal is such as still not limited to cattle, sheep, pig, horse, and primate is such as still not limited to monkey and people.
The present invention proposes the application at treatment glomerulonephritis medicine of Indole-3-carbinol, di-indole methyl hydride and derivant thereof.
Find in animal experiment, Indole-3-carbinol, di-indole methyl hydride and derivant thereof can protect the renal function of rat, improve the pathology infringement of kidney; urine protein can be reduced; regulate lipid metabolism, suppress mesangial cell proliferation and extracellular matrix to gather, thus reach the brightic object for the treatment of.
Meanwhile, small-molecule drug used in the present invention is easy to obtain, and cheap, stable in properties, is convenient to storage and transport, has broad application prospects.
Detailed description of the invention
Be clearly and completely described the technical scheme in the embodiment of the present invention below in conjunction with the embodiment of the present invention, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
[compound preparation]
Embodiment 1
(5-chloro-indole-3-methanol and 5, the preparation of 5 '-dichloro di-indole methyl hydride)
0.86ml phosphoryl chloride phosphorus oxychloride is slowly joined 2.9ml be cooled in advance in the dimethyl formamide of 0 DEG C.8.6mmol 5-chloro-indole (being purchased from Nanjing R&M Fine Chemical Co., Ltd.) is dissolved in the dimethyl formamide of 1.0ml, then slowly add in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, the suspension formed was 37 DEG C of heating 60 minutes, until the yellow solution of clarification becomes flaxen pasty mass.Then in this pasty mass, add the frozen water of 1ml, more slowly add the aqueous solution that 10ml contains 3.75 grams of KOH.Be heated to boil rear cooling by this mixture, filter, washing, air drying can obtain 5-chloro-indole-3-acetaldehyde.
1.0 grams of 5-chloro-indole-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.Then in reactant, add 50ml water, be cooled to 0 DEG C, filter, lucifuge vacuum drying obtains 5-chloro-indole-3-methanol, yield about 90%.
It is in the phosphate buffer of 5.5 that 1.0 grams of 5-chloro-indole-3-methanol are joined pH, stirring at room temperature 6 hours, and course of reaction is monitored by thin layer chromatography (TLC).Product is filtered, and namely lucifuge vacuum drying obtains 5,5 '-dichloro di-indole methyl hydride, yield about 85%.
Embodiment 2
(5-nitroindoline-3-methanol and 5, the preparation of 5 '-dinitro di-indole methyl hydride)
5-nitroindoline can be bought by business and obtain (Nanjing R&M Fine Chemical Co., Ltd.).0.92ml phosphoryl chloride phosphorus oxychloride is slowly joined 2.9ml be cooled in advance in the dimethyl formamide of 0 DEG C.Be dissolved in the dimethyl formamide of 1.0ml by 8.2mmol5-nitroindoline, then slowly add in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, the suspension formed was 42 DEG C of heating 90 minutes, until the yellow solution of clarification becomes flaxen pasty mass.Then in this pasty mass, add the frozen water of 1ml, more slowly add the aqueous solution that 10ml contains 3.75 grams of KOH.Be heated to boil rear cooling by this mixture, filter, washing, air drying can obtain 5-nitroindoline-3-acetaldehyde.
1.0 grams of 5-nitroindoline-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.Then in reactant, add 50ml water, be cooled to 0 DEG C, filter, lucifuge vacuum drying obtains 5-nitroindoline-3-methanol, yield about 87%.
It is in the phosphate buffer of 5.5 that 1.0 grams of 5-nitroindoline-3-methanol are joined pH, stirring at room temperature 6 hours, and course of reaction is monitored by thin layer chromatography (TLC).Product is filtered, and namely lucifuge vacuum drying obtains 5,5 '-dinitro bis (indolyl) methane, yield about 80%.
Embodiment 3
(5-amyl group Indole-3-carbinol and 5, the preparation of 5 '-diamyl-di-indole methyl hydride)
5-amyl group indole can be bought by business and obtain (Nanjing R&M Fine Chemical Co., Ltd.).0.82ml phosphoryl chloride phosphorus oxychloride is slowly joined 2.9ml be cooled in advance in the dimethyl formamide of 0 DEG C.Be dissolved in the dimethyl formamide of 1.0ml by 9.2mmol5-amyl group indole, then slowly add in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, the suspension formed heats 40-60 minute at 37 DEG C, until the yellow solution of clarification becomes flaxen pasty mass.Then in this pasty mass, add the frozen water of 1ml, more slowly add the aqueous solution that 10ml contains 3.75 grams of KOH.Be heated to boil rear cooling by this mixture, filter, washing, air drying can obtain 5-amyl group indole-3-acetaldehyde.
1.0 grams of 5-amyl group indole-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.Then in reactant, add 50ml water, be cooled to 0 DEG C, filter, lucifuge vacuum drying obtains 5-amyl group Indole-3-carbinol, yield about 85%.
It is in the phosphate buffer of 5.5 that 1.0 grams of 5-amyl group Indole-3-carbinols are joined pH, stirring at room temperature 10 hours, and course of reaction is monitored by thin layer chromatography (TLC).Product is filtered, and namely lucifuge vacuum drying obtains 5,5 '-diamyl bis (indolyl) methane, yield about 70%.
Embodiment 4
The preparation of-dimethoxy-di-indole methyl hydride (N-methoxy-Indole-3-methanol and N, the N ')
N-methoxy-Indole can be bought by business and obtain (Nanjing R&M Fine Chemical Co., Ltd.).0.86ml phosphoryl chloride phosphorus oxychloride is slowly joined 2.9ml be cooled in advance in the dimethyl formamide of 0 DEG C.Be dissolved in the dimethyl formamide of 1.0ml by 8.9mmolN-methoxy-Indole, then slowly add in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, the suspension formed heats 60-90 minute at 40 DEG C, until the yellow solution of clarification becomes flaxen pasty mass.Then in this pasty mass, add the frozen water of 1ml, more slowly add the aqueous solution that 10ml contains 3.75 grams of KOH.Be heated to boil rear cooling by this mixture, filter, washing, air drying can obtain N-methoxy-Indole-3-acetaldehyde.
1.0 grams of N-methoxy-Indole-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.Then in reactant, add 50ml water, be cooled to 0 DEG C, filter, lucifuge vacuum drying obtains N-methoxy-Indole-3-methanol, yield about 80%.
It is in the phosphate buffer of 5.5 that 1.0 grams of N-methoxy-Indole-3-methanol are joined pH, stirring at room temperature 12 hours, and course of reaction is monitored by thin layer chromatography (TLC).Product is filtered, and namely lucifuge vacuum drying obtains N, N '-dimethoxy bis (indolyl) methane, yield about 70%.
Embodiment 5
(1-butyl-2 methyl indole-3-methanol and 1, the preparation of 1 '-dibutyl-2,2 '-dimethyl di-indole methyl hydride)
1-butyl-2 methyl indole can be bought by business and obtain (Nanjing R&M Fine Chemical Co., Ltd.).0.82ml phosphoryl chloride phosphorus oxychloride is slowly joined 2.9ml be cooled in advance in the dimethyl formamide of 0 DEG C.8.2mmol 1-butyl-2 methyl indole is dissolved in the dimethyl formamide of 1.0ml, then slowly add in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, the suspension formed was 42 DEG C of heating 90 minutes, until the yellow solution of clarification becomes flaxen pasty mass.Then in this pasty mass, add the frozen water of 1ml, more slowly add the aqueous solution that 10ml contains 3.8 grams of KOH.Be heated to boil rear cooling by this mixture, filter, washing, air drying can obtain 1-butyl-2 methyl indole-3-acetaldehyde.
1.0 grams of 1-butyl-2 methyl indole-3-acetaldehyde is dissolved in 5.0ml methanol, continues to add solid sodium borohydride, until excessive.Then in reactant, add 50ml water, be cooled to 0 DEG C, filter, lucifuge vacuum drying obtains 1-butyl-2 methyl indole-3-methanol, yield about 85%.
It is in the phosphate buffer of 5.5 that 1.0 grams of 1-butyl-2 methyl indole-3-methanol is joined pH, stirring at room temperature 6 hours, and course of reaction is monitored by thin layer chromatography (TLC).Product is filtered, and namely lucifuge vacuum drying obtains 1,1 '-dibutyl-2,2 '-dimethyl bis (indolyl) methane, yield about 80%.
Embodiment 6
(4-bromo indole-3-methanol and 4, the preparation of 4 '-dibromo di-indole methyl hydride)
0.86ml phosphoryl chloride phosphorus oxychloride is slowly joined 2.9ml be cooled in advance in the dimethyl formamide of 0 DEG C.8.6mmol 4-bromo indole (being purchased from Nanjing R&M Fine Chemical Co., Ltd.) is dissolved in the dimethyl formamide of 1.0ml, then slowly add in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, the suspension formed was 37 DEG C of heating 60 minutes, until the yellow solution of clarification becomes flaxen pasty mass.Then in this pasty mass, add the frozen water of 1ml, more slowly add the aqueous solution that 10ml contains 3.75 grams of KOH.Be heated to boil rear cooling by this mixture, filter, washing, air drying can obtain 4-bromo indole-3-acetaldehyde.
1.0 grams of 4-bromo indole-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.Then in reactant, add 50ml water, be cooled to 0 DEG C, filter, lucifuge vacuum drying obtains 4-bromo indole-3-methanol, yield about 90%.
It is in the phosphate buffer of 5.5 that 1.0 grams of 4-bromo indole-3-methanol are joined pH, stirring at room temperature 6 hours, and course of reaction is monitored by thin layer chromatography (TLC).Product is filtered, and namely lucifuge vacuum drying obtains 4,4 '-dibromo di-indole methyl hydride, yield about 85%.
[zoopery]
Material
Respectively by I3C, DIM, the chloro-Indole-3-carbinol of 5-(5-Cl-I3C), 5,5 '-two chloro-di-indole methyl hydride (5,5 '-Cl-DIM), 5-amyl group-Indole-3-carbinol (5-C5-I3C), 5,5 '-diamyl-di-indole methyl hydride (5,5 '-C5-DIM), 5-Methoxv-indole-3-methanol (5-MOE-I3C), 5,5 '-dimethoxy-di-indole methyl hydride (5,5 '-MOE-DIM), 5-nitro-indole-3-methanol (5-NO-I3C), 5,5 '-dinitro-di-indole methyl hydride (5,5 '-NO-DIM), N-Methvl-indole-3-methanol (N-Me-I3C), N, N '-dimethyl-di-indole methyl hydride (N, N '-Me-DIM), N-Methoxv-indole-3-methanol (N-MOE-I3C), N, N '-dimethoxy-di-indole methyl hydride (N, N '-MOE-DIM), 2-amyl group-Indole-3-carbinol (2-C5-I3C), 2,2 '-diamyl-di-indole methyl hydride (2,2 '-C5-DIM), 2-Methoxv-indole-3-methanol (2-MOE-I3C), 2,2 '-dimethoxy-di-indole methyl hydride (2,2 '-MOE-DIM), 1-butyl-2-Methvl-indole-3-methanol (1Bu-2Me-I3C), 1,1 '-dibutyl-2,2 '-dimethyl-di-indole methyl hydride (1,1 ' Bu-2,2 ' Me-DIM), it is for subsequent use that the bromo-Indole-3-carbinol of 4-(4-Br-I3C) and 4,4 '-two bromo-di-indole methyl hydride (4,4 '-Br-DIM) are made into the oral liquid storage of 3.0mg/ml with Semen Maydis oil dissolving.
Experimental technique
Fed 1 week by rat adaptability, detecting urine protein urine examination result is negative rat 240, is divided into 24 groups and often organizes 10, be divided into Normal group at random, model control group and use I3C respectively, DIM, the chloro-Indole-3-carbinol of 5-(5-Cl-I3C), 5,5 '-two chloro-di-indole methyl hydride (5,5 '-Cl-DIM), 5-amyl group-Indole-3-carbinol (5-C5-I3C), 5,5 '-diamyl-di-indole methyl hydride (5,5 '-C5-DIM), 5-Methoxv-indole-3-methanol (5-MOE-I3C), 5,5 '-dimethoxy-di-indole methyl hydride (5,5 '-MOE-DIM), 5-nitro-indole-3-methanol (5-NO-I3C), 5,5 '-dinitro-di-indole methyl hydride (5,5 '-NO-DIM), N-Methvl-indole-3-methanol (N-Me-I3C), N, N '-dimethyl-di-indole methyl hydride (N, N '-Me-DIM), N-Methoxv-indole-3-methanol (N-MOE-I3C), N, N '-dimethoxy-di-indole methyl hydride (N, N '-MOE-DIM), 2-amyl group-Indole-3-carbinol (2-C5-I3C), 2,2 '-diamyl-di-indole methyl hydride (2,2 '-C5-DIM), 2-Methoxv-indole-3-methanol (2-MOE-I3C), 2,2 '-dimethoxy-di-indole methyl hydride (2,2 '-MOE-DIM), 1-butyl-2-Methvl-indole-3-methanol (1Bu-2Me-I3C), 1,1 '-dibutyl-2,2 '-dimethyl-di-indole methyl hydride (1,1 ' Bu-2,2 ' Me-DIM), the treatment group that the bromo-Indole-3-carbinol of 4-(4-Br-I3C) and 4,4 '-two bromo-di-indole methyl hydride (4,4 '-Br-DIM) are treated.
Except normal group, after other group rats adopt 10% chloral hydrate anesthesia, through back excision left kidney, after accomplishing one week, carry out pre-immunity.BSA3mg is added at every rat back subcutaneous branch injection complete Freund's adjuvant 0.1ml, in 1 weekend, 2 weekend dorsal sc injection incomplete Freund's adjuvant 0.1ml add BSA3mg, after 3 weeks, continuous 4 times of lumbar injection BSA, every minor tick 1h, injected dose often only respectively 0.5,1,1.5,3mg, next day every lumbar injection BSA2mg.After formal immunity completes, first day rises, carry out the next day of tail vein lumbar injection, every rat intravenous injection BSA dosage is from 0.5mg, each increase 0.5mg, to 2.5mg, continue dosage 0.5mg weekly, to every consumption per day 5mg, lumbar injection amount is 1 times of tail vein injection amount, to every consumption per day 10mg, immunity 2 weeks rear tail vein injection escherichia coli endomycin 100 μ g/ only, cut back after normal group anesthesia expose left kidney and sew up, afterwards with identical with modeling rat, from tail vein, abdominal cavity, the normal saline of subcutaneous branch injection respective amount, and contrasted with normal saline gavage, whole rat gets nephridial tissue in facing immunity 8 weeks rear putting to death.Wherein started gastric infusion in treatment group in the 6th week, every day 1 this, dose is 30mg/Kg.d, and all the other groups fill with equivalent tap waters, each group gavage 7 weeks.
Detection method
1, in the 2nd, 4,6,8, rat is placed in clean metabolic cage by 12 weekends, get 24n urine, carry out 24h urine protein quantitation mensuration with trichloroacetic acid method, get its average as following table 1;
Table 1:
From experiment, observe the change of rat urine albumen, experiment the 2nd, 4 weekends respectively organized and all do not occur obvious urine protein, the 6th, 8,12 weekends, all the other groups all occurred that urine protein increased, and all had significant difference with normal group except normal group.Model group urine protein all occur go up, although and have rise in treatment group, be starkly lower than model control group.Therefore visible model group glomerulonephritis disease obviously increases the weight of, and although treatment group has inflammation, under the effect of Indole-3-carbinol, di-indole methyl hydride and derivant thereof, inhibit the generation of urine protein, and amount is obviously low than model group, effectively can alleviate the effect of healing.
2, get nephridial tissue, fix with formalin solution emerging in 10%, specimens paraffin embedding slices, with the paraffin section of 3 μm, carry out HE, Masson, PAS dyeing, observe film making under an optical microscope; Get right upper pole cortex 1mm
3fix through 3% glutaraldehyde and 1% osmic acid sodium phosphate buffer pair, acetone serial dehydration, section, uranium acetate and the film making of lead citrate double staining projection electron microscopic observation, two groups of observed results are as table 2:
Table 2:
Light microscopic and Electronic Speculum result all show, the most glomerular mesangium district of model control group rat is obviously broadening, mesangial cell increases, blood capillary pressurized narrows or competes, even indivedual glomerule atrophy, and pathological change obviously alleviates in treatment group, prompting Indole-3-carbinol, di-indole methyl hydride and derivant thereof can suppress the hypertrophy of rat mesangial cell in vitro and extracellular matrix to increase effectively, improve or repair the pathological lesion of nephridial tissue.
Claims (8)
1. have following structural formula (I) for the application of Indole-3-carbinol at treatment glomerulonephritis medicine,
Wherein, R1 is hydrogen or C1-C10 alkyl or C1-C10 alkoxyl; R2 is hydrogen or C1-C10 alkyl or C1-C10 alkoxyl; R5 is hydrogen or halogen substituent group or nitro; R4, R6, R7 are hydrogen.
2. Indole-3-carbinol according to claim 1 is in the application for the treatment of glomerulonephritis medicine, it is characterized in that: in described structure formula I, R5 is halogenic substituent or nitro, and R1, R2, R4, R6, R7 are hydrogen.
3. Indole-3-carbinol according to claim 1 is in the application for the treatment of glomerulonephritis medicine, and it is characterized in that: in described structure formula I, R1 is C1-C10 alkyl or C1-C10 alkoxyl, and R2, R4, R5, R6, R7 are hydrogen.
4. Indole-3-carbinol according to claim 1 is in the application for the treatment of glomerulonephritis medicine, and it is characterized in that: in described structure formula I, R2 is C1-C10 alkyl or C1-C10 alkoxyl, and R1, R4, R5, R6, R7 are hydrogen.
5. there is the application of di-indole methyl hydride at treatment glomerulonephritis medicine of following structural formula (II),
Wherein, R1 and R1 ' is hydrogen or C1-C10 alkyl or C1-C10 alkoxyl; R2 and R2 ' is hydrogen or C1-C10 alkyl or C1-C10 alkoxyl; R5 and R5 ' is hydrogen or halogen substituent group or nitro; R4, R6, R7, R4 ', R6 ', R7 ' be hydrogen.
6. di-indole methyl hydride according to claim 5 is in the application for the treatment of glomerulonephritis medicine, it is characterized in that: in described structure formula II, R5 and R5 ' is halogenic substituent or nitro simultaneously, R1, R2, R4, R6, R7, R1 ', R2 ', R4 ', R6 ', R7 ' be hydrogen.
7. di-indole methyl hydride according to claim 5 is in the application for the treatment of glomerulonephritis medicine, it is characterized in that: in described structure formula II, R1 and R1 ' is C1-C10 alkyl or C1-C10 alkoxyl simultaneously, R2, R4, R5, R6, R7, R2 ', R4 ', R5 ', R6 ', R7 ' be hydrogen.
8. di-indole methyl hydride according to claim 5 is in the application for the treatment of glomerulonephritis medicine, it is characterized in that: in described structure formula II, R2 and R2 ' is C1-C10 alkyl or C1-C10 alkoxyl simultaneously, R1, R4, R5, R6, R7, R1 ', R4 ', R5 ', R6 ', R7 ' be hydrogen.
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| CN108245509A (en) * | 2018-01-29 | 2018-07-06 | 南京大学 | The application of DIM and its derivative in preparing prevention chemotherapy and causing damage medicine |
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| CN102389419A (en) * | 2011-10-08 | 2012-03-28 | 合肥博太医药生物技术发展有限公司 | Application of indole-3-carbinol, diindolylmethane and derivatives thereof to preparation of medicine for preventing and controlling atherosclerosis |
| WO2015008202A1 (en) * | 2013-07-16 | 2015-01-22 | Cadila Pharmaceuticals Limited | Indole-3-carbinol derivatives |
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