CN104892562B - Suppress compound of cyclooxygenase 2 and its preparation method and application - Google Patents
Suppress compound of cyclooxygenase 2 and its preparation method and application Download PDFInfo
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Abstract
Suppress the compound of cyclooxygenase 2, its structural formula is as follows：Shown by toxicology, pharmacodynamic experiment, the present invention suppresses the compound of cyclooxygenase 2 not affect Mouse Weight, and toxic and side effects are less, compared with ASP, suppress the compound of cyclooxygenase 2 less to mice gastrointestinal toxic and side effects, show that its safety is higher；In addition, the compound of present invention suppression cyclooxygenase 2 can be with the expression of Selective depression COX 2, and antiinflammatory action effect is good, hence it is evident that be better than GEP and ASP, with extraordinary application prospect.
Description
Technical field
The present invention relates to a kind of compound for suppressing Transitional cell carcinomas and its production and use.
Background technology
Inflammation is that body causes tissue or Lesion of Microcirculation and a kind of basic pathology process for producing to various inflammatory stimulus.
Inflammatory reaction is mediated by medium, and wherein prostaglandin (Prostaglandin, PG) plays important work in inflammatory reaction
With.Cycloxygenase (Cyclooxygenase, COX) is a kind of bifunctional enzyme, is catalysis membrane phospholipid arachidonic acid
(Arachidonic acid, AA) is converted into the rate-limiting enzyme of PG class materials.There are two kinds of isozymes in COX：COX-1 and COX-2.Work(
Energy type COX-1 is primarily present in normal cell, mediates the generation of low-level physiological PG, and Main Function is to protect and adjust
Gastrointestinal tract and hematoblastic normal physiological function；And induction type COX-2 is primarily present in inflammatory tissue cell, in inflammation mould
Type and rheumatoid arthritiss (Rheumatoid arthritis, RA) patient into fiber-like synovial tissue (Fibroblast
Like synovial tissue, FLST) in have great expression, some pathologic PG such as PGE are synthesized by metabolism AA2,
Simultaneously with the generation of reactive oxygen free radical, cause inflammatory reaction to amplify and strengthen, cause pain, have a fever, the disease such as redness
Shape[1].In acute, subacute and chronic inflammation model, Selective depression COX-2 enzymatic activitys have obvious anti-inflammatory effect,
Show that inductivity COX-2 plays a significant role in inflammation, COX-2 possibly as rheumatoid arthritis treatment act on potential
Target spot[2].
Nonsteroidal antiinflammatory drug (Non-steroidal anti-inflammatory drugs, NSAIDs) is that inflammation is controlled
The conventional medicament for the treatment of.1971, by studying, Vane etc. had found that NSAIDs is the activity by suppressing COX, block AA and be converted into
PGs is so as to playing a role.At present, according to the specificity to two kinds of COX isozymes effects, NSAIDs point is four big class：(1)COX-
1 selective depressant, such as aspirin (Aspirin, ASP)；(2) non-selective COX inhibitor (indomethacin)；(3)COX-2
Relative selectivity inhibitor (Meloxicam)；(4) specific C OX-2 selective depressants (celecoxib).Wherein COX-1 is selected
Property inhibitor and non-selective inhibitor due to suppressing the activity of the COX-1 of intrinsic expression, reducing physiological PGs generates,
Therefore, long-term taking is easily caused the side effect such as more serious injury of gastrointestinal tract.Typically, ASP long-term takings cause gastrorrhagia, stomach
The serious adverse reactions such as ulcer are extensively accepted.Pathogenesis mainly pass through the activity for suppressing COX-1, before reducing mucosa
The generation of row parathyrine (PG), the direct stimulating gastrointestinal road mucosa of free carboxyl simultaneously penetrate gastric epithelial cell film, have impact on glutinous
Film defense factor, mucosa cells secretion mucin and phospholipid surface, and then break gastric mucosal barrier.Simultaneously also suppress stomach, 12
The secretion of duodenum 12 epithelium carbonate, reduces the reparation and renewal of epithelium.Again because of the synthesis of suppression platelet Cycloxygenase, reduce
The synthesis of thromboxane A2, and reduce hematoblastic ability of aggregation, induce bleeding.Therefore, ASP performance drug action bases are not being changed
Free carboxyl is modified on the premise of group, it will get a good eye necessity to reduce to gastrointestinal stimulation.
NSAIDs of new generation with COX-2 selective depressants as representative, carries out specificity by the COX-2 to induction type
Suppress and do not affect the activity of COX-1, significant antiinflammatory action can be played, and the poison pair brought by tradition NSAIDs can be reduced
Effect.At present, COX-2 selective Ns SAIDs is mainly used in the treatment of the diseases such as RA, osteoarthritis and acute pain.COX-2 is selected
The mechanism of action of selecting property NSAIDs mainly passes through to suppress COX-2 enzymatic activitys, so as to suppress inflammatory mediator PGE2Generation, mitigate
Inflammatory reaction simultaneously alleviates various symptoms.However, Merck drugmaker in 2004 announces voluntarily to recall the said firm in the whole world
COX-2 selective Ns SAIDs rofecoxibs (Rofecoxib) of research and development, reason is that the medicine can cause cardiovascular due to long-term taking
Etc. aspect side effect.
Anti inflammatory immunity active component jasminoidin (Geniposide, GE) of the genipin (Genipin, GEP) for Chinese medicine Fructus Gardeniae
Aglycon part after hydrolysis, belongs to iridoidses.In recent years, existing document report confirms that GE and GEP is respectively provided with antiinflammatory, antiallergic
And multiple pharmacologically actives such as immunosuppressant[3], additionally due to GE has a certain degree of liver toxicity, wherein think mostly its toxicity
Relevant with the structure of GE, and advise that by its structural modification be GEP or other metabolites[4-6].Akao T etc. pass through enzymatic isolation method
The intestinal bacteria metabolism of GE is studied, it is found that GE is hydrolyzed into GEP through intestinal β-D-Glucose glycosides enzyme in vivo and plays pharmacology
Effect[7].GEP main mechanisms are to suppress the degraded of NF- κ B/IKB- β, COX-2 mediations during minimizing inflammatory reaction
PGE2Generate with the NO that nitricoxide synthase (Nitric oxide synthase, NOS) is mediated, significantly improve the disease of RA patient
Shape[8-9].But, research recently finds, relatively low in normal rat vivo biodistribution availability after GEP is oral, it is considered to may to be mainly
Hemiacetal structure on its pyranoid ring is unstable in acid condition, causes through gastrointestinal tract sour environment Partial digestion.
Therefore, it is badly in need of the compound use that a kind of toxic and side effects are little, antiinflammatory action is good, be capable of Selective depression Transitional cell carcinomas
To treat inflammation.
List of references：
[1]J.S.Lee,J.Y.Cho,H.Song,E.H.Hee,K.B.Hahm.Revaprazan,a novel acid
pump antagonist,exerts anti-inflammatory action against helicobacter pylori-
induced COX-2expression by inactivating akt signaling.J Clin Biochem Nutr.51
(2012)77-83.
[2]J.C.Phillips.Fractals and self-organized criticality in anti-
inflammatory drugs.Physica.Section A:Statistical Mechanics and its
Applications.415(2014)538-543.
[3]M.M.Dai,H.Wu,H.Li,J.Chen,J.Y.Chen,S.L.Hu,C.Shen,Effects and
mechanisms of Geniposide on rats with adjuvant arthritis[J]
.Int.Immunopharmacol.1(2014)46-53.
[4]J.Chen,H.Wu,M.M.Dai,H.Li,J.Y.Chen,S.L.Hu.Identification and
distribution of four metabolites of geniposide in rats with adjuvant
arthritis.Fitoterapia.97(2014):111-121.
[5]J.Chen,H.Wu,G.B.Xu,M.M.Dai,S.L.Hu,L.L.Sun,W.Wang,S.P.Li,
G.Q.Li.Determination of geniposide in adjuvant arthritis rat plasma by ultra-
high performance liquid chromatography tandem mass spectrometry method and
its application to oral bioavailability and plasma protein binding ability
studies.J Pharm Biomed Anal.108(2015):122-128.
[6]Q.H.Shi,J.J.Cao,F.Li,H.Y.Zhao,Z.X.Liu,J.H.Ran,X.C.Zheng,X.L.Li,
Y.Zhou,D.Ge,H.M.Zhang,L.Wang,Y.Ran,J.F.Fu,Geniposide suppresses LPS-induced
nitric oxide,PGE2and inflammatory cytokine by downregulating NF-κB,MAPK and
AP-1signaling pathways in macrophages[J].Int.Immunopharmacol.2(2014)298-306.
[7]W.L.Chang,H.Y.Wang,L.Shian,J.H.Lai,H.C.Lin,Immunosuppressive
iridoids from the fruits of Gardenia jasminoides[J].J.Nat.Prod.11(2005)1683-
1685.
[8]H.J.Koo,K.H.Lim,H.J.Jung,Anti-inflammatory evaluation of gardenia
extract,geniposide and genipin[J].J Ethnopharmacol.3(2006)496-500.
[9]H.Li,H.Wu,C.Shen,J.Y.Chen,S.L.Hu,H.Wu.Comparative Pharmacokinetics
Study after Oral Administration of Geniposide in Normal Rats and Adjuvant-
induced Arthritis Rats by UPLC-MS/MS.Basic Clin.Pharmacol.Toxicol.113(2013)
294-299.
Content of the invention
The technical problem to be solved is to provide that a kind of toxicity is low, antiinflammatory action is good, being capable of Selective depression ring
The compound of oxidase -2.
In order to solve above-mentioned technical problem, the present invention is adopted the following technical scheme that：Suppress the compound of Transitional cell carcinomas, its
Structural formula is as follows：
The compound and its pharmaceutically acceptable salt that the present invention also provides described suppression Transitional cell carcinomas is anti-in preparation
Application in scorching medicine, the especially application in anti-arthritic drugs.
The salt that " pharmaceutically acceptable salt " is including but not limited to formed with mineral acid, such as hydrochlorate, phosphate, diphosphonic acid
Salt, hydrobromate, sulfate, sulfinate, nitrate and similar salt；And with organic acid formed salt, such as malate,
Maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, mesylate, to toluene sulphur
Hydrochlorate, 2- isethionates, benzoate, salicylate, stearate and alkanoate such as acetate and similar salt.Class
As, pharmaceutically acceptable cation includes but is not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.
The present invention also provides the preparation method of the compound of described suppression Transitional cell carcinomas, comprises the following steps：
(1) genipin methylates the synthesis of intermediate a
The genipin of 1 weight portion is dissolved in the absolute methanol of 40 60 weight portions, boron trifluoride second after cooling, is added
Ether, is then stirred reaction at room temperature, adds saturation NaHCO after reaction completely3It is quenched, then with organic solvent pair
Reactant liquor is extracted and is separated and collected organic faciess, finally to organic faciess anhydrous Na2SO4Process is dried, then is evaporated off organic
Solvent, is obtained colourless oil liquid, obtains final product genipin and methylates intermediate a；
(2) suppress the synthesis of the compound of Transitional cell carcinomas
The genipin for taking 1 weight portion methylates intermediate a, adds triethylamine to adjust pH value to 89, slow after cooling
The acetyl salicylic acyl chlorides of 3 weight portions is added, is then reacted under condition of ice bath, after reaction completely, add saturation NaHCO3Enter
Row quenching, is then extracted and is separated and collected organic faciess, finally carried out silicagel column to organic faciess with organic solvent to reactant liquor
Image processing, is obtained white solid, as suppresses the compound of Transitional cell carcinomas.
Wherein, used as catalyst, triethylamine is used as acid binding agent for boron trifluoride diethyl etherate.
Beneficial effects of the present invention are embodied in：
1. shown by toxicology, pharmacodynamic experiment, the present invention suppresses the compound of Transitional cell carcinomas not have Mouse Weight
Have an impact, toxic and side effects are less, compared with ASP, suppress the compound of Transitional cell carcinomas less to mice gastrointestinal toxic and side effects, table
Its safety bright is higher；In addition, the present invention suppress Transitional cell carcinomas compound can with the expression of Selective depression COX-2, and
And antiinflammatory action effect is good, hence it is evident that be better than GEP and ASP, with extraordinary application prospect.
2. the preparation method process is simple of the compound of present invention suppression Transitional cell carcinomas, mild condition, yield are higher, fit
Close industrialized production.
Description of the drawings
Fig. 1-1 is the high resolution mass spectrum figure of the compound for suppressing Transitional cell carcinomas.
Fig. 1-2 is the compound for suppressing Transitional cell carcinomas1H-NRM schemes.
Fig. 1-3 is the compound for suppressing Transitional cell carcinomas13C-NRM schemes.
Fig. 2-1 is small intestine movement of mice tissue paracortical area optical microscope.
Fig. 2-2 is ASP dosage group (550mg/kg) mouse small intestine tissue paracortical area optical microscope.
Fig. 2-3 is that the 6th group of (1142mg/kg) mouse small intestine of compound for suppressing Transitional cell carcinomas organizes paracortical area light
Learn microscope figure.
Fig. 3 is that the compounds for treating for suppressing Transitional cell carcinomas is administered the impact linear graph to CIA rat arthritis indexes.
Fig. 4 is that the compounds for treating for suppressing Transitional cell carcinomas is administered the impact linear graph to CIA rat articular swellings.
Fig. 5-1 is normal rat MLNs paracortical area optical microscope.
Fig. 5-2 is CIA rat MLNs paracortical area optical microscope.
Fig. 5-3 is that compound middle dose group (70mg/kg) the rat MLNs paracortical area optics for suppressing Transitional cell carcinomas shows
Micro mirror figure.
Fig. 5-4 is that compound high dose group (140mg/kg) the rat MLNs paracortical area optics for suppressing Transitional cell carcinomas shows
Micro mirror figure.
Fig. 6-1 is normal rat knee joint synovial layer optical microscope.
Fig. 6-2 is CIA rat knee joints synovial layer optical microscopes.
Fig. 6-3 is that compound middle dose group (70mg/kg) the rat knee joints synovial layer optics for suppressing Transitional cell carcinomas shows
Micro mirror figure.
Fig. 6-4 is that compound high dose group (140mg/kg) the rat knee joints synovial layer optics for suppressing Transitional cell carcinomas shows
Micro mirror figure.
Fig. 7 is impact bar diagram of the ConA different times variable concentrations to PBL multiplication capacities.
Fig. 8 is impact bar diagram of the compound of suppression Transitional cell carcinomas to CIA P of Rats BL multiplication capacities.
Fig. 9 be suppress Transitional cell carcinomas compound to CIA rat blood serums, thymus and spleen lymphocyte supernatant PGE2
Impact bar diagram.
Figure 10 is that the compound entirety for suppressing Transitional cell carcinomas is administered to COX-2 albumen relative expression's water in CIA P of Rats BL
Flat impact bar diagram.
Specific embodiment
The invention will be further described with reference to the accompanying drawings and examples：
This part to the present invention experiment used in material and test method carry out general description.It although is
Realize many materials that the object of the invention used and operational approach be it is known in the art that but here of the present invention work as far as possible
Describe in detail.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention, equipment and operation
Method is well known in the art.For succinct description, " suppressing the compounds of Transitional cell carcinomas " of the invention is described in the drawings as " suppression
The compound of COX-2 processed ".
Embodiment 1
Suppress the preparation method of the compound of Transitional cell carcinomas
1.1 genipin methylate the synthesis of intermediate a
3g genipin is dissolved in 180g absolute methanols, is rapidly added 1.68g trifluoros after 0 DEG C being cooled in ice bath groove
Change borate ether, be then stirred (220r min at room temperature-1) reaction, TLC detection reaction process, reaction is completely rear to be added
Saturation NaHCO3Be quenched, organic faciess are then extracted and separated and collected with organic solvent to reactant liquor, finally to organic
Anhydrous Na is mutually used2SO4Process is dried, then organic solvent is evaporated off, colourless oil liquid is obtained, obtained final product during genipin methylates
Mesosome a；
The synthesis of 1.2 compounds for suppressing Transitional cell carcinomas
Take 1g genipin to methylate intermediate a, add triethylamine to adjust pH value to 9, after 0 DEG C being cooled in ice bath groove
3g acetyl salicylic acyl chlorides is slowly added to, is then reacted under condition of ice bath, TLC detects reaction process, adds after reaction completely
Enter saturation NaHCO3Be quenched, organic faciess are then extracted and separated and collected with organic solvent to reactant liquor, finally to having
Machine mutually carries out silica gel column chromatography process, white solid 1.84g is obtained, as suppresses the compound of Transitional cell carcinomas, yield 46%.
Referring to Fig. 1-1, Fig. 1-2 and Fig. 1-3：
1H-NMR(600MHz,CDCl3) δ 8.00 (d, J=7.2Hz, 1H), 7.53 (t, J=7.7Hz, 1H), 7.41 (s,
1H), 7.08 (d, J=7.8Hz, 2H), 5.98 (s, 1H), 5.07 (d, J=3.4Hz, 1H), 4.95 (s, 2H), 3.70 (s, 3H),
3.53 (s, 3H), 3.22～3.18 (m, 1H), 3.11～3.07 (m, 1H), 2.30 (s, 3H), 2.08 (d, J=8.2Hz, 2H).
13C-NRM(151MHz,CDCl3)δ169.91,167.95,164.49,152.38,150.92,150.76,
138.10,136.21,131.22,126.24,124.04,124.43,111.59,111.01,77.23,63.30,57.34,
56.53,51.46,35.54,33.88,21.25,0.19.
MS:C21H21O8Na,[M+Na]+425.1202.
Embodiment 2
Suppress the preparation method of the compound of Transitional cell carcinomas
2.1 genipin methylate the synthesis of intermediate a
3g genipin is dissolved in 120g absolute methanols, is rapidly added 1.68g trifluoros after 0 DEG C being cooled in ice bath groove
Change borate ether, be then stirred (220r min at room temperature-1) reaction, TLC detection reaction process, reaction is completely rear to be added
Saturation NaHCO3Be quenched, organic faciess are then extracted and separated and collected with organic solvent to reactant liquor, finally to organic
Anhydrous Na is mutually used2SO4Process is dried, then organic solvent is evaporated off, colourless oil liquid is obtained, obtained final product during genipin methylates
Mesosome a；
The synthesis of 2.2 compounds for suppressing Transitional cell carcinomas
Take 1g genipin to methylate intermediate a, add triethylamine to adjust pH value to 8, after 0 DEG C being cooled in ice bath groove
3g acetyl salicylic acyl chlorides is slowly added to, is then reacted under condition of ice bath, TLC detects reaction process, adds after reaction completely
Enter saturation NaHCO3Be quenched, organic faciess are then extracted and separated and collected with organic solvent to reactant liquor, finally to having
Machine mutually carries out silica gel column chromatography process, white solid 2.08g is obtained, as suppresses the compound of Transitional cell carcinomas, yield 52%.
Referring to Fig. 1-1, Fig. 1-2 and Fig. 1-3：
1H-NMR(600MHz,CDCl3) δ 8.00 (d, J=7.2Hz, 1H), 7.53 (t, J=7.7Hz, 1H), 7.41 (s,
1H), 7.08 (d, J=7.8Hz, 2H), 5.98 (s, 1H), 5.07 (d, J=3.4Hz, 1H), 4.95 (s, 2H), 3.70 (s, 3H),
3.53 (s, 3H), 3.22～3.18 (m, 1H), 3.11～3.07 (m, 1H), 2.30 (s, 3H), 2.08 (d, J=8.2Hz, 2H).
13C-NRM(151MHz,CDCl3)δ169.91,167.95,164.49,152.38,150.92,150.76,
138.10,136.21,131.22,126.24,124.04,124.43,111.59,111.01,77.23,63.30,57.34,
56.53,51.46,35.54,33.88,21.25,0.19.
MS:C21H21O8Na,[M+Na]+425.1202.
Embodiment 3
Suppress the preparation method of the compound of Transitional cell carcinomas
3.1 genipin methylate the synthesis of intermediate a
3g genipin is dissolved in 150g absolute methanols, is rapidly added 1.68g trifluoros after 0 DEG C being cooled in ice bath groove
Change borate ether, be then stirred (220r min at room temperature-1) reaction, TLC detection reaction process, reaction is completely rear to be added
Saturation NaHCO3Be quenched, organic faciess are then extracted and separated and collected with organic solvent to reactant liquor, finally to organic
Anhydrous Na is mutually used2SO4Process is dried, then organic solvent is evaporated off, colourless oil liquid is obtained, obtained final product during genipin methylates
Mesosome a；
The synthesis of 3.2 compounds for suppressing Transitional cell carcinomas
Take 1g genipin to methylate intermediate a, add triethylamine to adjust pH value to 9, after 0 DEG C being cooled in ice bath groove
3g acetyl salicylic acyl chlorides is slowly added to, is then reacted under condition of ice bath, TLC detects reaction process, adds after reaction completely
Enter saturation NaHCO3Be quenched, organic faciess are then extracted and separated and collected with organic solvent to reactant liquor, finally to having
Machine mutually carries out silica gel column chromatography process, white solid 2.32g is obtained, as suppresses the compound of Transitional cell carcinomas, yield 58%.
Referring to Fig. 1-1, Fig. 1-2 and Fig. 1-3：
1H-NMR(600MHz,CDCl3) δ 8.00 (d, J=7.2Hz, 1H), 7.53 (t, J=7.7Hz, 1H), 7.41 (s,
1H), 7.08 (d, J=7.8Hz, 2H), 5.98 (s, 1H), 5.07 (d, J=3.4Hz, 1H), 4.95 (s, 2H), 3.70 (s, 3H),
3.53 (s, 3H), 3.22～3.18 (m, 1H), 3.11～3.07 (m, 1H), 2.30 (s, 3H), 2.08 (d, J=8.2Hz, 2H).
13C-NRM(151MHz,CDCl3)δ169.91,167.95,164.49,152.38,150.92,150.76,
138.10,136.21,131.22,126.24,124.04,124.43,111.59,111.01,77.23,63.30,57.34,
56.53,51.46,35.54,33.88,21.25,0.19.
MS:C21H21O8Na,[M+Na]+425.1202.
Embodiment 4
Suppress the acute toxicological experiment preliminary assessment of the compound of Transitional cell carcinomas
The compound for suppressing Transitional cell carcinomas is determined to healthy mice LD using improvement karber's method50, mice is randomly divided into 8
Group, raises 2 weeks by 10 per group.With picric acid as dyestuff (yellow).According to the compound that preliminary result obtains Transitional cell carcinomas
Per group of all lethal minimum dosage be 1300mg/kg, and per group do not occur death maximum dosage be
400mg/kg, group is away from for r=1.3.By suppress Transitional cell carcinomas compound be divided into 400mg/kg, 520mg/kg, 676mg/kg,
6 groups of 878.8mg/kg, 1142mg/kg, 1485.17mg/kg and ASP groups 550mg/kg, solvent group.Medication group in daily with
2 morning and evenings of 0.2ml/10g gastric infusions are each once.Continuous gavage is administered 14 days, and (photophobia, fur are erected observation of plant nervous system
Rise etc.), autonomic movement, muscular movement and tension force, irritant reaction, death to external world, obduction.
4.1 various dose medicines are to acute toxicity test in mice
Mice dead 7 altogether in continuous 14 days are raised in administration.Respectively suppress the compound of Transitional cell carcinomas
Dead 1 of the mice of 878.8mg/kg dosage groups the 8th day；Suppress the 1142mg/kg dosage groups of the compound of Transitional cell carcinomas
Dead 1 of mice the 8th day, the 13rd day dead 1.Suppress the compound 1485.17mg/kg dosage groups mice the of Transitional cell carcinomas
5 days, the 6th day, the 7th day, the 8th day each dead 1.Wherein, there is not exception in ASP groups and solvent group, the drink of mice during raising
Food and activity situation are normal, are specifically shown in Table 1.
1 various dose medicine of table is to acute toxicity test in mice result
According to the observation result of mice ordinary circumstance after administration, mice LD is measured using improvement Kou Shifa50(formula 1) and
95% confidence interval (formula 2)
LD50=lg-1[XmI (∑ p-0.5)]) (formula 1)
95% fiducial limit interval=log-1(logLD50±1.96×Slog LD50) (formula 2)
It is computed：With the median lethal dose(LD 50) (LD that group calculates the compound for suppressing Transitional cell carcinomas away from r=1.350) be
1409.9mg/kg, 95% credibility interval are 422.4443mg/kg～1278.2124mg/kg.Check in aspirin mice LD50For
1100mg/kg.As a result show：Compared with ASP, the compound toxic and side effects of Transitional cell carcinomas are suppressed to make moderate progress.
4.2 suppress impact of the compound multiple dose administration of Transitional cell carcinomas to Mouse Weight
After successive administration 14 days, Mouse Weight before and after record gavage compares the situation of change of body weight before and after administration.
Before and after suppressing the compound administration of Transitional cell carcinomas, Mouse Weight has increased slightly, but no significant difference.Such as 2 institute of table
Show.
Table 2 suppresses the impact of the compound multiple dose administration Mouse Weight of Transitional cell carcinomas
Administration is front to compare with after administration：P ＞ 0.01
As a result show：The compound multiple dose administration of Transitional cell carcinomas is suppressed not affect Mouse Weight.
4.3 gastric mucosa tissue evaluations
After continuous use 14d days, after last dose 2h, take out complete gastric tissue and be immersed in formalin, afterwards with life
Reason saline cleaning, gastric mucosa is faced upwards, is laid in glass dish on normal saline gauze, and perusal gastric mucosa changes stomach
Mucosa injury standards of grading:0=is normal, and 0.5=local is slightly rubescent, the whole gastric mucosas of 1=are rubescent or bleeding (<1mm), 2=
Big bleeding (>1mm), 3=aphthas (<2mm), the big ulcer of 4=(2mm), 5=perforated ulcers.
After perusal gastric mucosa tissue, normal mouse gastric mucosa tissue not damaged has no abnormal changes；ASP group mices
Gastric mucosa tissue is all rubescent, and sees a little bleeding.Compare with ASP groups, suppress the compound of Transitional cell carcinomas to gastric mucosa group
Knit damage abnormal substantially, wherein, the 6th group of gastric mucosa tissue appearance local is rubescent.Perusal mucosal lesion grade form
Compare tool with ASP groups after each dosage group successive administration to improve significantly.As shown in table 3.
Table 3 suppresses impact (n=10) of the compound of Transitional cell carcinomas to mice gastric mucosal damage index
Compared with solvent group,##P<0.01；Compared with ASP groups,**P<0.01
As a result show：Compared with ASP, suppress the compound of Transitional cell carcinomas to have mice mucosal lesion and significantly change
Kind.
4.4 intestinal tissue Pathologic changes
Mouse small intestine 10% formaldehyde of tissue is fixed, variable concentrations graded ethanol is dehydrated step by step, paraffin embedding, section, HE
Dyeing optics basis of microscopic observation mouse small intestine histopathology histological change.
By Fig. 2-1, normal small intestine tissue HE dyeing shows that intestinal wall fluff structures are neat, and epithelial cell is in the form of a column, arranges whole
Together, lamina propria body of gland is in the same size；By Fig. 2-2, ASP mices mucosal epithelium layer segment necrocytosiss (karyolysis), mucosa is intrinsic
Layer cell infiltration is more apparent, the simultaneously atrophy of lamina propria body of gland partial necrosis；By Fig. 2-3, compare with ASP groups, suppression Cycloxygenase-
To intestinal mucosal injury effect and less, wherein, the 6th group not clear to the necrosis of mice mucosal epithelial cells for each administration group of 2 compound
Aobvious, rarely seen part cytopathy, proper mucous membrane cell infiltration are still obvious, and lamina propria body of gland has no substantially necrosis and withers
Contracting, points out to suppress the compound phase of Transitional cell carcinomas for ASP can reduce the stimulation to intestinal mucosa.
As a result show：Compared with ASP, suppress the compound of Transitional cell carcinomas to stimulate mice intestinal tissue and significantly reduce.
Integrated embodiment " 4.1 " " 4.2 " " 4.3 " " 4.4 " result, suppress Transitional cell carcinomas compound toxic and side effects compared with
Little, compared with ASP, suppress the compound of Transitional cell carcinomas not affect Mouse Weight.
Embodiment 5
Suppress the preliminary assessment of the compound pharmacodynamicss of Transitional cell carcinomas
The foundation of 5.1 rat CIA models
The SD rats that newly buys are in constant temperature (24 ± 2 DEG C), periodicity of illumination 12h:Raise 1 week in 12h environment, 18h before experiment
Fasting, free water.In d0, [FCA, containing bacillus calmette-guerin vaccine for every 100 μ g chickens C II of rat toes subcutaneous injection and Freund's complete adjuvant
(1mg·ml-1), common 0.1ml].D21, the Emulsion of rat toes subcutaneous injection Isodose is used as exciting.Normal rats are noted
Penetrate normal saline (N.S).D0 is designated as to inject first.
5.2 packet and administration
The SD rats that newly buys are randomly divided into 8 groups：Normal group；CIA model group；ASP (55mg/kg) group；GEP(40mg/
Kg) group；(according to acute toxicity guideline, low dosage is to suppress the basic, normal, high dosage group of compound of Transitional cell carcinomasMiddle dosage isHigh dose is) and celecoxib (celecoxib, IB) (70mg/kg) sun
Property medicine group, 10 per group；The secondary parapodum pawls of d26 start to be administered after there is red and swollen, inflammation, each administration group difference continuous gavage administration
ASP, GEP, suppress the compound of Transitional cell carcinomas, IB and CIA model group with the 0.5% of equivalent normal saline gavage, daily
Once, medication 14 days.D40 puts to death rat, observes index of assessment of curative effect.
5.3 suppress the compounds for treating of Transitional cell carcinomas to be administered to CIA rat arthritis index scores
D17 after inflammation, each rat model is caused General Symptomies occur, remaining 3 limbs joint for showing as not injecting FCA are red
Swollen, degeneration, ear and afterbody tuberosity, walking disorder；From the figure 3, it may be seen that compared with normal group, rat Secondary cases joint after d18
Pathological changes, modeling success.Compared with model group, after each dosage group treatments of d21 and d24 can suppress CIA rats secondary
Property arthropathy (P<0.01).The each administration groups of d24 are compared with model group, and arthritis index substantially reduces (P ＜ 0.01), additionally,
Suppress the middle and high dosage group arthritis index compared with GEP groups and ASP groups of compound of Transitional cell carcinomas substantially to reduce, have aobvious
The difference of work property, prompting suppress the antiphlogistic effects of the middle and high dosage group of the compound of Transitional cell carcinomas to be better than GEP and ASP.
Cause scorching front and inflammation rat foot claw volume to be determined every 3d with sufficient capacity measurer after occurring, obtain swelling (Δ
=cause scorching metapedes volume to cause scorching front foot volume)；Refer to (toe) joints per only sufficient 1 ankle joint of pawl meter and 5, every rat is most
24 arthroncuss.After inflammation is caused d8, every 3 days (d8, d12, d16, d20, d24), after administration every 2 days (d26, d29,
D32, d35, d38, d40) arthritis index scoring is carried out, observe the secondary affection of every group of rat.Refer to per the arthritis of only sufficient pawl
Number standards of grading：0=is normal；There is erythema and slight swelling in 1=ankle joint；2=ankle joint is to plantar joint or metacarpal joint erythema
With slight swelling；There is erythema and moderate swelling to metatarsophalangeal joints or metacarpal joint in 3=ankle joint；4=ankle joint goes out to toe joint
Existing erythema and severe swelling.Every rat at most comments 12 points.
Rat injection FCA after show as acute local inflammation within first 3 days, then gradually mitigate, i.e., acute inflammation alleviate
Phase (d7-d12), then because of delayed hypersensitivity, countermeasure and forelimb sufficient pawl swelling is shown as, inflammation tuberosity occur in ear, afterbody
And erythema.As shown in Figure 4, model group secondary parapodum swelling of d17, d21, d24 after inflammation is caused is compared with normal group and is dramatically increased
(P<0.01), the secondary parapodum swellings of d17 are compared with normal group and dramatically increase (P each administration group before administration<0.01), show to make
Mould success.Compared with model group, each therapeutic administratp group can significantly inhibit the sufficient pawl swelling (P of CIA rats in d21, d24<0.05 or
P<0.01).Additionally, the middle and high dosage group of the compound of suppression Transitional cell carcinomas is compared with GEP groups and ASP groups, rat paw edema
Degree substantially lowers, and has the difference of significance, prompting to suppress the antiphlogistic effects of the middle and high dosage group of the compound of Transitional cell carcinomas to be better than
GEP and ASP.
5.4 suppress the compounds for treating of Transitional cell carcinomas to be administered to CIA rat MLNs and FLST pathomorphology situations
Rat is put to death, metapedes inflammatory ankle joint tissue is taken and mesenteric lymph node is placed in 4% paraformaldehyde fixed, sufficient pawl
Tissue decalcification, dehydration, routine paraffin wax are embedded, section, and Histopathologic changes are observed in HE dyeing under an optical microscope.In optics
Basis of microscopic observation, the pathomorphism feature of MLNs is：Normal rat MLNs paracortical area does not substantially expand, lymph follicle compared with
Little, number is less, is dispersed in distribution, and macrophage is not substantially (Fig. 5-1)；CIA rat MLNs paracortical area substantially expands, in medullary substance
Inflammatory cell infiltration, lymph node are in specificity follicle hypertrophy (Fig. 5-2)；Suppress in the compound of Transitional cell carcinomas, high dose group
(70mg/kg, 140mg/kg) improves above pathological change to some extent, significantly reduces the paracortical area of expansion, medullary substance
Inflammatory cell infiltration and lymph foilicie hyperplasia are reduced, and number tails off (Fig. 5-3,5-4).
Observe under an optical microscope, normal rat knee joint synovial layer is made up of 1-3 layer synovial cells, the number of plies under synovial membrane
Amount reduces (Fig. 6-1)；CIA rat knee joints FLS cellular layers increase, it is seen that a large amount of inflammatory cell hypertrophy, synovial membrane lower floor cell number
Amount increases, and sees that loose connective tissue and a large amount of blood vessel hyperplasias, proliferation of fibrous tissue degree substantially increase (Fig. 6-2)；Suppress epoxy
Change in the compound of enzyme -2, high dose group (70mg/kg, 140mg/kg) improves above pathological change to some extent, makes FLS
Cellular layer minimizing, inflammatory cell minimizing, loose connective tissue and a large amount of blood vessel hyperplasias, proliferation of fibrous tissue degree substantially weaken
(Fig. 6-3,6-4).
Embodiment 6
Suppress the compound entirety of Transitional cell carcinomas that the proliferation activity to CIA P of Rats BL is administered
The dose-effect of the CIA P of Rats BL breeder reactions of 6.1 Con A inductions, time-effect relationship
96 orifice plates are taken, and 100 μ L PBL suspensions (final concentrations 1 × 10 of CIA rats are added per hole6/ mL) add 100 μ L to contain Con
A (5 μ g/mL of final concentration) and each concentration suppress the compound (2.5,5,10,20,40,80,160 μM of final concentration) of Transitional cell carcinomas
DMEM culture fluid, separately set single plus culture fluid group as matched group.Whole volume is 200 μ L, and each concentration sets 3 multiple holes, 37 DEG C,
5%CO2Incubator culture 24,36,48,60,72h, mtt assay detect absorbance, determine optimal dose-effect, timeliness.As a result, this experiment
Induced with variable concentrations (0.2,1,5,25,125 μ g/mL) interaction in vitro CIA-PBL different times (24,36,48,60,72h)
PBL breeds, and mtt assay detects cell proliferation level.As a result as shown in fig. 7, the suitable concentration of ConA induction PBL is 5 μ g/mL, most
48h between in good time.
6.2 suppress the compound entirety of Transitional cell carcinomas that the impact to CIA P of Rats BL multiplication capacities is administered
Take 96 orifice plates, arrange 8 groups altogether, per group of 6 holes, add per hole 100 μ L lymphocyte suspensions of CIA rats (final concentration 1 ×
106/mL), blank control group adds 100 μ L blank DMEM culture fluid；Model group adds the DMEM containing ConA (5 μ g/mL of final concentration)
Culture fluid；The compound group of Transitional cell carcinomas is suppressed to add 100 μ L respectively containing ConA (5 μ g/mL of final concentration) and suppress epoxidation
The DMEM culture fluid of the compound (2.5,5,10,20,40 μM of final concentration) of enzyme -2；200 μ L are to the whole volume of group, 37 DEG C, 5%
CO2Incubator culture 48h, mtt assay detect absorbance.As a result as shown in figure 8, compared with normal group, MODEL C IA rats in vitro is divided
Breed hyperfunction (p ＜ 0.01) from the PBL for extracting.Compared with model group, suppress compound administration group P of Rats BL of Transitional cell carcinomas
Growing ability reaction is in suppression trend, and has between suppression dependency, but each compound administration group for suppressing Transitional cell carcinomas not
See significant difference.The breeder reaction of positive drug group is also suppressed (P ＜ 0.01).
Embodiment 7
The compound entirety of Transitional cell carcinomas is suppressed to be administered in CIA rat blood serums, thymus and spleen lymphocyte culture
PGE in clear2The impact of level
After putting to death rat, the blood for taking out is stood 1h, 15min (3000r min are centrifuged-1, 4 DEG C) and serum is isolated, put
Standby in -80 DEG C of Refrigerator stores.The thymus and spleen of taking-up are placed in the PBS solution containing 5% calf serum and are washed, taken appropriate
Thymus and spleen tissue, are put in the DMEM solution containing 10% calf serum, make after filtration cell suspension (final concentration 1 ×
10-7mg·L-1).In 24 well culture plates, cell suspension 500 μ L (final concentration of 5mg L are added per hole-1).37 DEG C are put, 5%
CO2Culture 48h in incubator, 2000rpm low-temperature centrifugation 15min, the supernatant of absorption be placed in -80 DEG C of refrigerator freezings preserve standby
With.PGE is detected using ELASA methods2Level, with reference to test kit, concrete steps say that step is carried out.As shown in Figure 9, with just
Often rat is compared, the PGE of CIA rat cytokines2In serum, thymus T cells supernatant, splenic T lymphocyte supernatant
It is obvious unbalance that secretion is showed.Compared with CIA rat models, suppress Transitional cell carcinomas compound (35,70,140mg
kg-1) the obvious Imbalance of group energy, hence it is evident that suppress PGE2Secretion level.The compound of Transitional cell carcinomas is relatively suppressed respectively to be administered
Group is to PGE2Adjustment effect, find to suppress each administration group rat blood serum of compound of Transitional cell carcinomas, thymic lymphocytes and
The PGE of spleen lymphocyte2Contents level is into a kind of suppression of dosage accordance with tolerance, and suppresses the compound of Transitional cell carcinomas same
Etc. dosage group PGE2(70mg·kg-1) substantially mutually maintain an equal level with IB groups.
Embodiment 8
Suppress the Selective depression test of the compound of Transitional cell carcinomas
Application vitro enzyme reaction system is carried out using EIASA methods.With reference to kit specification, 96 hole elisa Plates set reagent
Blank control wells, S1-S8Reference substance (laboratory is made by oneself, and purity is up to more than 98%) hole, COX-1, COX-2 blank control wells, COX-
1st, COX-2100% enzymatic activitys hole, sample well etc., set two multiple holes per hole.950 μ L reaction buffer [0.1M are added in sample well
Tris-HCl (pH 8.0) EDTA containing 5mM and 2mM phenol], 10 μ L hemes, 10 μ L COX-1 or COX-2,20 μ L times
The 1b of the variable concentrations than diluting；100% enzymatic activity hole is removed and is not added with 1b, remaining same sample well；COX-1 or COX-2 blanks
Hole adds COX-1 the or COX-210 μ L of 970 μ L reaction buffers, 10 μ L hemes and inactivation.10 minute are incubated in advance in 37 DEG C of each hole
Afterwards, 37 DEG C after adding arachidonic acid (100 μm of ol/L) to mix, after water-bath 2 minutes, add 50 μ L1MHCl to terminate enzyme reaction and take
After going out, each pipe adds 100 μ L SnCl2Solution is mixed puts room temperature lucifuge 5 points of kinds of reaction.Standard control hole adds the difference of doubling dilution
The PGE of concentration2, prostate PGE is detected with EIASA methods2, with PGE2Growing amount calculate enzyme activity.Calculate 503nhibiting concentration
IC50And selectivity index, analyze its inhibition strength and selectivity to enzymatic activity.The results are shown in Table 4.
Table 4. suppresses the compound of Transitional cell carcinomas, IB and diclofenac (diclofenac) and COX-1, COX-2's
503nhibiting concentration IC50And selectivity index
As shown in Table 4, suppress IC of the compound of Transitional cell carcinomas to COX-1, COX-250Respectively 99 μM/L, 0.5 μM/
L, with certain inhibitory action.Relative to IB, the compound of Transitional cell carcinomas is suppressed not assume the difference of significance.Suppress
The compound of Transitional cell carcinomas is respectively 198 and 367 with the selectivity index of IB, and the selectivity much larger than diclofenac refers to
Number, has higher selectivity with COX-2.
Embodiment 9
Suppress the compound entirety of Transitional cell carcinomas that the impact to COX-2 protein levels in CIA P of Rats BL is administered
By PBL with 1 × 106/ ml is inoculated on 6 orifice plates, adds the 4%DMEM culture fluid containing ConA (5 μ g/ml of final concentration)
Culture 48h.Albumen is extracted, western bloting detect the expression of COX-2.As a result as shown in Figure 10：Normal group only may be used
A small amount of COX-2 is detected, is compared with Normal group, model group COX-2 level significantly raises (P ＜ 0.01)；Each administration concentration suppression
The chemical levels of Transitional cell carcinomas processed are low compared with model group, and (P ＜ 0.01,0.05) and between each group there is significant difference in P ＜；
And the effect of COX-2 horizontal down-regulations is in obvious dosage accordance with tolerance relation；Positive control drug IB groups also can significance reduction COX-2
Protein level (P ＜ 0.01), these results show to suppress the compound of Transitional cell carcinomas similar to the effect of IB, are given by overall
Medicine can suppress the expression of COX-2 albumen in CIA P of Rats BL.
It should be understood that example as herein described and embodiment are only for explanation, those skilled in the art can be made according to it
Various modifications or change, in the case of without departing from spirit of the invention, belong to protection scope of the present invention.
Claims (4)
1. the compound of Transitional cell carcinomas is suppressed, and its structural formula is as follows：
2. application of the compound for suppressing Transitional cell carcinomas as claimed in claim 1 in anti-inflammatory drug is prepared.
3. application of the compound for suppressing Transitional cell carcinomas as claimed in claim 2 in anti-inflammatory drug is prepared, its feature exist
In：The anti-inflammatory drug is anti-arthritic drugs.
4. as claimed in claim 1 suppress Transitional cell carcinomas compound preparation method, it is characterised in that including following step
Suddenly：
(1) genipin methylates the synthesis of intermediate a
The genipin of 1 weight portion is dissolved in the absolute methanol of 40 60 weight portions, boron trifluoride diethyl etherate is added after cooling, so
It is stirred reaction afterwards at room temperature, after reaction completely, adds saturation NaHCO3It is quenched, then with organic solvent to reaction
Liquid is extracted and is separated and collected organic faciess, finally to organic faciess anhydrous Na2SO4Process is dried, then is evaporated off organic molten
Agent, is obtained colourless oil liquid, obtains final product genipin and methylates intermediate a；
(2) suppress the synthesis of the compound of Transitional cell carcinomas
The genipin for taking 1 weight portion methylates intermediate a, adds triethylamine to adjust pH value to 89, is slowly added to 3 after cooling
The acetyl salicylic acyl chlorides of weight portion, is then reacted under condition of ice bath, adds saturation NaHCO after reaction completely3Quenched
Going out, organic faciess then being extracted and separated and collected with organic solvent to reactant liquor, silica gel column chromatography is carried out to organic faciess finally
Process, white solid is obtained, as suppresses the compound of Transitional cell carcinomas.
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| Title |
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| Genipin induces cyclooxygenase-2 expression via NADPH oxidase,MAPKs, AP-1, and NF-jB in RAW 264.7 cells;Tilak Khanal et al.;《Food and Chemical Toxicology》;20131201;第64卷;126-134 * |
| The different inhibitory effects of Huang-Lian-Jie-Du-Tang on cyclooxygenase 2 and 5-lipoxygenase;Li Li et al.;《Journal of Ethnopharmacology》;20120804;第143卷;732-739 * |
| 基于分子对接技术对栀子苷衍生物的虚拟设计;孙亮亮 等;《广东化工》;20141231;第41卷(第23期);12，13，30 * |
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