CN106977425B - Hydroxamic acid derivs and the preparation method and application thereof with dnmt rna and histon deacetylase (HDAC) inhibitory activity - Google Patents
Hydroxamic acid derivs and the preparation method and application thereof with dnmt rna and histon deacetylase (HDAC) inhibitory activity Download PDFInfo
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- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
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- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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Abstract
The present invention relates to a kind of hydroxamic acid derivs and the preparation method and application thereof with dnmt rna and histon deacetylase (HDAC) inhibitory activity; a kind of hydroxamic acid derivs or its pharmaceutically acceptable salt, hydroxamic acid derivs structural formula is as shown in formula I:Wherein, Ar is aromatic group, the aromatic group is selected from replace or non-substituted phenyl ring, replace or non-substituted aromatic heterocycle, replace or non-substituted benzheterocycle；Aromatic heterocycle replace or non-substituted and heterocycle；N=1,2,3,4,5 or 6；L1Link position be phenyl ring ortho position, meta or para position；L1For saturation or unsaturated carbon chains.
Description
Technical field
The invention belongs to field of medicaments, and in particular to there is one kind dnmt rna and histon deacetylase (HDAC) to press down
Make active hydroxamic acid derivs and the preparation method and application thereof.
Background technique
Cancer is to cause first cause of disease of human death now, and the anti-tumor drug for researching and developing high-efficiency low-toxicity is extremely urgent.It is swollen
The occurrence and development of tumor were both closely related with gene unconventionality, also had close relationship with epigenetic change.With gene unconventionality
(amplification, transposition, deletion and the point mutation of such as oncogene or tumor suppressor gene) is different, and the change of epigenetic is not related to DNA sequence dna
Variation, the hereditary information of parent can be kept in cell division, but can take a turn for the worse under certain condition, make malignant cell group
Body is changed into normal cell.Therefore the enzyme that regulating and controlling effect is played in epigenetic is considered as new the one of anti-tumor drug research and development
For target spot.
Dnmt rna (DNA methyltransferases, DNMTs) and histon deacetylase (HDAC) (Histone
Deacetylases, HDACs) distinguish the methylation of catalytic dna and the deacetylation of histone, it is the important regulating and controlling of epigenetic
Mode.DNMTs and HDACs high expression energy silencing tumor suppressor gene in cell, promotes the occurrence and development of tumour.Largely
DNMTs inhibitor and HDACs inhibitor are developed to treat tumour, and some DNMTs inhibitor and HDACs inhibitor are facing
Good antitumous effect is shown in bed, there are two DNMTs inhibitor (azacitidine, Decitabine) and five at present
HDACs inhibitor (Vorinostat, Romidepsin, Belinostat, Panobinostat, Chidamide) listing.
DNA methylation, DNA methylase inhibitor and chromatin remodeling have closely connection in physiological function, together shadow
Ring the expression of tumor suppressor gene.DNMTs and HDACs can also be influenced each other by direct or indirect mode.On the one hand, research is found
When the inhibitor of DNMTs or HDACs is applied alone, the high expression of another enzyme may still lead to the silencing of tumour tumor suppressor gene, such
Compensatory mechanism makes tumour cell generate drug resistance, reduces therapeutic effect.On the other hand, clinical research shows low dosage
DNMT inhibitor and hdac inhibitor drug combination have apparent synergistic effect.Therefore the suppression of DNMTs and HDACs are targeted simultaneously
Preparation can may more effectively be such that the tumor suppressor gene of silencing expresses again, and tumour cell is made to be more difficult to generate drug resistance, but mesh
The report of preceding this respect not yet.
Summary of the invention
An object of the present invention is to provide a kind of hydroxamic acid multiple target point with DNMTs and HDACs inhibitory activity
Inhibitor and preparation method thereof.
Hydroxamic acid multiple target point inhibitor provided by the present invention, structural formula is as shown in formula I.
In above-mentioned Formulas I, Ar is aromatic group, the aromatic group is selected from replace or non-substituted phenyl ring, replace or
Non-substituted aromatic heterocycle, replace or non-substituted benzheterocycle, replace or non-substituted aromatic heterocycle and heterocycle；
Preferably, the heteroaromatic is selected from 4 yuan, 5 yuan, 6 yuan or 7 yuan heteroaromatics, includes 1,2 or 3 hetero atom on heterocycle,
Hetero atom is independently selected from N, S, O；
The heteroaromatic is selected from pyridyl group, pyridinyl-N-oxide, pyrimidine radicals, pyridazinyl, furyl, thienyl, thiazole
Base, imidazole radicals, pyranose, pyrroles；
The benzheterocycle is selected from quinoline, isoquinolyl, purine radicals, indyl, benzimidazole, pyrrolopyridine, dihydro
Benzo dioxin, benzodioxole；
Substituent group on aromatic group is 1-5, preferably 1,2,3,4 or 5；Substituent group be selected from C1-C6 alkyl,
The alkenyl of C1-C6, the alkynyl of C1-C6, hydroxyl, nitro, methoxyl group, trifluoromethyl, trifluoromethoxy, amino, acrylamido,
Cyano, fluorine-based, chloro, bromo, iodo；
Preferably, the aromatic group is selected from
N=1,2,3,4,5 or 6；
L1Link position be phenyl ring ortho position, meta or para position；L1For carbon key or alkyl chain, including but not limited to methylene
Base, ethylene group, vinyl, acetenyl.
Compound pharmaceutically acceptable salt shown in above-mentioned Formulas I also belongs to protection scope of the present invention.
Wherein, the pharmaceutically acceptable salt is inorganic acid salt or acylate.
The inorganic acid salt is selected from the salt that any one following inorganic acid are formed: hydrochloric acid, sulfuric acid or phosphoric acid.
The acylate is selected from the salt that any one following organic acid are formed: acetic acid, trifluoroacetic acid, malonic acid, lemon
Acid and p-methyl benzenesulfonic acid.
Hydroxamic acid derivs shown in above-mentioned Formulas I be preferably it is following any one:
Hydroxamic acid compound shown in above-mentioned Formulas I is prepared by the method comprising the following steps；
1) under condensing agent effect, Formula II compound represented is reacted to obtain formula with formula III compound represented
IV compound represented；Or Formula II compound represented is prepared into corresponding acyl with thionyl chloride, oxalyl chloride or phosphorus oxychloride
It is reacted to obtain formula IV compound represented with formula III compound represented after chlorine derivative；
Ar, n or L in Formula II, III or IV1Ar, n or L corresponding with Formulas I1Definition it is identical；
In formula III, R is the alkyl of C1-C4.
2) compound shown in formula IV is reacted in alkaline solution with azanol or hydroxylamine hydrochloride, obtains compound shown in Formulas I.
In above method step 1), the condensing agent is selected from following at least one: benzotriazole-N, N, N', N'- tetramethyl
Base urea hexafluorophosphoric acid ester N, N'- carbonyl dimidazoles, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3- dimethylamino
Propyl) -3- ethyl carbodiimide etc..
The reaction of the step 1) carries out in organic solvent, and the organic solvent is selected from dimethylformamide, dimethyl
One of acetamide, chloroform, methylene chloride, acetone, tetrahydrofuran, acetonitrile etc. are a variety of.
Step 1) the condensing agent and Formula II compound represented, the molar ratio of formula III compound represented can be successively
For 1-4:1-2:1-4, concretely 1.5:1:1.1.
The reaction temperature of the reaction of the step 1) is 20-80 DEG C, and the reaction time is 3-12 hours.
In above method step 2), the alkali is selected from ammonium hydroxide, triethylamine, diisopropyl ethyl amine, sodium hydroxide, hydroxide
One of potassium, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide etc. are a variety of.
The reaction of the step 2) carries out in aqueous solution or organic solvent, and organic solvent is selected from dimethylformamide, chlorine
One of imitative, methylene chloride, methanol, ethyl alcohol, acetone, tetrahydrofuran, acetonitrile etc. are a variety of.
The molar ratio that compound shown in formula IV is reacted with azanol or hydroxylamine hydrochloride, alkali is 1:1-10:1-20, concretely 1:
5:5。
The reaction temperature of the step 2) reaction is 20-80 DEG C, and the reaction time is 0.5-10 hours；
Compound prepared by the present invention passes through high resolution mass spectrum, nuclear magnetic resonance, the test such as fusing point, it was demonstrated that prepared chemical combination
Object is correct, is compound shown in general formula I.
It is also another object of the present invention to provide the applications of compound shown in formula I and its pharmaceutically acceptable salt.
The purposes of compound shown in formula I or its pharmaceutically acceptable salt is its application in the following aspects:
1) application in dnmt rna and/or histon deacetylase (HDAC) inhibitor is being prepared；
2) application in preparation eucaryote tumor cell proliferation inhibitor；
3) application in preparation prevention and/or tumor.
The dnmt rna (DNMTs) include in mammalian cells known hypotype (DNMT1, DNMT3A,
DNMT3B)；The histon deacetylase (HDAC) (HDACs) includes known hypotype in mammalian cells, mainly include but
It is not limited to HDAC1, HDAC2, HDAC3, HDAC8, HDAC4, HDAC5, HDAC7, HDAC9, HDAC6, HDAC10, HDAC11.
The eucaryote is mammal；The tumour cell is cancer cell；The cancer cell be leukaemia cancer cell,
Breast cancer cell, liver cancer cells, pancreatic cancer cell, lung carcinoma cell, brain cancer cell, ovarian cancer cell, uterine cancer cells, carcinoma of testis
Cell, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, bladder cancer cell or rectum cancer cell；Preferably
For the chronic marrow original leukaemia cell of people and human tissue cell's lymphoma cell.
The leukaemia cancer cell is specially human chronic myelogenous leukemia (CML) cell line k562, and the lymthoma is thin
Born of the same parents are specially human tissue cell lymphoma cell U937, and the lung carcinoma cell is specially human lung carcinoma cell NCI-H520, the people
Brain glioblastoma cell is specially U251, and the black cancer cell is specially A375, and the glioblastoma cells are specially
People's glioblastoma cells A172 and human brain astrocytes blastoma cell U-118MG, the cervical cancer cell are specially
Human cervical cancer cell lines Hela, the nasopharyngeal carcinoma cell are specially human nasopharyngeal epithelioma 1 CNE-2, and the liver cancer cells are specifically people
Hepatoma H22 cells, the breast cancer cell are specially human breast cancer cell line Bcap-37 and MDA-MB-231.
The tumour is cancer；The cancer be leukaemia, lymthoma, lung cancer, black cancer, glioblastoma, cervical carcinoma,
Nasopharyngeal carcinoma, liver cancer, breast cancer, the cancer of the brain, cancer of pancreas, oophoroma, uterine cancer, carcinoma of testis, cutaneum carcinoma, gastric cancer, colon cancer, bladder cancer
Or the carcinoma of the rectum.
Compound shown in formula I or its pharmaceutically acceptable salt can also be used for preparation prevention and/or treatment tumour
Drug.
The prevention and/or treatment prepared using I compound represented of formula or its pharmaceutically acceptable salt as effective component is swollen
The drug of tumor, also belongs to protection scope of the present invention.
The dnmt rna and/or histone of the compound shown in formula I or the preparation of its pharmaceutically acceptable salt go second
Deacerylase inhibitors, eucaryote tumor cell proliferation inhibitor and prevention and/or treat tumour drug can by injection,
Injection, collunarium, eye drip, infiltration, absorption, the method physically or chemically mediated import body such as muscle, intradermal, subcutaneous, vein, glue
Membrane tissue；Or body is imported after other material mixings or package.
When needs, one or more pharmaceutically acceptable carriers can also be added in said medicine.The load
Body includes diluent, excipient, filler, adhesive, wetting agent, disintegrating agent, the sorbefacient, surface of pharmaceutical field routine
Activating agent, absorption carrier, lubricant etc..
The prevention and/or tumor of the compound shown in formula I or the preparation of its pharmaceutically acceptable salt can make
At diversified forms such as injection, tablet, pulvis, granule, capsule, oral solution, paste, cremes.The drug of above-mentioned various dosage forms
It can be prepared according to the conventional method of pharmaceutical field.
Compound provided by the invention is by kinds of tumor cells system test (including leukaemia cell, lymphoma cell etc.)
And dnmt rna, histon deacetylase (HDAC) inhibitory activity test, it was demonstrated that compound shown in formula I is a kind of potential
There is the anti-tumor drug of inhibitory activity to dnmt rna and histon deacetylase (HDAC).Compound provided by the invention is former
Material is easy to get, and preparation method is simple, experiments have shown that it has good anticancer effect, has in anti-tumor drug design research and development field good
Good application prospect.
Specific embodiment
The present invention will be described below by way of specific embodiments, but it's not limited to that for the scope of the present invention.
Experimental method described in following embodiments is unless otherwise specified the conventional method of organic synthesis；The reagent
And biomaterial obtains from commercial channels unless otherwise specified.
Embodiment 1
The chloro- N- of 5- (4- (3- (azanol base) -3- propionyl) phenethyl) -2- methoxy benzamide (compound 1)
Embodiment 1a
Tert-butyl (4- bromophenylethyl) carbamate
4- Bretylium Tosylate (10g, 50mmol) is dissolved in 250 milliliters of methylene chloride, addition di-tert-butyl dicarbonate (12g,
55mmol), it stirs 3 hours at room temperature, successively with saturated aqueous ammonium chloride, saturated sodium bicarbonate aqueous solution, water, saturated common salt
Water washing reaction solution, organic phase are spin-dried for obtaining crude product after anhydrous magnesium sulfate is dry.Crystallization obtains title compound (white in ether
Solid, 14.70g, 98% yield).1HNMR (400MHz, Chloroform-d) δ 7.42 (d, J=8.4Hz, 2H), 7.07 (d, J
=8.3Hz, 2H), 4.51 (s, 1H), 3.35 (br, 2H), 2.75 (t, J=7.0Hz, 2H), 1.43 (s, 9H)
Embodiment 1b
(E) -3- (4- (2- ((tertbutyloxycarbonyl) amino) ethyl) phenyl) methyl acrylate
By embodiment 1a (3.0g, 10mmol), Anhydrous potassium carbonate (2.764g, 20mmol), two triphenylphosphine two of catalytic amount
Palladium chloride is placed in 50ml round-bottomed flask, and dimethylformamide (DMF) 30ml is added, and deaeration in condenser is simultaneously added after being replaced with nitrogen
Methyl acrylate (1.8ml, 20mmol).Overnight in 120~130 DEG C of reactions.Water is added after reaction and is extracted with ethyl acetate
It takes.Organic phase is spin-dried for after anhydrous magnesium sulfate is dry, and obtained after being washed with deionized water title compound (white solid,
2.53g, 83% yield).1H NMR (400MHz, Chloroform-d) δ 7.68 (d, J=16.0Hz, 1H), 7.47 (d, J=
7.8Hz, 2H), 7.22 (d, J=7.8Hz, 2H), 6.42 (d, J=16.1Hz, 1H), 4.59 (s, 1H), 3.81 (s, 3H),
3.43-3.31 (m, 2H), 2.82 (t, J=7.0Hz, 2H), 1.34 (s, 9H)
Embodiment 1c
3- (4- (2- ((tertbutyloxycarbonyl) amino) ethyl) phenyl) methyl propionate
Embodiment 1b (3.05g, 10mmol) is dissolved in 200ml methanol, the palladium carbon of 10% mass fraction of 300mg is added,
Flow back in autoclave 3h under the hydrogen of 2 atmospheric pressure.It filters later, rotation is (white except title compound is obtained after filtrate
Color solid, 3.00g, 98% yield).1H NMR(400MHz,Chloroform-d)δ7.24–6.96(m,4H),4.54(s,
1H), 3.67 (s, 3H), 3.36 (d, J=6.3Hz, 2H), 2.93 (t, J=7.8Hz, 2H), 2.76 (t, J=7.0Hz, 2H),
2.70–2.55(m,2H),1.43(s,9H).
Embodiment 1d
3- (4- (2- aminoethyl) phenyl) methyl propionate
Embodiment 1c (2.54g, 8.28mmol) is dissolved in methylene chloride (40ml), trifluoroacetic acid is added dropwise under ice bath
(12ml, 165mmol), reacts at room temperature 3h later.Liquid is removed with Rotary Evaporators rotation, sodium bicarbonate aqueous solution is added and with acetic acid
Ethyl ester extraction.Organic phase removes ethyl acetate after being dried over anhydrous sodium sulfate, crude product is recrystallized to give title compound in ether
Object (faint yellow solid, 1.42g, 83% yield).1H NMR(400MHz,Chloroform-d)δ7.16–7.08(m,4H),
3.67 (s, 3H), 2.99-2.88 (m, 4H), 2.72 (t, J=6.9Hz, 2H), 2.64-2.60 (m, 2H)
Embodiment 1e
3- (4- (2- (the chloro- 2- methoxy benzamide base of 5-) ethyl) phenyl) methyl propionate
By embodiment 1d (621mg, 3mmol), the chloro- benzoic acid of 2- methoxyl group -5- (839mg, 4.5mmol), condensing agent
HBTU (2.56g, 6.75mmol) and DMAP (73mg, 0.6mmol) are dissolved in DMF, and room temperature reaction is overnight.Silicon after reaction
Rubber column gel column chromatographic isolation obtains title compound (white solid, 844mg, 75% yield).1H NMR(400MHz,Chloroform-d)
δ 8.17 (d, J=2.8Hz, 1H), 7.81 (s, 1H), 7.36 (dd, J=8.8,2.8Hz, 1H), 7.18 (s, 4H), 6.85 (d, J
=8.8Hz, 1H), 3.75 (s, 3H), 3.72 (t, J=6.8Hz, 3H), 3.67 (s, 3H), 2.95 (t, J=7.8Hz, 2H),
2.89 (t, J=6.8Hz, 2H), 2.63 (t, J=7.8Hz, 2H)；13C NMR(101MHz,CDCl3)δ172.71,163.27,
155.35,138.12,136.56,131.60,131.40,128.46,127.91,126.15,122.42,112.19,55.49,
51.06,40.34,35.11,34.54,29.94.
Embodiment 1f
The chloro- N- of 5- (4- (3- (azanol base) -3- propionyl) phenethyl) -2- methoxy benzamide
Embodiment 1e (100mg, 0.26mmol) is added in methanol (2ml), be subsequently added into hydroxylamine hydrochloride (180mg,
2.6mmol) with sodium tert-butoxide (375mg, 3.9mmol), reaction is stayed overnight at room temperature.Reaction dissolvent and column color are removed after reaction
Spectrum separates to obtain title compound (faint yellow solid, 31mg, 32% yield).170~172 DEG C of fusing point,1H NMR(400MHz,
DMSO-d6) δ 10.36 (s, 1H), 8.70 (s, 1H), 8.23 (t, J=5.6Hz, 1H), 7.66 (d, J=2.8Hz, 1H), 7.50
(dd, J=8.9,2.8Hz, 1H), 7.20-7.11 (m, 5H), 3.81 (s, 3H), 3.48 (q, J=6.8Hz, 2H), 2.78 (t, J
=7.5Hz, 4H), 2.25 (t, J=7.7Hz, 2H)；13C NMR(101MHz,DMSO)δ168.15,163.33,155.63,
138.77,136.79,131.42,129.48,128.51,128.14,124.61,124.24,114.09,56.18,40.67,
34.40,33.76,30.36.HRMS (ESI) m/z calculated value [M-H] -375.1112, measured value 375.1122.
Embodiment 2
(E) the chloro- N- of -5- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -2- methoxy benzamide
(compound 2)
Embodiment 2a
(E) -3- (4- (2- aminoethyl) phenyl) methyl acrylate
Embodiment 1b (2.53g, 8.28mmol) is dissolved in methylene chloride (40ml), trifluoroacetic acid is added dropwise under ice bath
(12ml, 165mmol), reacts at room temperature 3h later.Liquid is removed with Rotary Evaporators rotation, sodium bicarbonate aqueous solution is added and with acetic acid
Ethyl ester extraction.Organic phase removes ethyl acetate after being dried over anhydrous sodium sulfate, crude product is recrystallized to give title compound in ether
Object (faint yellow solid, 1.15g, 67% yield).1H NMR(400MHz,DMSO-d6)δ7.75(br,2H),7.74–7.60(m,
3H), 7.32 (d, J=8.0Hz, 2H), 6.64 (d, J=16.0Hz, 1H), 3.73 (s, 3H), 3.06 (t, J=7.8Hz, 1H),
2.88 (t, J=7.9Hz, 2H)；13C NMR(101MHz,DMSO)δ166.57,144.11,139.98,132.49,129.19,
128.52,117.37,51.34,33.12,33.05.
Embodiment 2b
(E) -3- (4- (2- (the chloro- 2- methoxy benzamide of 5-) ethyl) phenyl) methyl acrylate
By embodiment 2a (615mg, 3mmol), the chloro- benzoic acid of 2- methoxyl group -5- (839mg, 4.5mmol), condensing agent
HBTU (2.56g, 6.75mmol) and DMAP (73mg, 0.6mmol) are dissolved in DMF, and room temperature reaction is overnight.Silicon after reaction
Rubber column gel column chromatographic isolation obtains title compound (white solid, 908mg, 81% yield).1H NMR(400MHz,DMSO-d6)δ8.26
(t, J=5.6Hz, 1H), 7.73-7.57 (m, 4H), 7.50 (dd, J=8.8,2.8Hz, 1H), 7.32 (d, J=8.0Hz, 2H),
7.15 (d, J=8.9Hz, 1H), 6.62 (d, J=16.1Hz, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.52 (dt, J=
5.6,7.1Hz, 2H), 2.87 (t, J=7.1Hz, 2H)；13C NMR(101MHz,DMSO)δ166.62,163.44,155.61,
144.31,142.20,131.96,131.37,129.43,129.22,128.32,124.73,124.24,117.01,114.08,
56.17,51.29,40.29,34.65.
Embodiment 2c
(E) the chloro- N- of -5- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -2- methoxy benzamide
Embodiment 1e (100mg, 0.27mmol) is added in methanol (2ml), be subsequently added into hydroxylamine hydrochloride (180mg,
2.6mmol) with sodium tert-butoxide (375mg, 3.9mmol), reaction is stayed overnight at room temperature.Reaction dissolvent and column color are removed after reaction
Spectrum separates to obtain title compound (faint yellow solid, 37mg, 37% yield).158~160 DEG C of fusing point,1H NMR(400MHz,
DMSO-d6) δ 10.74 (s, 1H), 9.04 (s, 1H), 8.26 (t, J=5.6Hz, 1H), 7.63 (d, J=2.8Hz, 1H), 7.56-
7.48 (m, 3H), 7.44 (d, J=15.7Hz, 1H), 7.30 (d, J=7.8Hz, 2H), 7.15 (d, J=8.9Hz, 1H), 6.43
(d, J=15.8Hz, 1H), 3.82 (s, 3H), 3.51 (q, J=6.7Hz, 2H), 2.85 (t, J=7.1Hz, 2H)；13C NMR
(101MHz,DMSO)δ163.43,155.62,140.93,132.82,131.37,129.44,129.19,127.41,124.77,
124.26,118.37,114.11,56.18,40.36,34.61.HRMS (ESI) m/z calculated value [M+H]+375.1112, actual measurement
Value 375.1122.
Embodiment 3
(E) the chloro- N- of -5- (3- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -2- methoxy benzamide
(compound 3)
Embodiment 3a
Tert-butyl (3- bromophenylethyl) carbamate
Using Bretylium Tosylate as raw material, the preparation method is the same as that of Example 1 a.Yield is 97%.1H NMR(400MHz,
Chloroform-d) δ 7.36 (dd, J=7.5,1.4Hz, 2H), 7.21-7.15 (m, 1H), 7.12 (d, J=7.7Hz, 1H),
4.55 (s, 1H), 3.36 (q, J=6.8Hz, 2H), 2.77 (t, J=7.1Hz, 2H), 1.44 (s, 9H)
Embodiment 3b
(E) -3- (3- (2- ((tertbutyloxycarbonyl) amino) ethyl) phenyl) methyl acrylate
Using embodiment 3a as raw material, the preparation method is the same as that of Example 1 b.Yield is 86%.1H NMR(400MHz,DMSO-d6)δ
7.64 (d, J=16.1Hz, 1H), 7.58-7.48 (m, 2H), 7.34 (t, J=7.8Hz, 1H), 7.26 (d, J=7.6Hz, 1H),
6.92 (t, J=5.6Hz, 1H), 6.63 (d, J=16.0Hz, 1H), 3.73 (s, 3H), 3.26-3.04 (m, 2H), 2.72 (t, J
=7.3Hz, 2H), 1.36 (s, 9H)；13C NMR(101MHz,DMSO)δ166.54,155.41,144.55,140.14,
133.84,130.83,128.72,128.34,126.10,117.56,77.38,54.78,51.34,40.97,34.99,
28.13.
Embodiment 3c
(E) -3- (3- (2- aminoethyl) phenyl) methyl acrylate
Using embodiment 3b as raw material, preparation method is the same as embodiment 2a.Yield is 72%.1H NMR(400MHz,DMSO-d6)δ
7.98 (br, 2H), 7.72-7.56 (m, 3H), 7.39 (t, J=7.6Hz, 1H), 7.33 (d, J=7.6Hz, 1H), 6.68 (d, J
=16.1Hz, 1H), 3.73 (s, 1H), 3.07 (t, J=7.9Hz, 1H), 2.91 (br, 1H)；13C NMR(101MHz,DMSO)δ
166.52,144.31,138.12,134.19,130.78,129.07,128.39,126.74,117.94,51.39,32.84.
Embodiment 3d
(E) -3- (3- (2- (the chloro- 2- methoxy benzamide base of 5-) ethyl) phenyl) methyl acrylate
Using embodiment 3c as raw material, preparation method is the same as embodiment 2b.Yield is 77%.1H NMR(400MHz,DMSO-d6)δ
8.26 (t, J=5.7Hz, 1H), 7.69-7.56 (m, 4H), 7.50 (dd, J=8.8,2.8Hz, 1H), 7.38 (t, J=7.5Hz,
1H), 7.33 (t, J=7.6Hz, 1H), 7.15 (d, J=8.9Hz, 1H), 6.65 (d, J=16.0Hz, 1H), 3.79 (s, 3H),
3.73 (s, 3H), 3.54 (dt, J=5.7,7.1Hz, 2H), 2.86 (t, J=7.1Hz, 2H)；13C NMR(101MHz,DMSO)δ
166.54,163.49,155.56,144.48,140.10,133.94,131.32,130.88,129.36,128.84,128.45,
126.28,124.88,124.22,117.67,114.05,56.14,51.36,40.23,34.45.
Embodiment 3e
(E) the chloro- N- of -5- (3- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -2- methoxy benzamide
Using embodiment 3d as raw material, preparation method is the same as embodiment 2c.Yield is 35%.124~126 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 8.27 (t, J=5.6Hz, 1H), 7.63 (d, J=2.8Hz, 1H), 7.50 (dd, J=8.8,
2.8Hz, 1H), 7.48-7.38 (m, 3H), 7.36 (t, J=7.5Hz, 1H), 7.27 (d, J=7.5Hz, 1H), 7.15 (d, J=
8.9Hz, 1H), 6.47 (d, J=15.8Hz, 1H), 3.80 (s, 3H), 3.53 (q, J=6.7Hz, 2H), 2.85 (t, J=
7.1Hz,2H)；13C NMR(101MHz,DMSO)δ163.45,162.59,155.59,139.98,137.80,134.92,
131.36,129.71,129.41,128.85,127.56,125.38,124.76,124.24,119.25,114.07,56.15,
40.44,34.63.HRMS (ESI) m/z calculated value [M-H] -373.0955, measured value 373.0954.
Embodiment 4
(E) the chloro- N- of -2- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -5- (trifluoromethyl) benzene first
Amide (is changed
Close object 4)
Embodiment 4a
(E) -3- (4- (2- (2- chloro- 5- (trifluoromethyl) benzamido) ethyl) phenyl) methyl acrylate
Using the chloro- 5- of 2- (trifluoromethyl) benzoic acid and embodiment 2a as raw material, preparation method is the same as embodiment 2b.Yield is
65%.1H NMR(400MHz,DMSO-d6) δ 8.70 (t, J=5.6Hz, 1H), 7.81 (dd, J=8.5,2.2Hz, 1H), 7.74
(d, J=8.4Hz, 1H), 7.70-7.56 (m, 4H), 7.33 (d, J=7.9Hz, 2H), 6.61 (d, J=16.1Hz, 1H), 3.72
(s, 3H), 3.51 (td, J=5.6,7.1Hz, 2H), 2.88 (t, J=7.1Hz, 2H)；19F NMR(376MHz,DMSO)δ-
61.17；13C NMR(101MHz,DMSO)δ166.61,164.75,144.30,142.00,137.68,134.33,131.98,
130.73,129.30,128.25,127.74,127.22,125.49,124.77,116.98,51.30,40.05,34.49.
Embodiment 4b
(E) the chloro- N- of -2- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -5- (trifluoromethyl) benzene first
Amide
Using embodiment 4a as raw material, preparation method is the same as embodiment 2c.Yield is 29%.162~163 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 10.72 (s, 1H), 9.03 (s, 1H), 8.69 (t, J=5.6Hz, 1H), 7.81 (dd, J=8.4,
2.3Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 7.63 (d, J=2.2Hz, 1H), 7.50 (d, J=7.8Hz, 2H), 7.43 (d,
J=15.7Hz, 1H), 7.31 (d, J=7.8Hz, 2H), 6.43 (d, J=15.8Hz, 1H), 3.50 (q, J=6.7Hz, 2H),
2.87 (t, J=7.2Hz, 2H)；13C NMR(101MHz,DMSO)δ164.74,140.73,137.98,137.70,134.32,
132.82,130.72,129.28,127.75,127.42,127.33,125.50,125.46,124.78,122.07,118.31,
(39.15,38.97,34.45.HRMS ESI) m/z calculated value [M-H]-411.0723 measured value 411.0717.
Embodiment 5
(E) -4- hydroxy-n-(4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -3- methoxybenzoyl
Amine (compound 5)
Embodiment 5a
(E) -3- (4- (2- (4- hydroxy 3-methoxybenzene formamido) ethyl) phenyl) methyl acrylate
Using vanillic acid and embodiment 2a as raw material, preparation method is the same as embodiment 2b.Yield is
69%.1H NMR(400MHz,DMSO-d6) δ 9.56 (s, 1H), 8.36 (t, J=5.6Hz, 1H), 7.77-7.55 (m, 3H),
7.47-7.21 (m, 4H), 6.80 (d, J=8.3Hz, 1H), 6.61 (d, J=16.0Hz, 1H), 3.80 (s, 3H), 3.72 (s,
3H), 3.47 (dt, J=5.6,7.3Hz, 2H), 2.87 (t, J=7.3Hz, 2H)；13C NMR(101MHz,DMSO)δ166.63,
165.76,149.28,146.98,144.35,142.48,131.84,129.17,128.31,125.50,120.47,116.90,
114.67,111.18,55.54,51.30,40.40,35.01.
Embodiment 5b
(E) -4- hydroxy-n-(4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -3- methoxybenzoyl
Amine
Using embodiment 5a as raw material, preparation method is the same as embodiment 2c.Yield is 34%.150~152 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 8.33 (s, 1H), 7.46 (d, J=7.8Hz, 2H), 7.42-7.13 (m, 5H), 6.78 (d, J=
8.2Hz, 1H), 6.39 (d, J=15.8Hz, 1H), 3.79 (s, 3H), 3.50-3.41 (m, 2H), 2.83 (t, J=7.4Hz,
2H)；13C NMR(101MHz,DMSO)δ165.82,162.81,149.88,147.10,140.93,137.03,132.94,
129.11,127.27,125.09,120.54,119.00,114.75,111.22,55.54,40.51,35.01.HRMS(ESI)
M/z calculated value [M-H]-355.1294 measured value 355.1303.
Embodiment 6
(E) dioxane between-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) benzo [d] [1,3]
Amylene -5- formamide (compound 6)
Embodiment 6a
(E) -3- (4- (2- (benzo [d] [1,3] dioxole -5- formamide) ethyl) phenyl) methyl acrylate
Using piperic acid and embodiment 2a as raw material, preparation method is the same as embodiment 2b.Yield is 73%.1H NMR(400MHz,
DMSO-d6) δ 8.39 (t, J=5.6Hz, 1H), 7.75-7.54 (m, 3H), 7.40 (dd, J=8.2,1.7Hz, 1H), 7.34 (d,
J=1.7Hz, 1H), 7.28 (d, J=7.9Hz, 2H), 6.97 (d, J=8.1Hz, 1H), 6.60 (d, J=16.1Hz, 1H),
6.08 (s, 2H), 3.72 (s, 3H), 3.47 (td, J=5.6,7.2Hz, 2H), 2.86 (t, J=7.2Hz, 2H)；13C NMR
(101MHz,DMSO)δ166.64,165.14,149.46,147.15,144.35,142.40,131.85,129.17,128.43,
128.31,121.92,116.91,107.70,107.08,101.50,51.31,40.45,34.84.
Embodiment 6b
(E) dioxane between-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) benzo [d] [1,3]
Diene -5-
Formamide
Using embodiment 6a as raw material, preparation method is the same as embodiment 2c.Yield is 41%.186~187 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 10.72 (s, 1H), 9.02 (s, 1H), 8.40 (t, J=5.6Hz, 1H), 7.52-7.37 (m, 4H),
7.35 (d, J=1.7Hz, 1H), 7.27 (d, J=7.8Hz, 2H), 6.97 (d, J=8.1Hz, 1H), 6.41 (d, J=15.8Hz,
1H), 6.09 (s, 2H), 3.46 (q, J=6.7Hz, 2H), 2.84 (t, J=7.3Hz, 2H)；13C NMR(101MHz,DMSO)δ
165.16,162.76,149.45,147.16,141.15,138.08,132.68,129.14,128.50,127.39,121.92,
(118.29,107.69,107.09,101.49,40.53,34.82.HRMS ESI) m/z calculated value [M-H]-353.1137, actual measurement
Value 353.1129.
Embodiment 7
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -2,3- dihydrobenzo [b] [1,4] two
It dislikes English -6- formamide (compound 7)
Embodiment 7a
(E) -3- (4- (2- (2,3- dihydrobenzo [b] [1,4] dioxin -6- formamide) ethyl) phenyl) methyl acrylate
With 2,3- dihydro-Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid and embodiment 2a for raw material, preparation method is the same as embodiment 2b.?
Rate is 69%.1H NMR(400MHz,DMSO-d6) δ 8.37 (t, J=5.6Hz, 1H), 7.76-7.56 (m, 3H), 7.46-7.18
(m, 4H), 6.90 (d, J=8.1Hz, 1H), 6.59 (d, J=16.1Hz, 1H), 4.40-4.13 (m, 4H), 3.72 (s, 3H),
3.46 (td, J=5.6,7.2Hz, 2H), 2.85 (t, J=7.2Hz, 2H)；13C NMR(101MHz,DMSO)δ166.62,
165.21,145.79,144.33,142.76,142.43,131.85,129.16,128.28,127.52,120.42,116.93,
116.56,116.02,64.21,63.90,51.28,40.36,34.85.
Embodiment 7b
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -2,3- dihydrobenzo [b] [1,4] two
Dislike English -6-
Formamide
Using embodiment 7a as raw material, preparation method is the same as embodiment 2c.Yield is 35%.187~189 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 8.39 (t, J=5.6Hz, 1H), 7.48 (d, J=7.9Hz, 2H), 7.42 (d, J=15.7Hz,
1H), 7.37-7.30 (m, 2H), 7.26 (d, J=7.9Hz, 2H), 6.90 (d, J=8.1Hz, 1H), 6.42 (d, J=15.8Hz,
1H), 4.32-4.23 (m, 4H), 3.45 (q, J=6.7Hz, 2H), 2.84 (t, J=7.3Hz, 2H)；13C NMR(101MHz,
DMSO)δ165.20,162.68,145.78,142.76,141.15,137.96,132.69,129.13,127.53,127.37,
(120.42,118.32,116.56,116.02,64.21,63.90,40.45,34.82.HRMS ESI) m/z calculated value [M-H]-
367.1294 measured value 367.1302.
Embodiment 8
(E) the fluoro- N- of -5- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) niacinamide (compound 8)
Embodiment 8a
(E) -3- (4- (2- (5- fluoro niacinamide) ethyl) phenyl) methyl acrylate
Using 5- fluorine nicotinic acid and embodiment 2a as raw material, preparation method is the same as embodiment 2b.Yield is 65%.1H NMR
(400MHz,DMSO-d6) δ 8.87 (t, J=5.6Hz, 1H), 8.84 (t, J=1.8Hz, 1H), 8.74 (d, J=2.8Hz, 1H),
8.03 (ddd, J=9.6,2.9,1.7Hz, 1H), 7.76-7.54 (m, 3H), 7.31 (d, J=8.1Hz, 2H), 6.61 (d, J=
16.0Hz, 1H), 3.72 (s, 3H), 3.53 (dt, J=5.6,7.2Hz, 2H), 2.89 (t, J=7.2Hz, 2H)；19F NMR
(376MHz,DMSO)δ-126.86；13C NMR(101MHz,DMSO)δ167.18,163.86,160.49,157.96,145.00,
144.96,144.87,142.65,140.69,140.47,132.52,132.09,132.06,129.76,128.91,122.23,
122.03,117.56,51.87,41.08,35.19.
Embodiment 8b
(E) the fluoro- N- of -5- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) niacinamide
Using embodiment 8a as raw material, preparation method is the same as embodiment 2c.Yield is 33%.189~190 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 10.74 (s, 1H), 9.07 (s, 1H), 8.88 (t, J=5.6Hz, 1H), 8.85 (s, 1H), 8.74
(d, J=2.8Hz, 1H), 8.04 (d, J=9.4Hz, 1H), 7.50 (d, J=7.8Hz, 2H), 7.43 (d, J=15.8Hz, 1H),
7.29 (d, J=7.8Hz, 2H), 6.42 (d, J=15.8Hz, 1H), 3.52 (q, J=6.8Hz, 2H), 2.88 (t, J=7.2Hz,
2H).19F NMR(376MHz,DMSO)δ-126.86；13C NMR(101MHz,DMSO)δ163.28,162.66,159.93,
157.39,144.44,144.40,140.82,140.12,139.90,137.98,132.78,131.54,131.51,129.18,
(127.42,121.67,121.48,118.34,40.60,34.59.HRMS ESI) m/z calculated value [M+H]+330.1254, actual measurement
Value 330.1261.
Embodiment 9
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) quinoline -6- formamide (compound 9)
Embodiment 9a
(E) -3- (4- (2- (quinoline -6- formamide) ethyl) phenyl) methyl acrylate
Using QUINOLINE-6-CARBOXYLIC ACID and embodiment 2a as raw material, preparation method is the same as embodiment 2b.Yield is 71%.1HNMR
(400MHz,DMSO-d6) δ 8.99 (dd, J=4.2,1.7Hz, 1H), 8.85 (t, J=5.5Hz, 1H), 8.47 (td, J=4.2,
1.7Hz, 2H), 8.14 (dd, J=8.8,2.0Hz, 1H), 8.08 (d, J=8.8Hz, 1H), 7.71-7.57 (m, 4H), 7.33
(d, J=8.1Hz, 2H), 6.61 (d, J=16.1Hz, 1H), 3.72 (s, 3H), 3.57 (td, J=5.5,7.2Hz, 2H), 2.93
(t, J=7.2Hz, 2H)；13C NMR(101MHz,DMSO)δ166.63,165.63,151.88,148.52,144.34,
142.32,136.94,132.28,131.91,129.20,128.87,128.35,127.67,127.54,126.98,122.04,
116.95,51.30,40.58,34.82.
Embodiment 9b
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) quinoline -6- formamide
Using embodiment 9a as raw material, preparation method is the same as embodiment 2c.Yield is 38%.186~188 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 8.98 (dd, J=4.2,1.7Hz, 1H), 8.83 (t, J=5.6Hz, 1H), 8.51-8.43 (m,
2H), 8.15 (dd, J=8.8,1.9Hz, 1H), 8.07 (d, J=8.8Hz, 1H), 7.61 (dd, J=8.3,4.2Hz, 1H),
7.50 (d, J=7.8Hz, 2H), 7.43 (d, J=15.8Hz, 1H), 7.32 (d, J=7.8Hz, 2H), 6.42 (d, J=
15.8Hz, 1H), 3.62-3.52 (m, 2H), 2.92 (t, J=7.3Hz, 2H)；13C NMR(101MHz,DMSO)δ165.64,
162.70,151.86,148.53,141.05,137.98,136.92,132.76,132.33,129.18,128.86,127.66,
(127.55,127.42,126.99,122.03,118.35,40.66,34.80.HRMS ESI) m/z calculated value [M-H]-
360.1348 measured value 360.1350.
Embodiment 10
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -1H- benzo [d] imidazoles -5- formyl
Amine (compound 10)
Embodiment 10a
(E) -3- (4- (2- (1H- benzo [d] imidazoles -5- formamido) ethyl) phenyl) methyl acrylate
Using 1H- benzimidazole-5-carboxylic acid and embodiment 2a as raw material, preparation method is the same as embodiment 2b.Yield is 76%.1H
NMR(400MHz,DMSO-d6) δ 12.71 (s, 1H), 8.54 (t, J=5.6Hz, 1H), 8.33 (s, 1H), 8.20-8.07 (m,
1H), 7.75-7.56 (m, 5H), 7.32 (d, J=7.9Hz, 2H), 6.60 (d, J=16.1Hz, 1H), 3.72 (s, 3H), 3.53
(q, J=6.8Hz, 2H), 2.95-2.87 (m, 2H)；13C NMR(101MHz,DMSO)δ167.75,166.62,166.58,
144.34,143.62,142.52,131.84,129.18,128.29,127.07,124.31,121.18,118.99,116.92,
109.53,51.27,40.50,34.93.
Embodiment 10b
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -1H- benzo [d] imidazoles -5- formyl
Amine
Using embodiment 10a as raw material, preparation method is the same as embodiment 2c.Yield is 32%.179~181 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 12.68 (s, 1H), 10.74 (s, 1H), 9.03 (s, 1H), 8.54 (t, J=5.5Hz, 1H), 8.32
(s, 1H), 8.14 (s, 1H), 7.72 (br, 1H), 7.62 (br, 1H), 7.49 (d, J=7.8Hz, 2H), 7.42 (d, J=
15.8Hz, 1H), 7.30 (d, J=7.8Hz, 2H), 6.42 (d, J=15.8Hz, 1H), 3.57-3.47 (m, 2H), 2.89 (t, J
=7.3Hz, 2H)；HRMS (ESI) m/z calculated value [M-H]-349.1301 measured value 349.1306.
Embodiment 11
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -1H- pyrrolo- [2,3-b] pyridine -
3- formyl
Amine (compound 11)
Embodiment 11a
(E) -3- (4- (2- (1H- pyrrolo- [2,3-b] pyridine-3-carboxamide base) ethyl) phenyl) methyl acrylate
Using 7- azaindole -3- carboxylic acid and embodiment 2a as raw material, preparation method is the same as embodiment 2b.Yield is 61%.1H
NMR(400MHz,DMSO-d6) δ 12.13 (s, 1H), 8.47 (dd, J=8.0,1.6Hz, 1H), 8.29 (d, J=4.7Hz, 1H),
8.18 (t, J=5.7Hz, 1H), 8.14 (d, J=2.5Hz, 1H), 7.68-7.61 (m, 3H), 7.32 (d, J=8.1Hz, 2H),
7.19 (dd, J=7.9,4.7Hz, 1H), 6.60 (d, J=16.1Hz, 1H), 3.72 (s, 3H), 3.54-3.49 (m, 2H), 2.90
(t, J=7.3Hz, 2H)
Embodiment 11b
(E)-N- (4- (3- (hydroxylamino) -3- oxopropyl -1- alkenyl) phenethyl) -1H- pyrrolo- [2,3-b] pyridine -
3- formyl
Amine
Using embodiment 11a as raw material, preparation method is the same as embodiment 2c.Yield is 27%.196~198 DEG C of fusing point,1H NMR
(400MHz,DMSO-d6) δ 12.06 (s, 1H), 10.73 (s, 1H), 9.04 (s, 1H), 8.43 (dd, J=7.9,1.7Hz, 1H),
8.26 (dd, J=4.7,1.7Hz, 1H), 8.15-8.08 (m, 2H), 7.49 (d, J=7.7Hz, 2H), 7.42 (d, J=
15.8Hz, 1H), 7.30 (d, J=7.7Hz, 2H), 7.16 (dd, J=7.9,4.7Hz, 1H), 6.42 (d, J=15.8Hz, 1H),
3.49 (q, J=6.8Hz, 2H), 2.87 (t, J=7.3Hz, 2H)；13C NMR(101MHz,DMSO)δ163.79,162.69,
148.27,143.29,141.27,137.99,132.69,129.16,129.07,127.72,127.40,118.31,116.68,
109.48,35.26.HRMS (ESI) m/z calculated value [M-H]-349.1301 measured value 349.1293.
Embodiment 12, mtt assay cell inhibitory effect active testing
Cell in vitro proliferation inhibition test uses mtt assay, using following two cell line: human chronic myelogenous leukemia
(CML) cell line k562, human tissue cell lymphoma cell U937.
K562 and U937 be suspension cell, with containing volume fraction be 10% fetal calf serum RPIM-1640 culture solution, 37
DEG C, volume fraction be 5% CO2Under the conditions of routine culture.
Concrete operations are as follows:
Firstly, it is 5mM/L that the compound (i.e. sample) that embodiment 1-26 is prepared is configured to compound concentration respectively
DMSO (dimethyl sulfoxide) solution, then by the solution of acquisition through gradient dilution, a series of sample for obtaining concentration gradients is molten
Liquid.
Then, the K562 cell or U937 cell of logarithmic growth phase, with 1.5 × 105The cell density of a/mL connects
Kind is in 96 orifice plates, 99 holes μ L/, and then 1 μ L of sample solution is added in every hole, and making sample effect final concentration is respectively 0.01,0.05,
0.1,0.5,1,5,10,25,50 μM.Every kind of sample, each concentration set three multiple holes, and it is right that positive controls, feminine gender is arranged
According to group and blank control group, wherein positive controls are separately added into positive control medicine histon deacetylase (HDAC) inhibitor
SAHA and dnmt rna inhibitor SGI-027, the DMSO of negative control group addition and sample solution with concentration, blank pair
Cell is not added according to group.MTT solution is added after acting on 72h, 10 holes μ L/ are centrifuged at 2000rpm, 4 DEG C after continuing culture 4 hours
5 minutes, dimethyl sulfoxide (DMSO) is added after sucking supernatant, 100 holes μ L/ keep the temperature about 10 minutes in 37 DEG C, then with micro vibration
It swings device to vibrate about 5 minutes, makes crystallization dissolution completely, measure OD value at 490nm with microplate reader.
Cell proliferation inhibition rate (Inhibition Rate, IR%) is calculated as follows:
IR%=(negative control OD- sample OD)/(negative control OD- blank control OD) × 100%,
By calculating, the cell in vitro proliferation inhibition activity of compound prepared by the present invention is obtained, the results are shown in Table 1.Its
In, IC50It is indicated greater than 50 μM with "-", IC50It is indicated greater than 10 μM and less than 50 μM with "+", IC50Greater than 5 μM and less than 10 μM
It is indicated with " ++ ", IC50It is indicated greater than 1 μM less than 5 μM with " +++ ", IC50It is indicated less than 1 μM with " ++++".Test result shows
Majority of compounds shows good anti-K562 and U937 cultivation effect, wherein 2,3,6 pairs of U937 Proliferation Abilities of compound
IC50Less than 1 μM.
The tumor cell in vitro proliferation inhibition activity of the compound of 1 embodiment 1~11 of table preparation
Note: IC50Indicate half-inhibitory concentration.
Embodiment 13, the test of dnmt rna inhibitory activity
Using isotope labelling S-adenosylmethionine (3H-SAM) test compound turns DNA methyl in 100mM
The inhibitory activity of enzyme (DNMT1, DNMT3A, DNMT3B) is moved, and with the dnmt rna inhibitor of reported in literature
NSC319745 is compareed.Compound and corresponding a certain amount of dnmt rna hypotype are mixed in advance, are incubated at room temperature
After 15min, be added artificial synthesized biotin labeling oligonucleotides substrate and3H-SAM simultaneously reacts 4h at room temperature.Then will
Reaction system is transferred in the coated high pass orifice of Streptavidin, reacts at room temperature 1h.Radioactive activity passes through liquid scintillation
Counting method obtains.By comparing the inhibitory activity for obtaining compound to enzyme with negative control group (no inhibitor group).Compound pair
The results are shown in Table 2 for the inhibition percentage (%Inhibition) of different subtype dnmt rna enzyme.Showing of test result
Closing object has certain inhibitory activity to dnmt rna, and different to different subtype rejection ability.Majority of compounds pair
The inhibitory activity of DNMT1 is suitable with NSC319745 activity, and DNMT3A/3B inhibitory activity is weaker.Compound 9 is to DNMT3B's
Inhibitory activity is better than the inhibitory activity to DNMT1/3A.Compound 10 is all larger than 30% to the inhibiting rate of three hypotypes, and right
The inhibitory activity of DNMT3B is similar to compound N SC319745.Compound 4 shows strongest in listed compound
DNMT1 inhibitory activity (inhibiting rate be greater than 60%), and to DNMT3B inhibiting rate nearly 50%, and it is weaker to DNMT3A inhibitory activity
(inhibiting rate 23%).
The dnmt rna inhibitory activity of the compound of 2 embodiment 1~11 of table preparation
Embodiment 14, the test of histon deacetylase (HDAC) inhibitory activity
Using two hypotype HDAC1 and HDAC6 of histon deacetylase (HDAC) family as research object, compound is tested to group
The inhibitory activity of albumen deacetylase, each compound set ten concentration gradients, three multiple holes, and the HDAC suppression to have listed
Preparation SAHA is compareed.Compound is dissolved into reaction buffer first, certain volume is added later goes second containing histone
The peptide buffer solution of trypsase and acetylation is added as reaction substrate in the buffer solution of acylase after incubation at room temperature 15 minutes
To start deacetylation, while compound concentration and enzyme content being made to reach setting value, is incubated at room temperature after being gently mixed 60 seconds,
Record the kinetic parameter reacted under certain exciting light and wavelength of transmitted light in 1 hour.By with negative control group (no inhibitor
Group) compare the inhibitory activity for obtaining compound to enzyme, and compound is calculated, the half of histon deacetylase (HDAC) is inhibited
Concentration (IC50), the results are shown in Table 3, wherein IC50It is indicated greater than 10nM and less than 100nM with "+", IC50Less than 10nM with "+
+ " indicate.Test result shows all compounds to the half-inhibitory concentration (IC of HDAC1/650) it is less than 100nM, it shows to have
Good HDAC1/6 inhibitory activity.IC of the compound 5,6,7,9,10 to HDAC1/650Inhibitory activity less than 10nM, with SAHA
Quite.
The histon deacetylase (HDAC) inhibitory activity of the compound of 3 embodiment 1~11 of table preparation
Claims (13)
1. a kind of hydroxamic acid derivs or its pharmaceutically acceptable salt, hydroxamic acid derivs structural formula is as shown in formula I:
Wherein, Ar is aromatic group, and the aromatic group is selected from
N=1,2,3,4,5 or 6；
L1Link position be phenyl ring ortho position, meta or para position；L1It is straight for saturation or unsaturated carbon chains, the saturation selected from C1-C6
Alkane, the saturated alkane containing branch or substituent group of C1-C6, the unsaturated linear paraffin of C1-C6, C1-C6 containing branch or
The unsaturated alkane of substituent group；
The compound of formula I is shown in following table:
2. hydroxamic acid derivs according to claim 1 or its pharmaceutically acceptable salt, wherein described pharmaceutically
The salt of receiving is inorganic acid salt or acylate；
The inorganic acid salt is selected from the salt that any one following inorganic acid are formed: hydrochloric acid, sulfuric acid or phosphoric acid；
The acylate be selected from any one following organic acid formed salt: acetic acid, trifluoroacetic acid, malonic acid, citric acid and
P-methyl benzenesulfonic acid.
3. the preparation side of -2 described in any item hydroxamic acid derivs or its pharmaceutically acceptable salt according to claim 1
Method comprising following steps:
1) under condensing agent effect, Formula II compound represented is reacted to obtain formula IV institute with formula III compound represented
The compound shown；Or Formula II compound represented is prepared into corresponding acyl chlorides with thionyl chloride, oxalyl chloride or phosphorus oxychloride and is spread out
It is reacted to obtain formula IV compound represented with formula III compound represented after biology；
Wherein, in, Ar is aromatic group, the aromatic group is selected from replace or non-substituted phenyl ring, replace or it is non-substituted
Aromatic heterocycle, replace or non-substituted benzheterocycle, replace or non-substituted aromatic heterocycle and heterocycle；
N=1,2,3,4,5 or 6；
The link position of L1 is the ortho position of phenyl ring, meta or para position；L1 is saturation or unsaturated carbon chains；
R is the alkyl of C1-C4.
2) compound shown in formula IV is reacted in alkaline solution with azanol or hydroxylamine hydrochloride, obtains compound shown in Formulas I.
4. the preparation method according to requiring 3, in step 1), the condensing agent is selected from benzotriazole-N, N, N', N'- tetra-
Methylurea hexafluorophosphoric acid ester N, N'- carbonyl dimidazoles, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3- dimethylamine
Base propyl) one of -3- ethyl carbodiimide or a variety of.
5. the preparation method according to claim 4, wherein the step 1) condensing agent and Formula II compound represented, formula
The molar ratio of III compound represented is followed successively by 1-4:1-2:1-4；
In above method step 2), the alkali be selected from ammonium hydroxide, triethylamine, diisopropyl ethyl amine, sodium hydroxide, potassium hydroxide,
One of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide are a variety of；
The molar ratio that compound shown in formula IV is reacted with azanol or hydroxylamine hydrochloride, alkali is 1:1-10:1-20.
6. preparation method according to claim 5, wherein compound shown in formula IV is reacted with azanol or hydroxylamine hydrochloride, alkali
Molar ratio be 1:5:5.
7. the purposes according to the power described in any item compounds of claim 1-2 or its pharmaceutically acceptable salt is it under
State the application of aspect:
1) application in dnmt rna and/or histon deacetylase (HDAC) inhibitor is being prepared；
2) application in preparation eucaryote tumor cell proliferation inhibitor；Or
3) application in preparation prevention and/or tumor.
8. purposes according to claim 7, the dnmt rna includes hypotype in mammalian cells
DNMT1, DNMT3A, DNMT3B；The histon deacetylase (HDAC) includes hypotype HDAC1 in mammalian cells,
HDAC2, HDAC3, HDAC8, HDAC4, HDAC5, HDAC7, HDAC9, HDAC6, HDAC10, HDAC11；
The eucaryote is mammal；The tumour cell is cancer cell；The cancer cell is leukaemia cancer cell, mammary gland
Cancer cell, liver cancer cells, pancreatic cancer cell, lung carcinoma cell, brain cancer cell, ovarian cancer cell, uterine cancer cells, carcinoma of testis are thin
Born of the same parents, skin cancer cell, stomach cancer cell, nasopharyngeal carcinoma cell, colon cancer cell, bladder cancer cell or rectum cancer cell.
9. purposes according to claim 8, the cancer cell is that the chronic marrow original leukaemia cell of people and human tissue cell drench
Bar oncocyte.
10. purposes according to claim 8, the leukaemia cancer cell is specially human chronic polymorpho nuclear leukemia cells system
K562, the lymphoma cell are specially human tissue cell lymphoma cell U937, and the lung carcinoma cell is specially that human lung cancer is thin
Born of the same parents NCI-H520, the human glioma cell are specially U251, and the black cancer cell is specially A375, and the colloid is female
Cell carcinoma cells are specifically people's glioblastoma cells A172 and human brain astrocytes' blastoma cell U-118MG, described
Cervical cancer cell is specially Human cervical cancer cell lines Hela, and the nasopharyngeal carcinoma cell is specially human nasopharyngeal epithelioma 1 CNE-2, described
Liver cancer cells are specially HepG2 cell lines, and the breast cancer cell is specially human breast cancer cell line Bcap-37 and MDA-
MB-231。
11. purposes according to claim 7, the tumour is cancer；The cancer is leukaemia, lymthoma, lung cancer, melanin
Cancer, glioblastoma, cervical carcinoma, nasopharyngeal carcinoma, liver cancer, breast cancer, the cancer of the brain, cancer of pancreas, oophoroma, uterine cancer, carcinoma of testis, skin
Skin cancer, gastric cancer, colon cancer, bladder cancer or the carcinoma of the rectum.
12. a kind of pharmaceutical composition, it comprises as the active constituent such as described in any item compounds of claim 1-2 or
Its pharmaceutically acceptable salt and pharmaceutically acceptable auxiliaries.
13. pharmaceutical composition according to claim 12, dosage form be selected from injection, tablet, pulvis, granule,
Capsule, oral solution, paste, creme.
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