CN103751190B - Triazole class compounds is preparing the application in aldehyde dehydrogenase 2 activator - Google Patents
Triazole class compounds is preparing the application in aldehyde dehydrogenase 2 activator Download PDFInfo
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- CN103751190B CN103751190B CN201310549552.3A CN201310549552A CN103751190B CN 103751190 B CN103751190 B CN 103751190B CN 201310549552 A CN201310549552 A CN 201310549552A CN 103751190 B CN103751190 B CN 103751190B
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- aldehyde dehydrogenase
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Abstract
The invention provides class formation Isosorbide-5-Nitrae as shown in the formula (I), 5-replacement-1,2,3-triazoles compounds is preparing the application in aldehyde dehydrogenase 2 activator.The compounds of this invention can be used for the vigor of the aldehyde dehydrogenase 2 improving human body thus treats and the prevention disease relevant with aldehyde dehydrogenase 2 and organ injury, this comprise alcoholism and because of drink that spirituosity material causes to human organ, the particularly damage of liver and harm; Also myocardial infarction is comprised, all kinds of tumor (especially esophageal carcinoma) and Other diseases.
Description
(1) technical field
The present invention relates to a class Isosorbide-5-Nitrae, 5-replacement-1,2,3-triazoles compounds is preparing the application in aldehyde dehydrogenase 2 activator.
(2) background technology
Ethanol, i.e. ethanol are that point two steps are carried out under the effect of ethanol dehydrogenase (alcohol dehydrogenase, ADH) and aldehyde dehydrogenase (aldehyde dehydrogenase, ALDH) by drinking the metabolism after entering human body.
The first step, ethanol generates acetaldehyde under the catalysis of ethanol aldehyde dehydrogenase:
CH
3CH
2OH→CH
3CH=O+H
2O （1）
Second step, acetaldehyde generates acetic acid and water under the catalysis of ethanol aldehyde dehydrogenase:
CH
3CH=O→CH
3COOH+H
2O （2）
The end product of this two step reaction is acetic acid and water.Acetic acid is the Main Ingredients and Appearance of tablet vinegar, is safe from harm to human body.But the product acetaldehyde of reaction 1 is to the toxic effect of cell.When acetaldehyde can not be built up by degrading rapidly in people, just there will be blush, giddy, the alcoholism symptom such as vomiting.Therefore aldehyde dehydrogenase is the key enzyme preventing ethanol from endangering.
Aldehyde dehydrogenase is extensively present in human body, and according to the difference in intracellular distribution and sequence, aldehyde dehydrogenase is divided into multiple hypotype.They are all be prothetic group with NAD, complete acetaldehyde-dehydrogenase reaction.The aldehyde dehydrogenase 2 (ALDH2) being wherein arranged in liver cell mitochondria is that alcohol metabolism plays a major role.The acetaldehyde that reaction 1 generates is decomposed by ALDH2 usually in hepatocyte.Therefore the vigor height of aldehyde dehydrogenase 2 is the key factor determining people's ethanol tolerance degree.Converting acetaldehyde can be become acetic acid rapidly by the aldehyde dehydrogenase 2 of high vigor; Otherwise the aldehyde dehydrogenase 2 of low vitality effectively can not complete this step reaction, makes acetaldehyde assemble in hepatocyte, causes hepar damnification.
Intramitochondrial aldehyde dehydrogenase 2 albumen is the tetramer be made up of 4 same monomers.The total number of atnino acid of every bar monomer is 500.According to test and the contrast of the ALDH2 gene order to different ethnic group, research worker finds in gook population, to there is a kind of anomaly ALDH2 gene, i.e. ALDH2(487K).In the ALDH2 of this anomaly, the aminoacid being positioned at 487 is Lys.And unmanifest ALDH2 is Glu at the aminoacid of 487.In China, Japan, Taiwanese, the crowd of about 40% has this anomaly aldehyde dehydrogenase 2 gene 487K, and wherein major part is heterozygote, namely has one to be anomaly aldehyde dehydrogenase 2 in one pair of genes, and another is normal.The heterozygosis tetramer that the Intramitochondrial aldehyde dehydrogenase 2 of this kind of human hepatocyte is generally made up of two anomaly monomers and two normal monomers, sub-fraction is homozygote in addition, and namely one pair of genes all makes a variation.
Compare with normal aldehyde dehydrogenase 2, with ALDH2(487K) the hepatocellular acetaldehyde-dehydrogenase enzyme activity of anomaly gene almost completely loses.The forfeiture of vigor is caused by two kinds of reasons.One is that this anomaly aldehyde dehydrogenase 2 is to the K of NAD
mvalue significantly rises, so that cannot in conjunction with NAD in cell; Second reason is the stability decline of aldehyde dehydrogenase 2, shows that its half-life only has 50% of normal aldehyde dehydrogenase 2.Aldehyde dehydrogenase 2 vigor is lost the acetaldehyde produced when causing drinking and is collected in hepatocyte and can not be changed into acetic acid rapidly, and thus this kind of crowd is very low to the tolerance of ethanol.Low alcohol consumption just there will be alcoholism symptom, hepatocyte is sustained damage, affects liver health.Clearly, the vigor improving ALDH2 improves ethanol tolerance thus liver-protective optimal path.
Nearest research finds that aldehyde dehydrogenase is preventing from making important function in myocardial infarction.The size of myocardial infarction area and the vigor of aldehyde dehydrogenase 2 are directly inversely.Using rat as in the experiment of model, the area of the myocardial infarction of artificial induction can be reduced by aldehyde dehydrogenase 2 activator.In addition, the action principle of widely used emergency cardiac care medicine nitroglycerin is by changing into NO to realize, and aldehyde dehydrogenase 2 plays pivotal role in this course, and it is the main cause causing nitroglycerin to lose efficacy that aldehyde dehydrogenase 2 vigor is lost.
Research also finds, aldehyde dehydrogenase 2 disappearance can promote the incidence rate of kinds cancer. as in the crowd often drunk, the sickness rate of the esophagus of anomaly aldehyde dehydrogenase 2 (487K) colony is eight to ten one times of non-anomaly.But in the crowd do not drunk, the esophageal carcinoma incidence rate of anomaly aldehyde dehydrogenase 2 relatively unmanifest property aldehyde dehydrogenase 2 does not then change.
The above results clearly shows that the vigor improving aldehyde dehydrogenase 2 is the damage important channel alleviating the liver produced because drinking, and the important channel preventing myocardial infarction, esophageal carcinoma from occurring.One of method realizing this approach is the medicine of the specific raising aldehyde dehydrogenase 2 activity of exploitation energy.This method is to carrying ALDH2(487K) crowd of gene can be especially effective, also have correlation effect to the crowd carrying normal ALDH2 gene.
(3) summary of the invention
The object of the invention is to provide a class Isosorbide-5-Nitrae, and 5-replacement-1,2,3-triazoles compounds is improving the application in aldehyde dehydrogenase 2 vigor.
The technical solution used in the present invention is:
One class formation Isosorbide-5-Nitrae as shown in the formula (I), 5-replacement-1,2,3-triazoles compounds is preparing the application in aldehyde dehydrogenase 2 activator;
In formula (I), R is one of following:
Above-claimed cpd be one group can directly and aldehyde dehydrogenase 2 combine thus improve the compound of aldehyde dehydrogenase activity.When any one in this group compound is at finite concentration and aldehyde dehydrogenase mixing, the vigor of aldehyde dehydrogenase can be made to increase.The rising of vigor is linear with the concentration of the compound added in certain scope.This group compound both can improve wild type acetaldehyde-dehydrogenase enzyme activity, also can improve anomaly acetaldehyde-dehydrogenase enzyme activity, and to ALDH2(487K) the raising degree of vigor is especially obvious, reaches as high as 8.5 times.Then 1.4 times can be reached to the lifting of wild type aldehyde dehydrogenase 2 vigor.This group compound can significantly improve ALDH(487K) stability.This shows that the urea-denatured concentration of aldehyde dehydrogenase 2 rises to 4.5M by 3.6M.
Obviously, this group compound can be used for the vigor of the aldehyde dehydrogenase 2 improving human body thus treats and the prevention disease relevant with aldehyde dehydrogenase 2 and organ injury, this comprise alcoholism and because of drink that spirituosity material causes to human organ, the particularly damage of liver and harm; Also myocardial infarction is comprised, all kinds of tumor and Other diseases.
Concrete, described triazole class compounds can be used for preparation and improves the vigor of aldehyde dehydrogenase 2 or the medicine of stability.
Concrete, described triazole class compounds is for the preparation of the medicine of Dealcoholic sobering-up.
Or described triazole class compounds is for the preparation of the medicine preventing and treating the hepar damnification caused of drinking.
Or described triazole class compounds is for the preparation of the medicine for the treatment of myocardial infarction.
Or described triazole class compounds, for the preparation of antitumor drug, specifically can be used as the medicine of anti-treatment of esophagus cancer.
Beneficial effect of the present invention is mainly reflected in: the compounds of this invention can be used for the vigor of the aldehyde dehydrogenase 2 improving human body thus treats and the prevention disease relevant with aldehyde dehydrogenase 2 and organ injury, this comprise alcoholism and because of drink that spirituosity material causes to human organ, the particularly damage of liver and harm; Also myocardial infarction is comprised, all kinds of tumor (especially esophageal carcinoma) and Other diseases.
(4) accompanying drawing explanation
Fig. 1 is that the compound 1 of variable concentrations is on the impact of the activity of 487K mankind's aldehyde dehydrogenase 2; In figure, F represents fluorescence intensity, L representation compound concentration (nM).
Fig. 2 is that the compound 1 of variable concentrations is on the impact of aldehyde dehydrogenase 2 albumen urea resistance; In figure, fn is the percentage ratio that the aldehyde dehydrogenase 2 albumen of non denatured accounts for total aldehyde dehydrogenase 2 Tot Prot, and Urea represents carbamide, and M represents molar concentration; In figure ● for not adding denaturation curve during compound 1, ☆ is the curve after adding compound 1.
(5) detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this:
Embodiment 1:
Table 1 is the structural formula of compound involved in the present invention.When any one compound in table 1 is added into respectively containing 487K heterozygote, 487K homozygote and wild type aldehyde dehydrogenase 2 pheron, (wild type ALDH2 sequence is shown in SEQ ID No.1, anomaly ALDH2 sequence is shown in SEQ ID No.2) solution in after, the significant reaction being acetic acid by the converting acetaldehyde of the catalysis of aldehyde dehydrogenase 2 is accelerated, and shows that the vigor of aldehyde dehydrogenase 2 rises.The degree that the aldehyde dehydrogenase 2 vigor caused by the compound enumerated in table 1 rises depends on whether compounds in side chain group and aldehyde dehydrogenase 2 make a variation with 487K.Concrete outcome is in table 1.
Table 1: compound structure and activity data thereof
The multiple that vigor shown in table 1 improves is calculated by following formula:
F=（C-B）/B
In this formula, B is that the reaction 2(acetaldehyde of this kind of aldehyde dehydrogenase 2 catalysis when compound concentration is zero generates acetic acid and water) response speed.C is the response speed of the reaction 2 of this kind of aldehyde dehydrogenase 2 catalysis when compound concentration peaks.F is the multiple that vigor improves.Vigor described in table is measured by following method:
Utilize the Em=340nm of NADH, EX=460nm, recording intensity by detecting the fluorescent produced by NADH, measuring active.
(unmanifest aldehyde dehydrogenase 2 is 10ug/mL for the compound of certain concentration (0 ~ 1000nM) and mankind's aldehyde dehydrogenase 2 albumen of purification, anomaly aldehyde dehydrogenase 2 is 140ug/mL) mix 60 minutes, add acetaldehyde (2mM/mL) and NAD(1mg/mL) startup reaction.Course of reaction carrys out record to measure the fluorescent produced by NADH.
Fig. 1, for compound 1, indicates the result described in table 1 in detail.Fig. 1 compares the compound 1 of variable concentrations to the impact of the activity of 487K mankind's aldehyde dehydrogenase 2.In figure, result knows that the vigor of display aldehyde dehydrogenase 2 increases along with the increase of compound 1 concentration.This effect that increases is saturation curve, namely when compound reach finite concentration after, then the vigor increasing compound concentration aldehyde dehydrogenase 2 no longer increases, show the effect of compound by directly and aldehyde dehydrogenase 2 combine and produce.Although it is to be noted described in Fig. 1 to be compound 1, similar result is present in compound 2, compound 3, in compound 4 and compound 5.
Compound listed by table 1 can also increase the stability of aldehyde dehydrogenase 2.When adding compound (50nM) in the solution of the aldehyde dehydrogenase 2 of purification, aldehyde dehydrogenase 2 albumen strengthens the toleration of carbamide, shows that the urea concentration needed for degeneration aldehyde dehydrogenase 2 albumen increases.Fig. 2, still for compound 1, shows this result in detail.In fig. 2, transverse axis is the concentration of protein denaturant carbamide, and vertical pivot is the percentage ratio that the aldehyde dehydrogenase 2 albumen of non denatured accounts for total aldehyde dehydrogenase 2 Tot Prot.Fig. 2 shows, and the urea-denatured concentration of the mankind 487K aldehyde dehydrogenase 2 of purification is 4.6M, and after the mankind 487K aldehyde dehydrogenase 2 of purification and compound 1 mix 30 minutes, urea-denatured concentration brings up to 4.8M.Similar result is also present in compound 2, compound 3, in compound 4 and compound 5.
The above results shows that compound listed by table 1 both can improve the catalysis activity of aldehyde dehydrogenase 2, also can improve the stability of aldehyde dehydrogenase 2.
Claims (6)
1. class formation Isosorbide-5-Nitrae as shown in the formula (I), 5-replacement-1,2,3-triazoles compounds is preparing the application in aldehyde dehydrogenase 2 activator;
In formula (I), R is one of following:
2. apply as claimed in claim 1, it is characterized in that described triazole class compounds is for the preparation of the raising vigor of aldehyde dehydrogenase 2 or the medicine of stability.
3. apply as claimed in claim 2, it is characterized in that the medicine of described triazole class compounds for the preparation of Dealcoholic sobering-up.
4. apply as claimed in claim 2, it is characterized in that described triazole class compounds is for the preparation of the medicine preventing and treating the hepar damnification caused of drinking.
5. apply as claimed in claim 2, it is characterized in that the medicine of described triazole class compounds for the preparation for the treatment of myocardial infarction.
6. apply as claimed in claim 2, it is characterized in that described triazole class compounds is for the preparation of antitumor drug.
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