CN102389419A - Application of indole-3-carbinol, diindolylmethane and derivatives thereof to preparation of medicine for preventing and controlling atherosclerosis - Google Patents
Application of indole-3-carbinol, diindolylmethane and derivatives thereof to preparation of medicine for preventing and controlling atherosclerosis Download PDFInfo
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Abstract
The invention provides new application of indole-3-carbinol, diindolylmethane and derivatives thereof to preparation of a medicine for preventing and controlling atherosclerosis (AS). The indole-3-carbinol, diindolylmethane and derivatives thereof have obvious effects of resisting oxidation and improving endothelial functions, can ensure that the expression and proportion of all vaso-active substances in a human body are normal and the endothelial functions can be recovered normally, and have the good effects of reducing blood fat, and resisting AS. Meanwhile, the active ingredients of the used small molecule medicines can be obtained easily, and the indole-3-carbinol, diindolylmethane and derivatives thereof are low in price, have stable performance and are convenient to store and transport, and have wide application prospect.
Description
Technical field
The invention belongs to the biological medicine technology field, be specifically related to Indole-3-carbinol, di-indole methyl hydride and derivant thereof and prevent and treat the application in the atherosclerosis medicine in preparation.
Background technology
Atherosclerosis (AS) is one group and is called in the arteriosclerotic angiopathy the most common, most important a kind ofly, is the topmost paathogenic factor that causes cardiovascular and cerebrovascular diseases such as coronary heart disease.In recent years, the sickness rate of atherosclerosis (AS) has the trend of obvious increase in China.According to the postmortem result, in 40～49 years old crowd, the recall rate of coronary artery and atherosclerosis of aorta pathological changes is respectively 58.36% and 88.31%, and increases with advancing age and gradually.Generation and the endothelial function disturbance of AS are closely related, and the various kinds of cell factor and apoptosis influence the process of AS.Main treatment means is to use angiogenesis inhibitor and fat-reducing medicament at present, though interventional therapy can make revascularization, restenosis remains present insurmountable difficult medical problem, and especially late result does not have clear superiority.
Indole-3-carbinol (I3C) and 3,3 '-di-indole methyl hydride (DIM) are to come from The Cloud Terrace to belong to, the natural product of crucifer, effect such as this type material is widely used in Western society as food supplement for a long time, has tangible health care, and is anticancer.Nearest discovers, this type material can be through antioxidation expression of gene in the control agent, and effectively scavenger cell is because the free radical that processes such as lipid peroxidation produce.On the principle, the chemical compound of I3C and DIM class and derivant thereof can initiatively be removed free radical through promoting Expression of Related Genes, have tangible anti-oxidative damage, reduce inflammatory reaction, improve the effect of endothelial function; The chemical compound of I3C and DIM class and derivant thereof not only can make various vaso-active substances expression and ratio in vivo normal, but also can make endothelial function be able to recover; Effect with blood fat reducing preferably, anti-AS.Therefore can be used as the atherosclerotic medicine of a kind of control develops.
Summary of the invention
The object of the present invention is to provide a kind of Expression of Related Genes of can passing through to promote; Initiatively remove free radical; Thereby the small-molecule drug that can play anti-oxidative damage, reduce inflammatory reaction and improve the endothelial function effect, promptly Indole-3-carbinol, di-indole methyl hydride and derivant thereof are prevented and treated the application in the atherosclerosis medicine in preparation.
Indole-3-carbinol and derivant thereof with structural formula (I) of the present invention prevented and treated the application in the atherosclerosis medicine in preparation; In the structural formula (I), R1, R2, R4, R5, R6, R7 respectively do for oneself H or halogenic substituent or nitro or C1-C10 alkyl or C1-C10 alkoxyl.
Preferably, in the said structural formula (I), as R1, R2, R4, R5, R6, when R7 is hydrogen, the chemical 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; At this moment, the chemical compound shown in this structural formula (I) comprises: 5-chloro-Indole-3-carbinol, 5-bromo-Indole-3-carbinol, 5-fluoro-Indole-3-carbinol; 5-nitro-Indole-3-carbinol; 5-methyl-Indole-3-carbinol; 5-ethyl-Indole-3-carbinol; 5-propyl group-Indole-3-carbinol; 5-butyl-Indole-3-carbinol, 5-amyl group-Indole-3-carbinol, 5-methoxyl group-Indole-3-carbinol, 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; At this moment, the chemical compound shown in this structural formula (I) comprises: N-methyl-Indole-3-carbinol, N-ethyl-Indole-3-carbinol, N-propyl group-Indole-3-carbinol, N-butyl-Indole-3-carbinol, N-amyl group-Indole-3-carbinol, N-methoxyl group-Indole-3-carbinol, 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; At this moment, the chemical compound shown in this structural formula (I) comprises: 2-methyl-Indole-3-carbinol, 2-ethyl-Indole-3-carbinol, 2-propyl group-Indole-3-carbinol, 2-butyl-Indole-3-carbinol, 2-amyl group-Indole-3-carbinol, 2-methoxyl group-Indole-3-carbinol, 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 derivant thereof with structural formula (II) of the present invention prevented and treated the application in the atherosclerosis medicine in preparation,
Wherein, respectively do for oneself hydrogen or halogen substituent group or nitro or C1-C10 alkyl or C1-C10 alkoxyl of R1, R2, R4, R5, R6, R7, R1 ', R2 ', R4 ', R5 ', R6 ', R7 '.
Preferably, in the said structural formula (II), as R1, R2, R4, R5, R6, R7, R1 ', R2 ', R4 ', R5 ', R6 ', when R7 ' is hydrogen, the chemical compound shown in this moment this structural formula is di-indole methyl hydride;
When R5 and R5 ' are halogenic substituent or nitro or C1-C10 alkyl or C1-C10 alkoxyl simultaneously; R1, R2, R4, R6, R7, R1 ', R2 ', R4 ', R6 ', R7 ' are hydrogen; At this moment, chemical compound comprises shown in the structural formula (II): 5,5 '-two chloro-di-indole methyl hydrides, 5; 5 '-two bromo-di-indole methyl hydrides or 5,5 '-two fluoro-di-indole methyl hydrides; 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 amoxys-di-indole methyl hydride etc.
When R1 and R1 ' are C1-C10 alkyl or C1-C10 alkoxyl simultaneously, R2, R4, R5, R6, R7, R2 ', R4 ', R5 ', R6 ', R7 ' are hydrogen, at this moment; Chemical compound comprises shown in the structural formula (II): 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 amoxys-di-indole methyl hydride etc.
When R2 and R2 ' are C1-C10 alkyl or C1-C10 alkoxyl simultaneously, R1, R4, R5, R6, R7, R1 ', R4 ', R5 ', R6 ', R7 ' are hydrogen, at this moment; Chemical compound comprises shown in the structural formula (II): 2, and 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 amoxys-di-indole methyl hydride.
Indole-3-carbinol of the present invention, di-indole methyl hydride and derivant thereof are in the atherosclerotic application of control; A kind of use of single chemical compound Indole-3-carbinol or di-indole methyl hydride or derivatives thereof can prevent and treat atherosclerosis; So obvious, various forms of being mixed of above-claimed cpd also can reach certain therapeutic effect.
The substitutive derivative that uses the commercial indole substituent that gets to synthesize I3C possibly be to obtain these chemical compounds method the most easily.The derivant of DIM equally can be through the method preparation of formaldehyde condensation indole substituent.Yet the latter's inferior position is that the formation of by-product makes that the needed DIM derivant of separation and purification is more complicated.
Chemical compound provided by the present invention is to prepare substituted indole-3-acetaldehyde through using dimethyl formamide condensation indole substituent to synthesize, thereby substituted indole-3-acetaldehyde product is handled the substitutive derivative that its aldehyde radical of reduction obtains I3C through using methanol and sodium borohydride.Indole-3-carbinol (I3C) is very unstable in the gastric acid environment in vivo, condensation reaction can take place form oligomer 3,3 '-di-indole methyl hydride.The substitutive derivative of di-indole methyl hydride of the present invention (DIM) is that the substitution product through condensation Indole-3-carbinol (I3C) synthesizes, and this can the methods such as phosphate buffer processing of pH value about 5.5 realize (the derivant preparation of I3C and DIM is with reference to U.S. Pat 5948808) through for example taking.
Adopt Indole-3-carbinol of the present invention (I3C), di-indole methyl hydride (DIM) and derivant thereof; Combine with multiple pharmaceutically acceptable carrier; Through like oral cavity, vein, nasal cavity, rectum or other any administering modes that can carry the active substance of effective dose; Can be prepared into various liquid preparations such as injection, oral liquid formulations etc., also can be prepared into various effectively and be easy to solid preparation such as capsule, the suppository etc. of administration.Wherein, be used to inject or liquid preparation for oral use, its required carrier can be medically acceptable carriers such as sterilized water, Sterile Saline or water solublity organic carrier such as cyclodextrin, Semen Maydis oil, olive oil, ethyl oleate, glycols; The solid drug-delivery preparation can add solid preparation adjuvant commonly used such as excipient glucose, lactose, cellulose etc. in preparation; Also can add lubricant Polyethylene Glycol, magnesium stearate etc.; And the required adjunct ingredients of solid preparation such as binding agent, correctives, again through operation molding such as mixing, granulations.The effective dose of the active substance in above-mentioned these preparations is the amount that the atherosclerosis shape is obviously reduced; Research worker with routine techniques can be confirmed the most effectively dosage and the time consideration administering mode of the reagent that this invention provides; Drug metabolism; And some other pharmacokinetic parameter drug distribution for example, clearance rate etc.All right and the for example medication combined administration of conventional control atherosclerosis of other reagent of reagent provided by the present invention is so that the incidence of atherosclerosis degree effectively reduces.
The present invention is through carrying out illustration to the inductive Atherosclerosis Model of high fat in the body.The animal here includes, but are not limited to: mice, rat, performing animal includes, but are not limited to cat, Canis familiaris L., and some other animal for example but be not limited to cattle, sheep, pig, horse, primate for example but be not limited to monkey and people.
The present invention proposes Indole-3-carbinol, di-indole methyl hydride and derivative compound thereof and prevent and treat the new application in the atherosclerosis medicine in preparation; This medicine has the ability that promotes cell initiatively to remove free radical; Has tangible anti-oxidative damage; Reduce the inflammatory reaction level, improve the effect of endothelial function; This medicine not only can make various vaso-active substances expression and ratio in vivo normal, but also can make endothelial function be able to recover; Effect with blood fat reducing preferably, anti-AS.Indole-3-carbinol and di-indole methyl hydride and derivative compound thereof are obtained better curative effect in the inductive animal model of high fat, simultaneously, small-molecule drug used in the present invention is easy to obtain; Cheap; Stable in properties is convenient to storage and transport, has broad application prospects.
The specific embodiment
Following experimental example is not the restriction to flesh and blood of the present invention still in order to explain the present invention.
[compound]
Embodiment 1
(5-chloro-indole-3-methanol and 5, the preparation of 5 '-dichloro di-indole methyl hydride)
The 0.86ml phosphoryl chloride phosphorus oxychloride is slowly joined 2.9ml to be cooled in 0 ℃ the dimethyl formamide in advance.8.6mmol 5-chloro-indole (purchasing the sharp horse Fine Chemical Co., Ltd in Nanjing) is dissolved in the dimethyl formamide of 1.0ml; Slowly add in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling then; Formed suspension becomes flaxen pasty mass 37 ℃ of heating 60 minutes until clarifying yellow solution.In this pasty mass, add the frozen water of 1ml then, slowly add the aqueous solution that 10ml contains 3.75 gram KOH again.This mixture heated to boiling postcooling, is filtered, washing, air drying can obtain 5-chloro-indole-3-acetaldehyde.
1.0 gram 5-chloro-indole-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.In reactant, add 50ml water then, be cooled to 0 ℃, filter, the lucifuge vacuum drying obtains 5-chloro-indole-3-methanol, yield about 90%.
It is in 5.5 the phosphate buffer that 1.0 gram 5-chloro-indole-3-methanol are joined pH, stirring at room 6 hours, and course of reaction is monitored through thin layer chromatography (TLC).Product is filtered, and the lucifuge vacuum drying promptly 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)
The 5-nitroindoline can obtain (the sharp horse in Nanjing Fine Chemical Co., Ltd) through commercial the purchase.The 0.92ml phosphoryl chloride phosphorus oxychloride is slowly joined 2.9ml to be cooled in 0 ℃ the dimethyl formamide in advance.8.2mmol 5-nitroindoline is dissolved in the dimethyl formamide of 1.0ml, slowly adds then in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, formed suspension becomes flaxen pasty mass 42 ℃ of heating 90 minutes until clarifying yellow solution.In this pasty mass, add the frozen water of 1ml then, slowly add the aqueous solution that 10ml contains 3.75 gram KOH again.This mixture heated to boiling postcooling, is filtered, washing, air drying can obtain 5-nitroindoline-3-acetaldehyde.
1.0 gram 5-nitroindoline-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.In reactant, add 50ml water then, be cooled to 0 ℃, filter, the lucifuge vacuum drying obtains 5-nitroindoline-3-methanol, yield about 87%.
It is in 5.5 the phosphate buffer that 1.0 gram 5-nitroindoline-3-methanol are joined pH, stirring at room 6 hours, and course of reaction is monitored through thin layer chromatography (TLC).Product is filtered, and the lucifuge vacuum drying promptly 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 obtain (the sharp horse in Nanjing Fine Chemical Co., Ltd) through commercial the purchase.The 0.82ml phosphoryl chloride phosphorus oxychloride is slowly joined 2.9ml to be cooled in 0 ℃ the dimethyl formamide in advance.9.2mmol 5-amyl group indole is dissolved in the dimethyl formamide of 1.0ml, slowly adds then in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, formed suspension becomes flaxen pasty mass 37 ℃ of heating 40-60 minute until clarifying yellow solution.In this pasty mass, add the frozen water of 1ml then, slowly add the aqueous solution that 10ml contains 3.75 gram KOH again.This mixture heated to boiling postcooling, is filtered, washing, air drying can obtain 5-amyl group indole-3-acetaldehyde.
1.0 gram 5-amyl group indole-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.In reactant, add 50ml water then, be cooled to 0 ℃, filter, the lucifuge vacuum drying obtains 5-amyl group Indole-3-carbinol, yield about 85%.
It is in 5.5 the phosphate buffer that 1.0 gram 5-amyl group Indole-3-carbinols are joined pH, stirring at room 10 hours, and course of reaction is monitored through thin layer chromatography (TLC).Product is filtered, and the lucifuge vacuum drying promptly obtains 5,5 '-diamyl bis (indolyl) methane, yield about 70%.
Embodiment 4
(N-methoxyl group Indole-3-carbinol and N, the preparation of N '-dimethoxy-di-indole methyl hydride)
N-methoxyl group indole can obtain (the sharp horse in Nanjing Fine Chemical Co., Ltd) through commercial the purchase.The 0.86ml phosphoryl chloride phosphorus oxychloride is slowly joined 2.9ml to be cooled in 0 ℃ the dimethyl formamide in advance.8.9mmol N-methoxyl group indole is dissolved in the dimethyl formamide of 1.0ml, slowly adds then in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling, formed suspension becomes flaxen pasty mass 40 ℃ of heating 60-90 minute until clarifying yellow solution.In this pasty mass, add the frozen water of 1ml then, slowly add the aqueous solution that 10ml contains 3.75 gram KOH again.This mixture heated to boiling postcooling, is filtered, washing, air drying can obtain N-methoxyl group indole-3-acetaldehyde.
1.0 gram N-methoxyl group indole-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.In reactant, add 50ml water then, be cooled to 0 ℃, filter, the lucifuge vacuum drying obtains N-methoxyl group Indole-3-carbinol, yield about 80%.
It is in 5.5 the phosphate buffer that 1.0 gram N-methoxyl group Indole-3-carbinols are joined pH, stirring at room 12 hours, and course of reaction is monitored through thin layer chromatography (TLC).Product is filtered, and the lucifuge vacuum drying promptly obtains N, N '-dimethoxy bis (indolyl) methane, yield about 70%.
Embodiment 5
(1-butyl-2 methyl indole-3-methanol and 1,1 '-dibutyl-2, the preparation of 2 '-dimethyl di-indole methyl hydride)
1-butyl-2 methyl indole can obtain (the sharp horse in Nanjing Fine Chemical Co., Ltd) through commercial the purchase.The 0.82ml phosphoryl chloride phosphorus oxychloride is slowly joined 2.9ml to be cooled in 0 ℃ the dimethyl formamide in advance.8.2mmol 1-butyl-2 methyl indole is dissolved in the dimethyl formamide of 1.0ml; Slowly add in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling then; Formed suspension becomes flaxen pasty mass 42 ℃ of heating 90 minutes until clarifying yellow solution.In this pasty mass, add the frozen water of 1ml then, slowly add the aqueous solution that 10ml contains 3.8 gram KOH again.This mixture heated to boiling postcooling, is filtered, washing, air drying can obtain 1-butyl-2 methyl indole-3-acetaldehyde.
1.0 gram 1-butyl-2 methyl indole-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.In reactant, add 50ml water then, be cooled to 0 ℃, filter, the lucifuge vacuum drying obtains 1-butyl-2 methyl indole-3-methanol, yield about 85%.
It is in 5.5 the phosphate buffer that 1.0 gram 1-butyl-2 methyl indole-3-methanol are joined pH, stirring at room 6 hours, and course of reaction is monitored through thin layer chromatography (TLC).Product is filtered, and the lucifuge vacuum drying promptly 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)
The 0.86ml phosphoryl chloride phosphorus oxychloride is slowly joined 2.9ml to be cooled in 0 ℃ the dimethyl formamide in advance.8.6mmol 4-bromo indole (purchasing the sharp horse Fine Chemical Co., Ltd in Nanjing) is dissolved in the dimethyl formamide of 1.0ml; Slowly add in the phosphoryl chloride phosphorus oxychloride solution of aforementioned pre-cooling then; Formed suspension becomes flaxen pasty mass 37 ℃ of heating 60 minutes until clarifying yellow solution.In this pasty mass, add the frozen water of 1ml then, slowly add the aqueous solution that 10ml contains 3.75 gram KOH again.This mixture heated to boiling postcooling, is filtered, washing, air drying can obtain 4-bromo indole-3-acetaldehyde.
1.0 gram 4-bromo indole-3-acetaldehyde are dissolved in 5.0ml methanol, continue to add solid sodium borohydride, until excessive.In reactant, add 50ml water then, be cooled to 0 ℃, filter, the lucifuge vacuum drying obtains 4-bromo indole-3-methanol, yield about 90%.
It is in 5.5 the phosphate buffer that 1.0 gram 4-bromo indole-3-methanol are joined pH, stirring at room 6 hours, and course of reaction is monitored through thin layer chromatography (TLC).Product is filtered, and the lucifuge vacuum drying promptly obtains 4,4 '-dibromo di-indole methyl hydride, yield about 85%.
[zoopery example]
(oral liquid of I3C, DIM and derivative compound thereof is to the treatment of the inductive Atherosclerosis Model of high fat)
1, grouping and modeling method:
With I3C, DIM, 5-chloro-Indole-3-carbinol (5-Cl-I3C), and 5,5 '-two chloro-di-indole methyl hydrides (5,5 '-Cl-DIM), 5-amyl group-Indole-3-carbinol (5-C5-I3C); 5, and 5 '-diamyl-di-indole methyl hydride (5,5 '-C5-DIM), 5-methoxyl group-Indole-3-carbinol (5-MOE-I3C), 5; 5 '-dimethoxy-di-indole methyl hydride (5,5 '-MOE-DIM), 5-nitro-Indole-3-carbinol (5-NO-I3C), 5,5 '-dinitro-di-indole methyl hydride (5; 5 '-NO-DIM), N-methyl-Indole-3-carbinol (N-Me-I3C) and N, N '-dimethyl-di-indole methyl hydride (N, N '-Me-DIM); N-methoxyl group-Indole-3-carbinol (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-methoxyl group-Indole-3-carbinol (2-MOE-I3C), 2,2 '-dimethoxy-di-indole methyl hydride (2,2 '-MOE-DIM); 1-butyl-2-methyl-Indole-3-carbinol (1Bu-2Me-I3C) and 1,1 '-dibutyl-2,2 '-dimethyl-di-indole methyl hydride (1,1 ' Bu-2; 2 ' Me-DIM), to be made into the oral liquid storage of 2.0mg/ml with Semen Maydis oil dissolving subsequent use for 4-bromo-Indole-3-carbinol (4Br-I3C) and 4,4 '-two bromo-di-indole methyl hydrides (4,4 ' Br-DIM).
Get 192 of healthy new zealand white rabbits, male and female half and half, body weight 2.0kg ± 20g is divided into 24 groups at random with animal, 8 every group; Sub-cage rearing (the feeding environment temperature remains on 26 ℃, and indoor humidity is controlled at about 70%, automatic ventilator keep room ventilation), i.e. normal control group, is used I3C, DIM, 5-chloro-Indole-3-carbinol (5-Cl-I3C) respectively at the Atherosclerosis Model group; 5,5 '-two chloro-di-indole methyl hydrides (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-methoxyl group-Indole-3-carbinol (5-MOE-I3C), 5,5 '-dimethoxy-di-indole methyl hydride (5; 5 '-MOE-DIM), 5-nitro-Indole-3-carbinol (5-NO-I3C), 5,5 '-dinitro-di-indole methyl hydride (5; 5 '-NO-DIM), N-methyl-Indole-3-carbinol (N-Me-I3C) and N, N '-dimethyl-di-indole methyl hydride (N, N '-Me-DIM); N-methoxyl group-Indole-3-carbinol (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-methoxyl group-Indole-3-carbinol (2-MOE-I3C), 2,2 '-dimethoxy-di-indole methyl hydride (2,2 '-MOE-DIM); 1-butyl-2-methyl-Indole-3-carbinol (1Bu-2Me-I3C) and 1,1 '-dibutyl-2,2 '-dimethyl-di-indole methyl hydride (1,1 ' Bu-2; 2 ' Me-DIM), the treatment group of 4-bromo-Indole-3-carbinol (4Br-I3C) and 4,4 '-two bromo-di-indole methyl hydrides (4,4 ' Br-DIM) treatment.Observe each treated animal hair color, expression in the eyes, feed, activity, feces, write down body weight weekly one time; After adaptability fed for 1 week, the normal control group continued to feed with normal feedstuff, the Atherosclerosis Model group and with the method modeling of each therapeutic test group according to Zhu Yu: give the high lipid food feed; Prescription is: normal feedstuff 80%, yolk powder 15%, edible Adeps Sus domestica 5%, cholesterol gram every every day 1; The 100-120 that takes food every day gram is freely drunk water, and feeds for 3 weeks; Cholesterol in the feedstuff is deducted, fed for 5 weeks again.
Administration finishes the back fasting and can't help water 16h, puts to death animal with the aeroembolism method, gets the fresh ventral aorta BIAO and BEN that contains speckle, and the paraformaldehyde fixing organization with 10% is equipped with SABC and uses.
(1) the AS plaque area is obviously got ventral aorta 3cm in the place in pathological changes; At the dorsal surface longitudinal incision, be tiled on the filter paper, fix 10 minutes with 10% formalin; Dye with soudan III; Atheromatous plaque is dyed scarlet, and (1mm * 1mm) measures the AS plaque area of every tremulous pulse, calculates the percentage ratio that plaque area accounts for the blood vessel area with transparent graph paper.
(2) inner film thickness, media thickness and inner membrance/media thickness ratio: obviously draw materials at the place in pathological changes, BIAO and BEN is fixing with 35% sodium phosphate formalin flushing, uses FFPE after disposing, soaking.Thickness by 3～4 μ m cuts, and section is with HE dyeing, with HPIAS1000 computer graphic analytical system to inner film thickness, media thickness and inner membrance/media thickness ratio.
Table (1) I3C of the present invention, DIM and derivant water soluble preparation thereof are to the influence (n=8, meansigma methods ± standard deviation) of AS rabbit aorta plaque area
| Group | Aorta plaque area (mm 2) | The aorta gross area (mm 2) | Ratio (%) |
| Normal group | 0 | 129.12±3.23 | 0 |
| Model group | 32.35±1.67 | 133.10±3.16 | 0.24±0.018 |
| I3C | 13.64±0.89 | 134.21±2.68 | 0.11±0.021 |
| DIM | 14.84±1.23 | 135.56±2.45 | 0.12±0.013 |
| 5-Cl-I3C | 15.83±3.51 | 138.49±2.84 | 0.10±0.012 |
| 5，5’-Cl-DIM | 14.63±2.62 | 136.57±1.42 | 0.11±0.017 |
| 5-C5-I3C | 14.68±1.84 | 135.65±2.04 | 0.10±0.008 |
| 5，5’-C5-DIM | 15.21±2.41 | 133.52±1.85 | 0.11±0.015 |
| 5-MOE-I3C | 14.98±1.54 | 134.56±2.53 | 0.10±0.020 |
| 5，5’-MOE-DIM | 16.08±2.19 | 136.44±1.77 | 0.11±0.022 |
| 5-NO-I3C | 16.16±1.03 | 136.67±2.42 | 0.12±0.018 |
| 5，5’-NO-DIM | 13.33±2.46 | 132.78±1.68 | 0.09±0.019 |
| N-Me-I3C | 15.34±2.01 | 137.32±4.36 | 0.10±0.013 |
| N，N’-Me-DIM | 16.61±1.89 | 135.47±3.09 | 0.10±0.021 |
| N-MOE-I3C | 14.20±1.55 | 134.56±2.67 | 0.10±0.015 |
| N，N’-MOE-DIM | 17.03±2.61 | 137.53±5.31 | 0.12±0.014 |
| 2-C5-I3C | 14.19±1.35 | 135.90±6.53 | 0.12±0.014 |
| 2，2’-C5-DIM | 15.43±2.01 | 137.39±4.88 | 0.12±0.026 |
| 2-MOE-I3C | 13.46±1.31 | 135.59±3.78 | 0.11±0.016 |
| 2，2’-MOE-DIM | 15.83±2.53 | 134.36±4.85 | 0.11±0.022 |
| 1Bu-2Me-I3C | 14.42±0.53 | 131.45±6.33 | 0.11±0.017 |
| 1，1’Bu-2，2’Me-DIM | 16.71±3.21 | 140.32±5.53 | 0.12±0.011 |
| 4Br-I3C | 13.74±1.53 | 132.56±0.82 | 0.10±0.019 |
| 4，4’Br-DIM | 14.03±0.68 | 137.21±1.38 | 0.10±0.014 |
Data show with the form of mean+SD that all significant difference is confirmed through the ANOVA check.When P≤0.01, be regarded as having significant difference.
Thing I3C of the present invention, DIM or derivatives thereof have certain influence to speckle, and difference has significance (P≤0.01), explain and use I3C, DIM or derivatives thereof to have tangible anti-AS effect.
Table (2) I3C of the present invention, DIM and derivant water soluble preparation thereof are to the influence (n=8, meansigma methods ± standard deviation) of AS rabbit inner film thickness and media thickness
| Group | Inner film thickness (μ m) | Media thickness (μ m) | Inner membrance/media thickness is than (%) |
| Normal group | 110.45±18.32 | 359.78±19.32 | 30.06±3.20 |
| Model group | 252.43±20.41 | 369.04±15.43 | 58.39±3.45 |
| I3C | 148.34±23.35 | 353.85±9.26 | 24.92±2.69 |
| DIM | 145.64±15.65 | 360.79±10.24 | 28.13±6.34 |
| 5-Cl-I3C | 151.75±23.52 | 364.58±18.32 | 25.45±5.39 |
| 5，5’-Cl-DIM | 158.46±14.67 | 357.45±13.42 | 26.44±6.32 |
| 5-C5-I3C | 154.55±17.32 | 355.59±13.04 | 27.45±3.38 |
| 5，5’-C5-DIM | 147.64±15.35 | 363.69±14.71 | 26.88±3.59 |
| 5-MOE-I3C | 147.35±24.36 | 354.87±9.46 | 25.91±2.65 |
| 5，5’-MOE-DIM | 146.64±17.64 | 363.79±10.44 | 28.43±6.54 |
| 5-NO-I3C | 149.43±17.45 | 362.34±23.05 | 25.67±4.50 |
| 5，5’-NO-DIM | 153.66±21.09 | 368.43±14.36 | 24.86±2.98 |
| N-Me-I3C | 148.64±15.25 | 362.29±15.21 | 25.38±3.52 |
| N，N’-Me-DIM | 146.33±22.34 | 354.87±11.46 | 25.45±2.25 |
| N-MOE-I3C | 147.55±18.31 | 357.69±18.33 | 27.56±2.43 |
| N，N’-MOE-DIM | 150.45±16.32 | 357.29±12.04 | 28.45±3.39 |
| 2-C5-I3C | 148.94±17.35 | 363.39±16.71 | 25.88±3.09 |
| 2，2’-C5-DIM | 155.43±20.30 | 359.02±11.40 | 29.53±5.68 |
| 2-MOE-I3C | 149.65±18.45 | 363.49±13.31 | 26.78±3.49 |
| 2，2’-MOE-DIM | 147.35±23.26 | 354.37±9.43 | 27.31±2.65 |
| 1Bu-2Me-I3C | 148.53±15.45 | 361.49±20.01 | 29.04±5.33 |
| ?1，1’Bu-2，2’Me-DIM | 149.48±8.94 | 355.44±15.45 | 24.56±3.85 |
| ?4Br-I3C | 151.23±16.34 | 369.38±20.38 | 27.40±5.20 |
| ?4，4’Br-DIM | 150.42±15.45 | 362.45±16.45 | 29.30±6.83 |
Annotate: numerical value is lattice number in the eyepiece mircrometer gauge in the table (2), and 1 lattice approximate 1.0695 μ m
Data show with the form of mean+SD that all significant difference is confirmed through the ANOVA check.When P≤0.01, be regarded as having significant difference.
Model group inner film thickness and normal group contrast obviously thicken (P≤0.01); Behind the therapeutic intervention, obvious attenuation of inner film thickness and model group ratio, significant difference (P≤0.01) explains that thing I3C of the present invention, DIM or derivatives thereof have tangible anti-AS effect.
Claims (8)
1. the Indole-3-carbinol and the derivant thereof that have structural formula (I) are prevented and treated the application in the atherosclerosis medicine in preparation,
Wherein, respectively do for oneself H or halogenic substituent or nitro or C1-C10 alkyl or C1-C10 alkoxyl of R1, R2, R4, R5, R6, R7.
2. application according to claim 1 is characterized in that: in the said structural formula (I), R5 is halogenic substituent or nitro or C1-C10 alkyl or C1-C10 alkoxyl, and R1, R2, R4, R6, R7 are hydrogen.
3. application according to claim 1 is characterized in that: in the said structural formula (I), R1 is C1-C10 alkyl or C1-C10 alkoxyl, and R2, R4, R5, R6, R7 are hydrogen.
4. application according to claim 1 is characterized in that: in the said structural formula (I), R2 is C1-C10 alkyl or C1-C10 alkoxyl, and R1, R4, R5, R6, R7 are hydrogen.
5. the di-indole methyl hydride and the derivant thereof that have structural formula (II) are prevented and treated the application in the atherosclerosis medicine in preparation,
Wherein, respectively do for oneself hydrogen or halogen substituent group or nitro or C1-C10 alkyl or C1-C10 alkoxyl of R1, R2, R4, R5, R6, R7, R1 ', R2 ', R4 ', R5 ', R6 ', R7 '.
6. application according to claim 5; It is characterized in that: in the said structural formula (II); R5 and R5 ' are halogenic substituent or nitro or C1-C10 alkyl or C1-C10 alkoxyl simultaneously, and R1, R2, R4, R6, R7, R1 ', R2 ', R4 ', R6 ', R7 ' are hydrogen.
7. application according to claim 5 is characterized in that: in the said structural formula (II), R1 and R1 ' are C1-C10 alkyl or C1-C10 alkoxyl simultaneously, and R2, R4, R5, R6, R7, R2 ', R4 ', R5 ', R6 ', R7 ' are hydrogen.
8. application according to claim 5 is characterized in that: in the said structural formula (II), R2 and R2 ' are C1-C10 alkyl or C1-C10 alkoxyl simultaneously, and R1, R4, R5, R6, R7, R1 ', R4 ', R5 ', R6 ', R7 ' are hydrogen.
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| CN105030766A (en) * | 2015-06-24 | 2015-11-11 | 安徽四正医药科技有限公司 | Indole-3-carbinol, di-indolyl methane and application of derivatives of indole-3-carbinol and di-indolyl methane to medicine for treating allergic pharyngitis |
| CN106377524A (en) * | 2016-08-16 | 2017-02-08 | 黄晶 | Application of indole-3-carbinol or dimer thereof |
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