CN105175277B - A kind of inhibitor of 3 GAPD and its preparation method and application - Google Patents
A kind of inhibitor of 3 GAPD and its preparation method and application Download PDFInfo
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Abstract
The present invention provides inhibitor of 3 GAPDs and preparation method thereof and anti-cancer applications.The pharmacological evaluation of the present invention shows that such compound has stronger lethal effect, notable cancer cell specific induction of apoptosis to human colon cancer cell, gastric carcinoma cells, leukaemia.Further experiment shows that such compound is by suppressing 3 GAPDs in cancer cell glycolysis（GAPDH）, thus suppress ATP generation, and then kill cancer cell.
Description
Technical field
The present invention relates to a kind of inhibitor, a kind of inhibitor more particularly, to glyceraldehyde 3-phosphate dehydro-genase and its
Preparation method and application.
Background technology
Cancer has substituted angiocardiopathy to turn into the most disease of world's death toll, in recent decades, the medicine of cancer
Thing treatment achieve more significant progress, have developed some antineoplastics, effectively extend patient life cycle or
Improve the life quality of patient.But the drug resistance of tumour cell causes the drug therapy of cancer often to get half the result with twice the effort.Tumour is thin
Unrestricted the malignant proliferation ability and drug resistance of born of the same parents, which is depended in tumor tissues, has the Tumor Stem of special biological characteristics thin
Born of the same parents, and its presence is confirmed in the kinds of tumors such as breast cancer.In most of tumours, under aerobic conditions,
The activity of glycolysis is above normal cell, abbreviation Warburg effects (Science, 1956,124,269-270).3- phosphoric acid is sweet
Oily aldehyde dehydrogenase (GAPDH) is one of crucial catalyzing enzyme in glycolytic cycle, can be catalyzed the glyceraldehyde phosphate of substrate 3 and be converted into
1,3 diphospho glycerate acid.Therefore, the supply of tumour cell energy can theoretically be cut off by suppressing this enzymatic activity, and then be suppressed
Even kill tumour cell.GAPDH function is diversified, and it is not only involved in cellular energy metabolism, also take part in cell
Various activities, such as film merges and transports, DNA duplication suppresses the sugar of tumour cell with repairing etc., and using GAPDH as target spot
Metabolism, it is actually rare so as to cut off the research of its energy supply.Our team find that GAPDH is in colon in past research
Too high expression in cancer patient's sample, the bromo- Acetylformic acids of 3- can efficiently suppress GAPDH activity
(J.Bioenerg.Biomembr.2012,44,117–125).The current research of our team further discloses the bromo- 2- oxos of 3-
It is thin can effectively to kill the tumour cell side group with Tumor stem cell properties as glycolytic inhibitor for the compounds such as propionic acid
Born of the same parents, so as to improve antitumor curative effect (Cell Death Differ.2014,21,124-135).These results of study are for anti-swollen
The research and development of tumor medicine have extremely far-reaching influence.
The content of the invention
It is an object of the invention to provide a kind of new anticarcinogen, in order to realize this purpose, present invention firstly provides
A kind of inhibitor of glyceraldehyde 3-phosphate dehydro-genase, the structural formula of described inhibitor are as follows：
Described R2For H or Br, described M is O or N,
Described R1For C1-5 alkane, benzyl, benzyl, phenethyl, benzhydryl, adamantyl or hexamethylene.
Described R2Preferably Br.
Described M is preferably O.
When described M is preferably N, described R1Preferably two C1-5 alkane.
The structure of described inhibitor is preferably,
Further, there is provided a kind of preparation method of the inhibitor of above-mentioned glyceraldehyde 3-phosphate dehydro-genase, use are following
Reaction equation,
Described Bronsted acid is the concentrated sulfuric acid or perchloric acid；Solvent is tetrahydrofuran or dichloromethane；Solid particulate carrier is
Magnesium sulfate, sodium sulphate, aluminum oxide, zeolite molecular sieve or silica.
According to demand, there is provided application of the inhibitor of above-mentioned glyceraldehyde 3-phosphate dehydro-genase in cancer therapy drug is prepared.
It is an advantage of the current invention that
1. it is good to obtain compound anti-cancering activity.
2. the present invention is prepared using using the different alcohol of the sour proton catalysis of solid particle load with the bromo- Acetylformic acids of 3-
The bromo- Acetylformic acid esters of 3-.
Brief description of the drawings
Fig. 1 is suppression curve of the compound 4 to stomach cancer cell HGC27.
Fig. 2 is compound 1, the suppression curve of 3,4 pairs of glyceraldehyde 3-phosphate dehydro-genases (GAPDH).Seen by figure, three changes
Compound has obvious inhibitory action.
Embodiment
The present invention is further described with specific embodiment below in conjunction with the accompanying drawings.Unless stated otherwise, the present invention uses
Reagent, apparatus and method be the art routinely reagent, equipment and conventional use of method purchased in market.
The compound 1 of embodiment 1, the synthesis of the bromo- 2 oxopropanoic acid phenylethylesters of 3-
Toward magnesium sulfate (788mg, 6.55mmol) anhydrous methylene chloride (4mL) turbid solution in add the concentrated sulfuric acid (87 μ L,
1.64mmol), after half an hour being stirred at room temperature, be separately added into 3-BrPA (410mg, 2.46mmol) and benzyl carbinol (0.2mL,
1.64mmol).Reaction is carried out at room temperature, and reaction process is monitored with TLC and 1H-NMR.After reaction terminates, reaction solution dichloro
Methane dilutes, and is filtered under diminished pressure with diatomaceous funnel is covered with, and the brine It of filtrate saturation is to remove excessive 3- bromines third
Ketone acid, then with anhydrous sodium sulfate drying, finally remove solvent under reduced pressure, vacuum drying obtains 1, is orange liquid, yield is
95%.1H NMR(400MHz,CDCl3):δ 7.36-7.26 (m, 5H), 4.55 (t, J=7.2Hz, 2H), 4.30 (s, 2H), 3.10
(t, J=6.8Hz, 2H)；13C NMR(100MHz,CDCl3):δ184.4,159.2,136.6,128.9,128.7,127.0,
122.6,67.4,34.8,30.7.IR(KBr,cm-1):υ1741,1457,1240,1056；LC-MALD-TOF for
C11H11BrO3:271.073。
Embodiment 2, compound 2, the synthesis of the bromo- 2 oxopropanoic acid -1- phenylethyl -ester of 3-
2 are successfully prepared using the similarity condition of the synthesis bromo- 2 oxopropanoic acid phenylethylesters 1 of 3-, is green liquid, production
Rate is 93%.1HNMR(400MHz,CDCl3):δ 7.41-7.32 (m, 5H), 6.03 (q, J=6.4Hz, 1H), 4.30 (s, 2H),
1.68 (d, J=6.8Hz, 3H)；13C NMR(100MHz,CDCl3):δ184.6,158.7,139.8,128.7,128.6,
127.0,126.3,76.0,30.8,21.9；IR(KBr,cm-1):υ1733,1390,1274,1163,1053.
Embodiment 3, compound 3, the synthesis of the bromo- 2 oxopropanoic acid 3- pentyl esters of 3-
3 are successfully prepared using the similarity condition of the synthesis bromo- 2 oxopropanoic acid phenylethylesters 1 of 3-, is yellow liquid, production
Rate is 72%.1H NMR(400MHz,CDCl3):δ4.97-4.91(m,1H),4.29(s,2H),1.73-1.66(m,4H),
0.954-0.910(m,6H)；13C NMR(100MHz,CDCl3):δ185.1,159.5,80.9,30.7,26.3,9.5；IR
(KBr,cm-1):υ1736,1399,1265,671。
Embodiment 4, compound 4, the synthesis of the bromo- 2 oxopropanoic acid cyclohexyls of 3-
4 are successfully prepared using the similarity condition of the synthesis bromo- Acetylformic acid phenylethylesters 1 of 3-, is yellow liquid, production
Rate is 81%.1H NMR(400MHz,CDCl3)δ5.17-4.80(m,1H),4.30(s,1H),1.94-1.86(m,2H),1.80-
1.72(m,2H),1.64-1.51(m,4H),1.46-1.34(m,2H),13CNMR(100MHz,CDCl3):δ185.1,158.8,
76.4,31.2,30.9,25.1,23.5；IR(KBr,cm-1):υ2939,2861,1737,1263,1050；LC-MALD-TOF
for C9H13BrO3:249.978。
Embodiment 5, compound 5, the synthesis of the bromo- 2 oxopropanoic acid Buddha's warrior attendant alkyl esters of 3-
5 are successfully prepared using the similarity condition of the synthesis bromo- 2 oxopropanoic acid phenylethylesters 1 of 3-, is yellow liquid, production
Rate is 98%.1H NMR(400MHz,CDCl3):δ4.27(s,2H),2.20(s,9H),1.70-1.63(m,6H)；13C NMR
(100MHz,CDCl3):δ185.7,158.1,85.5,45.2,41.0,35.9,31.0；IR(KBr,cm-1):υ2915,2857,
1724,1455,1278,1162,1047；LC-MALD-TOF for C13H17BrO3:301.151。
Embodiment 6, compound 6, the synthesis of 3- bromo- N, N- diethyl -2- oxopropanamides
Under ice-water bath, toward pyruvic acid (662mg, 7.52mmol) dichloromethane solution (25mL) in plus HOBt (1.02g,
7.52mmol), EDCI (1.96g, 10.25mmol) and triethylamine (1.91mL, 13.67mmol), after stirring half an hour, two are added dropwise
Ethamine (0.704mL, 6.84mmol).Then, reaction solution is stirred at room temperature 18 hours.During reaction terminating, ethyl acetate is added
(50mL) dilutes and water (6mL).After two-phase laminated flow, aqueous phase is extracted with ethyl acetate (5mL × 3).Merge organic phase, by organic phase
With saturated common salt water washing (5mL × 1), anhydrous sodium sulfate drying, through silica gel column chromatography (petrol ether/ethyl acetate 6/1-4/1)
Isolated intermediate, light yellow oil (410mg, yield 42%).This intermediate (300mg, 2.1mmol) is dissolved in dichloro
In methane (5mL), bromine (0.13mL, 2.51mmol) dichloromethane solution (1mL) is slowly added dropwise, stirs 7h at room temperature.Instead
When should terminate, ethyl acetate (30mL) dilution is added, water (5mL), after separation, aqueous phase is extracted with ethyl acetate (5mL × 3), closes
And organic phase, by organic phase saturated common salt water washing (5mL × 1), anhydrous sodium sulfate drying, through silica gel column chromatography (oil
Ether/ethyl acetate 15/1-10/1) isolated 6 (122mg), it is yellow liquid, yield 27%.1HNMR(400MHz,
CDCl3) δ 4.26 (s, 2H), 3.45 (q, J=7.1Hz, 2H), 3.36 (q, J=7.1Hz, 2H), 1.25 (t, J=7.1Hz,
3H), 1.19 (t, J=7.1Hz, 3H)；13C NMR(100MHz,CDCl3)δ190.1,164.3,42.6,40.0,32.0,14.5,
12.6.
Embodiment 7, compound 7, the synthesis of the bromo- N- phenethyls 2- oxygen-hydrocinnamamides of 3-
7 are successfully prepared using the similarity condition of the synthesis bromo- oxygen -4- phenylbutanamides 6 of N- ethyls -2 of 3-.
1H NMR(400MHz,CDCl3) δ 7.33 (t, J=7.3Hz, 2H), 7.24 (d, J=7.5Hz, 1H), 7.19 (d, J
=7.3Hz, 2H), 6.95 (s, 1H), 4.49 (s, 2H), 3.60 (t, J=7.1Hz, 2H), 2.87 (t, J=7.1Hz, 2H)
Embodiment 8, compound 8, the synthesis of the bromo- phenylbutyric acid methyl esters of 2- oxygen -4 of 3-
Chloroacetic chloride (0.4mL, 5.61mmol) is slowly added dropwise under ice bath into absolute methanol solution (8mL), room temperature is stirred
1 hour is mixed to prepare anhydrous hydrogen chloride methanol solution.Freshly prepd anhydrous hydrogen chloride methanol solution is slowly added dropwise to 2- oxygen -4-
In methanol (2mL) solution of phenylbutyric acid (500mg, 2.81mmol), after being heated to reflux 3.5 hours, reaction solution is concentrated and dried,
Then dissolved with dichloromethane (5mL), sequentially add water (0.2mL), trifluoroacetic acid (2mL), will after being stirred at room temperature 2.5 hours
Reaction solution is concentrated and dried, and gained intermediate 2- epoxides -4-phenylbutyrate methyl esters, is light yellow oil (540mg, 100%).Will
This intermediate 2- epoxides -4-phenylbutyrate methyl esters (150mg, 0.78mmol) is dissolved in chloroform (1mL), and bromine is slowly added dropwise
The chloroformic solution (1mL) of (1.72mmol, 2.2equiv), is stirred at room temperature 24 hours.During reaction terminating, ethyl acetate is added
(30mL) dilutes, and water (5mL), after separation, aqueous phase is extracted with ethyl acetate (3mL × 3), merges organic phase, organic phase is used full
With brine It (3mL), anhydrous sodium sulfate drying, through Silica Gel Silica gel column chromatography (petrol ether/ethyl acetate 12/1-8/1) point
It is light yellow liquid from 8 (97mg) are obtained, yield 36%.1H NMR(400MHz,CDCl3)δ7.34-7.28(m,3H),
7.26-7.23(m,2H),5.30-5.25(m,1H),3.90(s,3H),3.57-3.51(m,1H),3.29-3.23(m,1H)；13C
NMR(100MHz,CDCl3)δ185.3,160.7,136.6,129.5,128.9,127.6,53.6,47.5,38.4；IR(KBr,
cm-1):υ2955,1735,1443,1261,1027.
Embodiment 9, compound 9,3, the synthesis of 3- bis- bromo- N, N- diethyl -2- oxygen propionamides
Using the reaction condition of the synthesis bromo- oxygen -4- phenylbutanamides 6 of N- ethyls -2 of 3-, while compound 9 is also obtain,
For yellow oil, separation yield is 25%.1H NMR(400MHz,CDCl3) δ 6.90 (s, 1H), 3.48 (q, J=7.2Hz
2H), 3.40 (q, J=7.2Hz, 2H), 1.30 (t, J=7.2Hz, 3H), 1.21 (t, J=7.2,3H)；13C NMR(100MHz,
CDCl3)δ182.0,162.4,42.9,42.3,40.3,14.4,12.4；IR(KBr,cm-1):υ1735,1643,1397,
1048；LC-Mass for C7H11Br2NO2[M+1]:301.1.
Embodiment 10, compound 10,3, the synthesis of 3 ,-two bromo- 2 oxopropanoic acid isopropyl esters
11 are successfully prepared using the similarity condition of the synthesis bromo- 2 oxopropanoic acid phenylethylesters 1 of 3-, is yellow liquid, production
Rate is 60%.1HNMR(400MHz,CDCl3):δ 6.64 (s, 1H), 5.35-5.08 (m, 1H), 1.36-1.34 (d, J=1.6Hz,
6H).13C NMR(100MHz,CDCl3)δ178.50,157.53,72.58,38.74,21.48；IR(KBr,cm-1):υ1651,
1399,1150,672。
Embodiment 11, compound 11,3, the synthesis of 3 ,-two bromo- 2 oxopropanoic acid tert-butyl esters
Toward magnesium sulfate (489.6mg, 4.07mmol) anhydrous methylene chloride (4mL) turbid solution in add the concentrated sulfuric acid (43 μ L,
0.81mmol), after half an hour being stirred at room temperature, be separately added into 3-BrPA (200mg, 0.81mmol) and the tert-butyl alcohol (0.3mL,
3.25mmol).Reaction is carried out at room temperature, and reaction process is monitored with TLC.After reaction terminates, reaction solution dichloromethane is dilute
Release, be filtered under diminished pressure with diatomaceous funnel is covered with, the brine It of filtrate saturation is to remove excessive 3,3- dibromoacetones
Acid, then with anhydrous sodium sulfate drying, finally remove solvent under reduced pressure, vacuum drying obtains compound 11, is yellow liquid, reaction
Yield is 42.3%.1HNMR(400MHz,CDCl3):δ6.64(s,1H),1.58(s,9H)。
Embodiment 12, compound 12,3, the synthesis of 3 ,-two bromo- 2 oxopropanoic acid cyclohexyls
Using synthesis 3,3, the similarity condition of-two bromo- 2 oxopropanoic acid tert-butyl esters is successfully prepared compound 12, is yellow
Liquid, reaction yield 61.8%.1H NMR(400MHz,CDCl3):δ7.40-7.33(m,10H),7.00(s,1H),4.33
(s,2H)。1H NMR(400MHz,CDCl3)δ6.65(s,1H),4.16(s,1H),1.99-1.86(m,3H),1.84-1.72(m,
3H),1.48-1.27(m,4H)。
Embodiment 13, compound 13,3, the synthesis of 3 ,-two bromo- 2 oxopropanoic acid 2- butyl esters
Using synthesis 3,3, the similarity condition of-two bromo- 2 oxopropanoic acid tert-butyl esters is successfully prepared compound 13, is yellow
Liquid, reaction yield 61.8%.1H NMR(400MHz,CDCl3) δ 6.66 (s, 1H), 5.07 (dd, J=12.6,6.3Hz,
1H), 1.80-1.70 (m, 2H), 1.36-1.34 (d, J=6.3Hz, 3H), 0.97-0.94 (t, J=9.2Hz, 3H)
Embodiment 14, compound 14,3, the synthesis of 3 ,-two bromo- 2 oxopropanoic acid benzhydryl esters
Using synthesis 3,3, the similarity condition of-two bromo- 2 oxopropanoic acid tert-butyl esters is successfully prepared compound 14, for white
Solid, reaction yield 40%.1HNMR(400MHz,CDCl3)δ7.56-7.21(m,10H),6.96(s,1H),5.95(s,
1H)。
Embodiment 15, compound 15,3, the synthesis of 3,-two bromo- 2 oxopropanoic acid -1- phenylethylesters
Using synthesis 3,3, the similarity condition of-two bromo- 2 oxopropanoic acid tert-butyl esters is successfully prepared compound 15, for white
Solid, reaction yield 56%.1HNMR(400MHz,CDCl3)δ7.38-7.24(m,4H),6.57(s,1H),6.03-5.95
(m, 1H), 1.63 (d, J=6.6Hz, 3H).
Embodiment 16, compound 16,3, the synthesis of 3 ,-two bromo- 2 oxopropanoic acid Buddha's warrior attendant alkyl esters
Using synthesis 3,3, the similarity condition of-two bromo- 2 oxopropanoic acid tert-butyl esters is successfully prepared compound 16, for white
Solid, reaction yield 52%.1H NMR(400MHz,CDCl3)δ5.85(s,1H),2.23-2.22(m,3H),2.18-2.17
(m,5H),1.69-1.68(m,5H),1.55(s,2H).
The effect of embodiment 17
By carrying out the cell experiment of 3 kinds of cancer cells, effect is counted, it is as follows.
Above table proves that compound effect provided by the invention is very good, and such compound is to human colon cancer cell, people
Stomach cancer cell, leukaemia have stronger lethal effect, notable cancer cell specific induction of apoptosis.
Claims (2)
- A kind of 1. application of inhibitor of glyceraldehyde 3-phosphate dehydro-genase in cancer therapy drug is prepared, it is characterised in that the 3- The inhibitor of GAPD is the application in resisting human gastric cancer medicine is prepared, and the structural formula of described inhibitor is as follows It is shown：
- 2. a kind of inhibitor of glyceraldehyde 3-phosphate dehydro-genase, it is characterised in that the structural formula of described inhibitor is as follows：
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