CN101812066A - Pyrazolo N-substituted dehydronorcantharidin imide derivative as well as synthesis method, activity test method and application thereof - Google Patents
Pyrazolo N-substituted dehydronorcantharidin imide derivative as well as synthesis method, activity test method and application thereof Download PDFInfo
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Abstract
The invention discloses a pyrazolo N-substituted dehydronorcantharidin imide derivative as well as a synthesis method, an activity test method and application thereof, belonging to the field of cantharidin derivatives. The pyrazolo N-substituted dehydronorcantharidin imide derivative has a structural general formula shown as a formula 1: in the formula 1, R1 is H, C1, F, CH3, OCH3, OH or NO2; and R2 is 2-phenyl-2H-1,2,3-triazole-4-substituent or quinoxaline-2-substituent. The novel N-substituted dehydronorcantharidin imide derivative introduces five-membered heterocyclic pyrazole rings into norcantharidin substituted arylamine and has favorable anti-tumor activity.
Description
Technical field:
The invention belongs to the cantharidin derivative field, more specifically relate to the plain imide derivative of a kind of novel pyrazolo N-substituted dehydronorcantharidiimide and synthetic method, activity test method and application.
Background technology:
Cantharidin (cantharidin) is China's Chinese medicine among the people, is the effective ingredient of treatment malignant tumor medicine.Modern study proves that it has certain curative effect to primary hepatocarcinoma, and leukocyte increasing is arranged, and does not suppress advantages such as immunity system, therefore, has very high medicinal researching value, causes people's extensive concern.But the toxicity of Cantharidin is bigger, synthetic very complicated, recently studies show that, lacked 2 in the Norcantharidin (norcantharidin), two methyl of 3, Norcantharidin has not only kept stronger anti-tumor activity and unique function of increasing leukocyte, and toxicity reduces greatly, has eliminated Cantharidin basically the urinary system telson is swashed side effect.
Therefore, relevant with a Cantharidin backbone modification synthetic work that is significant is to remove the prosposition methyl substituted.This structural modification can not influence antitumour activity and toxicity decreases, and, make synthesis step simplify.On the other hand, the activity research progress of cantharidin derivative shows that the structure activity relationship of Cantharidin is as follows: 1) dicyclo [2.2.1] heptane is the basic framework ring of Cantharidin, and the methyl of removing on 2-C or the 3-C can not influence its activity; 1-C or 4-C go up the introducing substituting group can make its active reduction, and the cantharidin derivative that has absolute steric configuration in the 1-C position has good inhibition selectivity to PP2B; Can introduce substituting group on 5-C or the 6-C, the introducing substituting group can influence the interaction to PP1 and PP2A on the contrary on 5-C or 6-C, strengthens the inhibition to PP2B simultaneously.Also can two keys between 5-C and the 6-C; 7-oxo bridge key is must be obligato, may be the cause that Sauerstoffatom energy and PP1 and PP2A form hydrogen bond; 2) on the anhydride rings anhydride moiety also principle can lose restraining effect to PP1 and PP2A.
Retrofit work to Cantharidin structure 5-C or 6-C is generally all just introduced substituting group, but the pharmacology test result is not ideal enough.
Summary of the invention:
The applicant finds that after deliberation the pyrazoles Hete rocyclic derivatives also has intensive physiology and pharmacologically active, and as antibiotic, effects such as spasmolytic anti-inflammatory coordinate plant growth and anti-platelet aggregation have important use in the production of medicine and agricultural chemicals.Just under this enlightenment, obviously improve or strengthen this feature of biological activity of compound in view of different activities heterocycle focusing energy in a part, and bioisostere principle, the applicant designs to synthesize in Norcantharidin substituted aromatic amines structure and carries out 1 on the two keys of 5-C and 6-C, 3[3+2] the dipole cycloaddition introduces five-membered ring pyrazoles ring, obtains the pyrazole derivatives of a series of N-of containing substituted dehydronorcantharidiimide imides.
Thus, main purpose of the present invention is to provide a kind of novel pyrazolo N-substituted dehydronorcantharidiimide plain imide derivative.
The technical scheme that the present invention takes is as follows, the plain imide derivative of a kind of pyrazolo N-substituted dehydronorcantharidiimide, its general structure as shown in Equation 1:
Formula 1
In the formula:
R
1Be H, Cl, F, CH
3, OCH
3, OH or NO
2
R
2Be 2-phenyl-2H-1,2,3-triazole-4-substituting group or quinoxaline-2-substituting group.
Secondary objective of the present invention provides the synthetic method of the plain imide derivative of a kind of above-mentioned pyrazolo N-substituted dehydronorcantharidiimide, may further comprise the steps:
(1), the dehydronorcantharidiimide element is synthetic: with the MALEIC ANHYDRIDE porphyrize, add ether, be stirred to dissolving under the room temperature condition, splash into furans, the Diels-Alder reaction takes place in stirring at room 24～48 hours, furans and MALEIC ANHYDRIDE, makes the dehydronorcantharidiimide element;
(2), the N-substituted dehydronorcantharidiimide imide is synthetic: the dehydronorcantharidiimide element is dissolved in the acetone solvent, under agitation drips the acetone soln of aniline, react and add manganese acetate, triethylamine and aceticanhydride, rising temperature for dissolving after 1 hour; Reacted 3～8 hours down at 50-60 ℃; The elimination insolubles, filtrate is freezing, pour in the mixture of ice and water, separate out solid, filter, filter cake washs with frozen water, recrystallizing methanol, vacuum-drying;
(3), the N-substituted dehydronorcantharidiimide imide C
5And C
6On two keys, the simple and easy method of using chloramine-T carries out 1,3[3+2] the dipole cycloaddition, introduce five-membered ring pyrazoles ring structure, obtain the pyrazolo N-substituted dehydronorcantharidiimide imide derivative.
The chemical equation of reaction is as follows:
Another aspect of the present invention also provides the activity test method of the plain imide derivative of a kind of above-mentioned pyrazolo N-substituted dehydronorcantharidiimide, may further comprise the steps:
(1), the A549 cell cultivated is centrifugal after with trysinization, with new substratum suspend again the back with liquid subpackage instrument mutidrop in each hole of 384 orifice plates with 300 A549 cells of 50ul volume plantation;
(2), with the A549 cell of step 1 at 37 ℃, 5%CO
2After cultivating 24h under the condition, stimulate with automatic fluid treatment system Bravo packing medicine, the concentration of treatment of all cpds has: 16uM 8uM 4uM 2uM 1uM 0.5uM 0.25uM 0.125uM, and every kind of processing has four repetitions;
(3), behind the A549 cell cultures 48h with step 2, detect with the activity of CCK-8 test kit pair cell: every hole adds 5ul CCK-8 solution, reads the absorption value of each hole wavelength at the 450nm place with microplate reader; In cell culture incubator, continue to hatch 100min, read the absorption value of wavelength once more with microplate reader at the 450nm place, the changing value of getting twice absorption value changes divided by the absorption value that does not add the compound treatment hole, gets every group of four multiple mean values and is hole inner cell activity.The inhibition efficient of compound pair cell=1-hole inner cell activity will input to http://bsmdb.tmd.ac.jp:3000/cbdb/ic50 according to the gradient of compound concentration and cytoactive, calculate finally to obtain IC50.
The present invention also provides the application of the plain imide derivative of a kind of above-mentioned pyrazolo N-substituted dehydronorcantharidiimide on synthesizing antineoplastic medicament.
The present invention compared with prior art has following beneficial effect:
This is the plain imide derivative of a kind of novel N-substituted dehydronorcantharidiimide, and it is introduced five-membered ring pyrazoles ring in the cantharidin substituted aromatic amines structure, and has good antineoplastic activity.
Further specify the present invention below in conjunction with specific embodiment, and only be used to illustrate the present invention, and be not construed as limiting the invention.
Embodiment
One, the preparation of the plain imide derivative of pyrazolo N-substituted dehydronorcantharidiimide
Embodiment 1: interior type-(3aR, 4S, 4aR, 7aS, 8S, 8aR)-6-(phenyl)-4,8-epoxy-1-phenyl-3-(2-phenyl-2H-1,2,3-triazole-4-substituting group)-4,4a, 6,7a, 8, the 8a-hexahydropyrrolo also [3,4-f] indazole also-5,7 (1H, 3aH)-diketone synthetic.
Step 1: dehydronorcantharidiimide element synthetic.
In the Erlenmeyer flask of 100mL, add and fully grind levigated 4.00g (40mmol) MALEIC ANHYDRIDE to the 15mL ether; After treating to dissolve fully, add 2.76g (40.5mmol) furans; Fully stir, room temperature was placed after 24-48 hour, and filtration under diminished pressure gets white crystals 5.51g, productive rate 83.0%, fusing point: 118-119 ℃.
Step 2:N-(4 '-phenyl)-7-oxabicyclo [2,2,1]-5-alkene-2,3-formyl imines synthetic.
Get the plain 3.20g of dehydronorcantharidiimide made in the step 1 (0.02mol) and be dissolved in 30mL acetone; Stir the acetone soln that will contain 1.86g (0.02mol) amino-benzene down and splash in the plain reaction flask of dehydronorcantharidiimide, exothermic heat of reaction also progressively has a large amount of precipitations to generate; Behind the room temperature reaction 1 hour, once add the 0.2g manganese acetate, 14mL triethylamine and 120mL aceticanhydride; After the intensification, precipitation is dissolving progressively, reacts 2-9 hour down at 50-60 ℃; Solution is clarified gradually, and the elimination insolubles is freezing with filtrate, pours in the 100mL mixture of ice and water, and the adularescent solid is separated out, and filters frozen water washing 2 times, recrystallizing methanol, vacuum-drying.Get product 3.32g, productive rate 68.8%.m.p.162-163℃；IR(KBr)v：3065，3020(ArH)；1775，1708(C＝O)；1627(C＝C)；1186(C-O-C)；714(＝C-H)cm-1。1H?NMR(DMSO-d6)δ：7.49(dd，J＝7.3，7.3Hz，2H，ArH)，7.42(dd，J＝7.3，7.3Hz，1H，ArH)，7.20(d，J＝7.3Hz，2H，ArH)，6.61(s，2H，C
5-H，C
6-H)，5.25(s，2H，C
1-H，C
4-H)，3.09(s，2H，C
2-H，C
3-H)。
Step 3: target end product synthetic.
Get step 2 made compound 0.24g (1mmol) and 2-phenyl-4-((2-phenylhydrazone) methyl)-2H-1,2,3-triazole 0.29g (1.1mmol) is dissolved in 20mL ethanol, adds 0.34g (1.2mmol) chloramine-T, reflux 3-8 hour, TLC followed the tracks of and determines whether reaction is complete.End product is cleaned with distilled water (30mL), uses dichloromethane extraction 2 times, each 15mL.Vacuum-drying.Recrystallizing methanol gets product 0.44g, productive rate 88.3%.M.p.278 ℃; IR (KBr) v:3473 (N-C=O), 3064 (ArH), 1714 (C=O), 1597 (C=N), 1189 (C-O-C) cm
-1 1H NMR (CDCl
3) δ: 8.53 (s, 1H, H-C=N), 8.20-6.93 (M, 15H, Ar-H), 5.51 (s, 1H, C
4-H) 5.34 (s, 1H, C
1-H) 4.65-4.62 (d, J=9.60Hz, 1H, C
5-H), 4.21-4.18 (d, J=9.60Hz, 1H, C
6-H), 3.41-3.39 (d, J=7.20Hz, 1H, C
3-H), 3.30-3.28 (d, J=7.20Hz, 1H, C
2-H) .ms (70ev): m/z 502 (M
+). ultimate analysis C
29H
22N
6O
3: C, 69.31; H, 4.41; N, 16.72.Found:C, 69.30; H, 4.43; N, 16.71.
Embodiment 2～12, and step is with embodiment 1, and difference is material choice, and is specifically as shown in table 1:
Table 1: the physicochemical data of novel pyrazoles cantharidin derivative
Two, the active testing of the plain imide derivative of pyrazolo N-substituted dehydronorcantharidiimide.
The experiment test object is as shown in table 1:
Table 1: experiment test object
Embodiment 1; Analyze these 15 kinds of compounds to the active influence of human lung adenocarcinoma cell A549 with cell counting kit-8.
(1) the A549 cell cultivated is centrifugal after with trysinization, with new substratum suspend again the back with liquid subpackage instrument mutidrop in each hole of 384 orifice plates with 300 A549 cells of 50ul volume plantation;
(2) at 37 ℃, 5%CO
2After cultivating 24h under the condition, stimulate with automatic fluid treatment system Bravo packing medicine, the concentration of treatment of all cpds has: 16uM 8uM4uM 2uM 1uM 0.5uM 0.25uM 0.125uM, and every kind of processing has four repetitions;
(3) behind the 48h, detect with the activity of CCK-8 test kit pair cell: every hole adds 5ul CCK-8 solution, reads the absorption value of each hole wavelength at the 450nm place with microplate reader; In cell culture incubator, continue to hatch 100min, read the absorption value of wavelength once more at the 450nm place with microplate reader.The changing value of getting twice absorption value changes divided by the absorption value that does not add the compound treatment hole, gets every group of four multiple mean values and is hole inner cell activity.The inhibition efficient of compound pair cell=1-hole inner cell activity will input to http://bsmdb.tmd.ac.jp:3000/cbdb/ic50 according to the gradient of compound concentration and cytoactive, calculate finally to obtain IC50.
Detected result is as shown in table 2; S3, S7 has certain inhibition effect to A549, and the growth of pair cell reaches 56% and 30% inhibition efficient under the concentration of 16uM, and the IC50 of S3 is 13.2uM, and the IC50 of S7 is 83.8uM; S15 has higher inhibition effect to A549, suppresses effect and reach 66% and 50% respectively when the concentration of 8uM and 16uM, and its IC50 is: 6.6uM.
Table 2: remaining cell viability behind the compound treatment cell 48h of different concns
| ? | ??S1 | ??S2 | ??S3 | ??S4 | ??S5 | ??S6 | ??S7 |
| ??16uM | ??0.814725 | ??0.821256 | ??0.444635 | ??1.03487 | ??1.135457 | ??1.071987 | ??0.700392 |
| ??8uM | ??1.014536 | ??1.008232 | ??0.821285 | ??1.049637 | ??1.0416 | ??0.929142 | ??0.938996 |
| ??4uM | ??0.983185 | ??1.06111 | ??0.952315 | ??0.928546 | ??1.10987 | ??1.086669 | ??0.901851 |
| ??2uM | ??0.843549 | ??0.898898 | ??0.992244 | ??1.031519 | ??1.067982 | ??1.097801 | ??1.047734 |
| ??1uM | ??1.135372 | ??1.098312 | ??1.028935 | ??0.986166 | ??1.016553 | ??1.069062 | ??1.0932 |
| ??0.5uM | ??0.995765 | ??0.932465 | ??1.058725 | ??0.994771 | ??1.087492 | ??1.03947 | ??0.989631 |
| ??0.25uM | ??1.060144 | ??0.849996 | ??0.995254 | ??1.121712 | ??0.915113 | ??0.961772 | ??1.009056 |
| ??0.125uM | ??0.942347 | ??0.908468 | ??0.862406 | ??0.983071 | ??0.994402 | ??0.936299 | ??0.908922 |
| ??S8 | ??S9 | ??S10 | ??S11 | ??S12 | ??S13 | ??S14 | ??S15 |
| ??1.093115 | ??0.858203 | ??1.134407 | ??0.974558 | ??0.790413 | ??0.80066 | ??1.006012 | ??0.338643 |
| ??1.133129 | ??1.032399 | ??1.014451 | ??0.964057 | ??1.127937 | ??0.996833 | ??0.843276 | ??0.503921 |
| ??1.036034 | ??1.074287 | ??0.962312 | ??0.927975 | ??1.054731 | ??1.028185 | ??0.842717 | ??0.927339 |
| ??0.94709 | ??1.05029 | ??1.025924 | ??0.820112 | ??1.128471 | ??0.90626 | ??1.033397 | ??0.939595 |
| ??1.033507 | ??1.006244 | ??1.033081 | ??0.950631 | ??1.019743 | ??1.147999 | ??1.008962 | ??1.16529 |
| ??1.097148 | ??1.044099 | ??1.082522 | ??0.911498 | ??0.92917 | ??1.046645 | ??0.949995 | ??1.15789 |
| ??1.049978 | ??0.969468 | ??0.948425 | ??0.870128 | ??0.897691 | ??1.136989 | ??1.114053 | ??0.954369 |
| ??0.89265 | ??0.938769 | ??0.953877 | ??0.870306 | ??0.845183 | ??0.86222 | ??0.846429 | ??0.624066 |
Embodiment 3: analyze these 15 kinds of compounds to the active influence of human lung adenocarcinoma cell A549 with cell counting kit-8.
Experimental procedure is identical with embodiment 1.
Experimental result is as shown in table 2: S3 has the obvious suppression effect to A549, is issued to 68% and 59% inhibition effect at 16uM and 8uM concentration.The IC50 of S3 is: 5.7uM; The IC50 of S7 is: 21.1uM; S15 has higher inhibition effect to A549, suppresses effect and reach 72% and 63% respectively when the concentration of 8uM and 16uM, and its IC50 is: 4.5uM.
Table 3: remaining cell viability behind the compound treatment cell 48h of different concns
| ? | ??S1 | ??S2 | ??S3 | ??S4 | ??S5 | ??S6 | ??S7 |
| ??16uM | ??0.784299 | ??0.740342 | ??0.329786 | ??0.869817 | ??0.790093 | ??1.032271 | ??0.769966 |
| ??8uM | ??0.574491 | ??0.930634 | ??0.412342 | ??0.826993 | ??0.77685 | ??1.23476 | ??0.982258 |
| ??4uM | ??0.528399 | ??0.844288 | ??0.938388 | ??1.150375 | ??1.227964 | ??1.015977 | ??1.02517 |
| ??2uM | ??0.755721 | ??0.840977 | ??1.073745 | ??1.067123 | ??1.248222 | ??1.152423 | ??0.989098 |
| ??1uM | ??0.859449 | ??0.89674 | ??1.227703 | ??1.070346 | ??1.19015 | ??1.240293 | ??1.254931 |
| ??0.5uM | ??0.87352 | ??1.212455 | ??1.006219 | ??1.02456 | ??1.316358 | ??1.039546 | ??1.298975 |
| ??0.25uM | ??0.747879 | ??1.023383 | ??0.829825 | ??1.048433 | ??0.938214 | ??1.140137 | ??1.187318 |
| ??0.125uM | ??0.778374 | ??0.855005 | ??0.960868 | ??0.940305 | ??1.151334 | ??1.118529 | ??0.939565 |
| ??S8 | ??S9 | ??S10 | ??S11 | ??S12 | ??S13 | ??S14 | ??S15 |
| ??1.021772 | ??0.827167 | ??0.870514 | ??1.138345 | ??0.914935 | ??0.800124 | ??0.816095 | ??0.283655 |
| ??1.098533 | ??0.950456 | ??0.891861 | ??0.910587 | ??1.226626 | ??0.926602 | ??1.163277 | ??0.375396 |
| ??1.238899 | ??0.92484 | ??0.956032 | ??0.940887 | ??1.073664 | ??1.013952 | ??0.936317 | ??0.84604 |
| ??1.156344 | ??1.075008 | ??1.043206 | ??1.107868 | ??0.881618 | ??1.147439 | ??1.035202 | ??1.22676 |
| ??1.197687 | ??1.102323 | ??0.950194 | ??0.882506 | ??1.058403 | ??1.07393 | ??1.185059 | ??1.142825 |
| ??1.044469 | ??1.021989 | ??1.086335 | ??1.170463 | ??1.384912 | ??1.036932 | ??1.128319 | ??1.179114 |
| ??0.991538 | ??0.957905 | ??0.916214 | ??1.078411 | ??1.228002 | ??0.966307 | ??1.065634 | ??1.200098 |
| ??1.069824 | ??1.091432 | ??1.082893 | ??1.022514 | ??0.906728 | ??0.803496 | ??0.915644 | ??1.188075 |
Claims (4)
1. the plain imide derivative of a pyrazolo N-substituted dehydronorcantharidiimide, its general structure be as shown in Equation 1:
In the formula:
R
1Be H, Cl, F, CH
3, OCH
3, OH or NO
2
R
2Be 2-phenyl-2H-1,2,3-triazole-4-substituting group or quinoxaline-2-substituting group.
2. the synthetic method of the plain imide derivative of the described pyrazolo N-substituted dehydronorcantharidiimide of a claim 1 may further comprise the steps:
(1), the dehydronorcantharidiimide element is synthetic: with the MALEIC ANHYDRIDE porphyrize, add ether, be stirred to dissolving under the room temperature condition, splash into furans, the Diels-Alder reaction takes place in stirring at room 24～48 hours, furans and MALEIC ANHYDRIDE, makes the dehydronorcantharidiimide element;
(2), the N-substituted dehydronorcantharidiimide imide is synthetic: the dehydronorcantharidiimide element is dissolved in the acetone solvent, under agitation drips the acetone soln of aniline, react and add manganese acetate, triethylamine and aceticanhydride, rising temperature for dissolving after 1 hour; Reacted 3～8 hours down at 50-60 ℃; The elimination insolubles, filtrate is freezing, pour in the mixture of ice and water, separate out solid, filter, filter cake washs with frozen water, recrystallizing methanol, vacuum-drying;
(3), the N-substituted dehydronorcantharidiimide imide C
5And C
6On two keys, the simple and easy method of using chloramine-T carries out 1,3[3+2] the dipole cycloaddition, introduce five-membered ring pyrazoles ring structure, obtain the pyrazolo N-substituted dehydronorcantharidiimide imide derivative.
3. the activity test method of the plain imide derivative of the described pyrazolo N-substituted dehydronorcantharidiimide of a claim 1 may further comprise the steps:
(1), the A549 cell cultivated is centrifugal after with trysinization, with new substratum suspend again the back with liquid subpackage instrument mutidrop in each hole of 384 orifice plates with 300 A549 cells of 50ul volume plantation;
(2), with the A549 cell of step 1 at 37 ℃, 5%CO
2After cultivating 24h under the condition, stimulate with automatic fluid treatment system Bravo packing medicine, the concentration of treatment of all cpds has; 16uM 8uM 4uM 2uM 1uM 0.5uM 0.25uM 0.125uM, every kind of processing has four repetitions;
(3), behind the A549 cell cultures 48h with step 2, detect with the activity of CCK-8 test kit pair cell: every hole adds 5ul CCK-8 solution, reads the absorption value of each hole wavelength at the 450nm place with microplate reader; In cell culture incubator, continue to hatch 100min, read the absorption value of wavelength once more with microplate reader at the 450nm place, the changing value of getting twice absorption value changes divided by the absorption value that does not add the compound treatment hole, gets every group of four multiple mean values and is hole inner cell activity.The inhibition efficient of compound pair cell=1-hole inner cell activity will input to http://bsmdb.tmd.ac.jp:3000/cbdb/ic50 according to the gradient of compound concentration and cytoactive, calculate finally to obtain IC50.
4. the application of the plain imide derivative of the described pyrazolo N-substituted dehydronorcantharidiimide of claim 1～2 on synthesizing antineoplastic medicament.
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