CN103922967A - Hydroxamic acid compounds and application thereof in preparation of medicines for inhibiting cancer cell proliferation and/or treating cancers - Google Patents

Hydroxamic acid compounds and application thereof in preparation of medicines for inhibiting cancer cell proliferation and/or treating cancers Download PDF

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CN103922967A
CN103922967A CN201410151843.1A CN201410151843A CN103922967A CN 103922967 A CN103922967 A CN 103922967A CN 201410151843 A CN201410151843 A CN 201410151843A CN 103922967 A CN103922967 A CN 103922967A
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alkyl
group
cyclic group
hydroxamic acid
alkane
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CN103922967B (en
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袁其朋
邓炳华
谢瑞
武新颖
屈悦
杨明
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Beijing University of Chemical Technology
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Beijing University of Chemical Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—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
    • 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
    • C07C259/06—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 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms

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Abstract

The invention relates to the field of medicinal chemistry and particularly relates to hydroxamic acid compounds and application thereof in preparation of medicines for inhibiting cancer cell proliferation and/or treating cancers. The hydroxamic acid compounds provided by the invention is capable of inhibiting cancer cell proliferation so as to treat cancers and especially has excellent activity of inhibiting proliferation of melanoma cell (A375), human lung cancer cell (A549), human gastric carcinoma cell (MGC80-3), human esophageal carcinoma cell (TE-1) and cell hepatoma carcinoma cell (HepG2).

Description

A kind of hydroxamic acid compound and the application in the medicine of preparing anticancer propagation and/or treatment cancer thereof
Technical field
The present invention relates to class hydroxamic acid compound and its production and use.
Background technology
Histon deacetylase (HDAC) (histone deacetylase; HDAC) and histone acetyltransferase (histone acetyltransferase; HAT) be in eukaryotic cell, extensively exist the proteolytic enzyme of the mutual antagonism of a class; they are regulating and controlling the acetylize of histone terminal amino acid residue jointly, make it in equilibrium state.The acetylize of histone and deacetylation are modified to a kind of mode that regulatory gene is transcribed, and the degree of acetylation of histone passes through the chromatinic structure of impact and then affects the expression of gene.Acetylation of histone state is diversity, and the acetylize of histone is carried out at specific gene position in site-specific mode.The acetylize of the lysine residue of the generation of tumour and nucleosome core histone nitrogen end and deacetylation unbalance has acetylize that substantial connection, histon deacetylase (HDAC) and histone acetyltransferase co-controlling histone in body in running balance.Histone acetyltransferase can be used as co-activator regulatory transcription, regulates the cell cycle, participates in DNA damage reparation.Histon deacetylase (HDAC) is relevant with chromosome translocation, transcriptional control, gene silencing, cell cycle, cytodifferentiation and propagation and apoptosis.Multinomial research shows that the disorder of histone acetyltransferase and histon deacetylase (HDAC) balance can make genetic expression out of control; thereby lead oncogenic generation, research NSC 630176 is for probing into tumour mechanism and development of new antitumor drug is significant.
In cancer cells; when histon deacetylase (HDAC) is excessive, can promote the deacetylation of histone; and then make histone and thymus nucleic acid (deoxyribonucleic acid; DNA) reactive force between increases; nucleosome becomes tight by lax; finally suppressed the expression of specific gene, especially some cancer suppressor gene.NSC 630176 can improve by the activity of inhibition of histone deacetylase the acetylize of karyomit(e) particular group albumen, and then promotes that cancer suppressor gene recovers to express, thus the growth of anticancer.NSC 630176 has certain tumour-specific, propagation and static mutant is all had to restraining effect, and some normal cells are not caused to cessation of growth cessation or apoptosis.NSC 630176 is the antitumor drug that a class has novel, efficient, the low toxicity of very big development potentiality, has huge researching value.
In NSC 630176, research comparatively successfully represents it is SAHA.
Vorinostat (SAHA) is firstly by U.S. FDA approval listing, to be used for the treatment of the medicine of transitivity cutaneous T cell lymphoma, but in research in recent years, finds that SAHA still exists bioavailability poor, the not strong defect of selectivity of anticancer propagation.Therefore, seek that structurally than SAHA, to have more compared with the hydroxamic acid compound of high resistance cancer cell multiplication activity be the important scientific research project of this field worker.If success, real have profound and significance to the exploitation of cancer therapy drug, brought huge national economy to be worth simultaneously.
The invention provides the hydroxamic acid compound as shown in logical formula I, experimental results show that it all has the ability of powerful inhibition propagation to multiple cancer cells, can have good result for the treatment of to suffering from the patient of cancer.Chinese patent application (publication number CN103159646A) discloses a kind of compound N-(2,5-Dimethoxyphenyl)-N '-hydroxyl suberamide and multiple cancer cells has been had to the effect that suppresses propagation, yet fails to reach preferably effect.United States Patent (USP) (US5369108) discloses a series of hydroxamic acid compound, also inhibited to the propagation of cancer cells.The invention provides a series of novel hydroxamic acid compound, the hydroxamic acid compound with excellent antitumor cell proliferation provided by the present invention is never mentioned or disclosed in above-mentioned patent.
United States Patent (USP) (US5369108) has first been described the method that employing acyl chlorides intermediate is prepared Vorinostat (SAHA), and not only productive rate is low brings serious environmental pollution simultaneously for this method, produces a large amount of refuses.Chinese patent application (publication number CN102264694A and CN103159646A) and J.Med.Chem.2005,48,5047-5051 has also reported the preparation method of SAHA, they all adopt other condensing agent and the N such as the special condensing agent BOP of card or dicyclohexylcarbodiimide (DCC), the auxiliarys such as N-diisopropylethylamine (DIEA), promote intermediate (IV) synthetic of first step.Condensing agent described in literary composition and auxiliary are not only expensive, produce the waste byproduct of condensing agent and the auxiliary of two molar equivalents after simultaneous reactions, cause the severe contamination of environment.And their purifying hydroxamic acid compounds need adopt silicagel column separating treatment, except the time is long, silica gel and a large amount of eluents have also been wasted.
The invention provides and a kind ofly take boric acid as catalyzer, outside dewatering and the novel method of the efficient synthetic Vorinostat (SAHA) that produces of no waste.This reaction not only has height atom economy, is also green and low-carbon (LC) chemical reaction simultaneously.
The document of quoting from the present invention, works, patent and Patent Application Publication book, wherein all or part all clearly with independently all in present patent application incorporated by reference.
Summary of the invention
The present invention relates to the design of a class hydroxamic acid with synthetic, in order to overcome the above-mentioned deficiency of prior art, the invention provides the more excellent hydroxamic acid compound of a kind of drug activity.Another technical problem that the present invention solves is to provide the preparation method of above-mentioned hydroxamic acid compound.Why the present invention can address the above problem is to realize by the following technical programs:
A hydroxamic acid compound, is characterized in that the structure shown in following logical formula I:
Wherein n is 4 to 8; R is alkyl or substituted alkyl.
A is selected from: hydrogen, chlorine, bromine, iodine, hydroxyl, alkyl, alkane cyclic group, cycloalkyl, fluorine substituted alkyl, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, fragrant cyclic group, heterocyclic radical, benzo cyclic group, heterocycle phenyl, cycloalkyloxy or alkane epoxy group(ing).
B is selected from: hydrogen, bromine, iodine, hydroxyl, alkyl, alkane cyclic group, cycloalkyl, fluorine substituted alkyl, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, fragrant cyclic group, heterocyclic radical, benzo cyclic group, heterocycle phenyl, cycloalkyloxy or alkane epoxy group(ing).
X is selected from: hydrogen, chlorine, bromine, iodine, hydroxyl, alkyl, alkane cyclic group, cycloalkyl, fluorine substituted alkyl, alkoxyl group, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, fragrant cyclic group, heterocyclic radical, benzo cyclic group, heterocycle phenyl, cycloalkyloxy or alkane epoxy group(ing).
Y is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, alkyl, alkane cyclic group, cycloalkyl, fluorine substituted alkyl, alkoxyl group, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, fragrant cyclic group, heterocyclic radical, benzo cyclic group, heterocycle phenyl, cycloalkyloxy or alkane epoxy group(ing).
Z is selected from: hydrogen, bromine, iodine, hydroxyl, alkyl, alkane cyclic group, cycloalkyl, fluorine substituted alkyl, alkoxyl group, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, fragrant cyclic group, heterocyclic radical, benzo cyclic group, heterocycle phenyl, cycloalkyloxy or alkane epoxy group(ing).
When wherein A is different from X, being hydrogen, is chlorine when A is different from X, is chlorine when A is different from Y.
As a kind of preferred version, hydroxamic acid compound of the present invention is selected from down the structure that is listed in the fragrant phenyl ring base in general formula (I):
As a kind of preferred version, the salt that described hydroxamic acid compound and mineral acid, organic acid, mineral alkali or organic bases form by chemical reaction, forms hydrate or solvate with water or solvent.
As a kind of most preferably scheme, described inorganic or organic acid is selected from: the Phenylsulfonic acid of hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, perchloric acid, acetic acid, citric acid, oxalic acid, lactic acid, oxysuccinic acid, Whitfield's ointment, tartrate, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, replacement, γ-picolinic acid, oleic acid, tannic acid, pantothenic acid, xitix, succinic acid, toxilic acid, gentisinic acid, fumaric acid, gluconic acid, uronic acid, glucaric acid, sucrose acid, formic acid, phenylformic acid, L-glutamic acid, pamoic acid or Sorbic Acid; Described inorganic or organic bases is selected from: sodium hydroxide, potassium hydroxide, lithium hydroxide, ironic hydroxide, calcium hydroxide, hydrated barta, aluminium hydroxide, magnesium hydroxide, zinc hydroxide, ammoniacal liquor, hydroxide organic quaternary ammonium salt, sodium carbonate, Quilonum Retard, calcium carbonate, barium carbonate, magnesiumcarbonate, carbonating organic quaternary ammonium salt, sodium bicarbonate, saleratus, lithium bicarbonate, Calcium hydrogen carbonate, barium bicarbonate, Magnesium hydrogen carbonate or carbonic acid hydrogenation organic quaternary ammonium salt.
As a kind of most preferably scheme, hydroxamic acid compound described in described solvate refers to and the stable material of chemically conventional solvent with covalent linkage, hydrogen bond, ionic linkage, Van der Waals force, complexing power or inclusion formation, solvent is wherein selected from: methyl alcohol, ethanol, propyl alcohol, butanols, ethylene glycol, propylene glycol, polyoxyethylene glycol or acetone.
The invention also discloses a kind of method of preparing the logical formula I compound of hydroxamic acid of the present invention, it is prepared by the following step and obtains:
Step (1):
Step (2):
Intermediate (IV)+NH 2oHHCl+M-OH (or M-OR ")
Wherein R is the alkyl of alkyl or replacement, and n is 4 to 8; M is basic metal; R ' is methyl, ethyl, n-propyl, sec.-propyl, the butyl of butyl or replacement, the amyl group of amyl group or replacement.R " be methyl, ethyl, propyl group, the tertiary butyl.A, B, X, Y and Z be independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, alkyl, alkane cyclic group, cycloalkyl, fluorine substituted alkyl, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, fragrant cyclic group, heterocyclic radical, benzo cyclic group, heterocycle phenyl, alkoxyl group, cycloalkyloxy, or alkane epoxy group(ing).
Above-claimed cpd (I) is prepared from by the following step.
Step (1): under boric acid catalysis, will lead to formula II compound and do to react in solvent situation at hydrocarbon polymer with logical formula III compound, thus preparation amide product (IV), the reaction times is 1 to 24 hour, temperature is 20 ℃ to 145 ℃.
Step (2): by NH 2oHHCl be dissolved in the metal hydroxides of organic solvent or an alkali metal salt of alcohol mixes, at 20 ℃ to 60 ℃, stir 0.5 to 3 hour, add after the product IV of step (1), at 20 ℃ to 60 ℃, continue to stir 1 to 5 hour, separated, purifying, thus required hydroxamic acid compound (I) obtained.
Compound of the present invention (II) is 1 to 0.01～1.00 with the mol ratio of boric acid, preferably than being 1 to 0.01～0.20.
Compound of the present invention (II) and compound (III) reactions steps (1) mole ratio be 1 to 1～1.20, preferably than being 1 to 1.03.
Hydrocarbon polymer as solvent of the present invention is pentane, hexane, heptane, octane, toluene, dimethylbenzene, trimethylbenzene or their miscellany.Preferred solvent is heptane, toluene or dimethylbenzene.
NH of the present invention 2the product (IV) of an alkali metal salt of OHHCl and alkali metal hydroxide or alcohol and step (1) mole ratio be (19～3): (18～2): 1.
An alkali metal salt of alkali metal hydroxide of the present invention or alcohol is selected from: lithium, sodium, potassium or caesium.
The metal-salt of alcohol of the present invention is sodium methylate, sodium ethylate or potassium tert.-butoxide, and preferably person is sodium methylate.
Following compounds is the synthetic wherein hydroxamic acid of a part of the present invention:
The synthetic wherein hydroxamic acid of a part of Table I the present invention
Embodiment
By following embodiment, foregoing of the present invention is remake and further explains in detail and open up and state, make those of ordinary skill in the art can understand more easily the present invention, but the scope that this should be interpreted as to theme of the present invention only limits to following example and limits any or all right of the present invention, more should not deviate from spirit of the present invention.
Hydroxamic acid embodiment 1:
The preparation of N-(3,4-3,5-dimethylphenyl)-N ˊ-hydroxyl suberamide (being called for short B113).
Step (1): weigh 3,4-xylidine 1.21g(10mmol), suberic acid mono-methyl 1.88g (10mmol); boric acid 0.31g (5mmol) is placed in tri-mouthfuls of round-bottomed flasks of 100ml; add 30ml toluene, nitrogen protection, magnetic agitation; oil bath is heated to refluxing toluene; with water trap, separate the water generating in reaction process, before reaction, in water trap, fill it up with toluene, the reaction times is 10h; by thin layer chromatography board, follow the tracks of reaction during this time, developping agent is ethyl acetate: sherwood oil=1:1.After having reacted, reaction solution poured in the 300ml sherwood oil in stirring, stirred after 0.5h, with sand core funnel vacuumizing filtration, obtain solid, and water cleans to remove catalyzer boric acid to solid, after draining again with sherwood oil cleaning solid and solid is drained.The final solid 2.27g that obtains, productive rate is: 78.0%;
Step (2): weigh KOH2.08g (37.08mmol) and be dissolved in 10ml methyl alcohol, add NH 2oHHCl2.72g(39.14mmol), mix rear 40 degrees Celsius of magnetic agitation 0.5h, cool to room temperature, the product 0.60g (2.06mmol) that adds again the first step reaction to obtain, by thin layer chromatography board, follow the tracks of reaction during this time, after reaction 0.5h finishes, reaction solution is poured in the 300ml frozen water in magnetic agitation, separate out solid, filter, with 20ml distillation, wash solid twice, each 10ml, vacuum is drained and with 20ml ether, is washed twice afterwards, each 10ml, then drain and with acetonitrile recrystallization, obtain B113 solid 0.30g afterwards, productive rate is: 49.7%, MS (ES +) m/z:293.1866 (M+H) +, 1hNMR (DMSO-d 6, 400MHz): δ=10.32 (s, 1H), 9.67 (s, 1H), 8.65 (s, 1H), 7.36 (s, 1H), 7.30 (d, J=8.0Hz, 1H), 7.02 (d, J=8.0Hz, 1H), (2.26 t, J=7.4Hz, 2H), 2.18 (s, 3H), (2.16 s, 3H), 1.94 (t, J=7.4Hz, 2H), 1.53 (m, 4H), 1.28 (m, 4H).
Hydroxamic acid embodiment 2:
The preparation of N-(the chloro-4-fluorophenyl of 3-)-N '-hydroxyl suberamide (hydroxamic acid) (being called for short B115).
Step (1): weigh the chloro-4-fluoroaniline of 3-1.46g(10mmol); suberic acid mono-methyl 1.88g (10mmol), boric acid 0.31g (5mmol) is placed in tri-mouthfuls of round-bottomed flasks of 100ml, adds 30ml toluene; nitrogen protection; magnetic agitation, oil bath is heated to refluxing toluene, separates the water generating in reaction process with water trap; before reaction, in water trap, fill it up with toluene; reaction times is 12h, during by thin layer chromatography board, follow the tracks of reaction, developping agent is ether: sherwood oil=1:1.After having reacted, reaction solution poured in the 300ml sherwood oil in stirring, stirred after 0.5h, with sand core funnel vacuumizing filtration, obtain solid, and water cleans to remove catalyzer boric acid to solid, after draining again with sherwood oil cleaning solid and solid is drained.The final solid 1.57g that obtains, productive rate is: 49.7%;
Step (2): weigh KOH2.02g (36mmol) and be dissolved in 10ml methyl alcohol, add NH 2oHHCl2.64g(38mmol), mix rear 40 degrees Celsius of magnetic agitation 0.5h, cool to room temperature, the product 0.63g (2mmol) that adds again the first step reaction to obtain, by thin layer chromatography board, follow the tracks of reaction during this time, after 0.5h, reaction is poured reaction solution in the 300ml frozen water in magnetic agitation into after finishing, separate out solid, filter, with 20ml distillation, wash solid twice, each 10ml, vacuum is drained and with 20ml ether, is washed twice afterwards, each 10ml, then drain and with acetonitrile recrystallization, obtain B115 solid 0.25g afterwards, productive rate is: 39.7%, MS(ES +) m/z:317.1068 (M+H) +, 1hNMR (DMSO-d 6, 400MHz): δ=10.33 (s, 1H), 10.08 (s, 1H), (8.65 s, 1H), 7.94 (d, J=7.0Hz, 1H), 7.46 (m, 1H), 7.35 (t, J=9.1Hz, 1H), 2.30 (t, J=7.4Hz, 2H), 1.94 (t, J=7.3Hz, 2H), 1.53 (m, 4H), 1.28 (m, 4H).
Hydroxamic acid embodiment 3:
The preparation of N-(the bromo-5-trifluoromethyl of 3-)-N ˊ-hydroxyl suberamide (being called for short B123).
Step (1): weigh the bromo-5-5-trifluoromethylaniline of 3-0.8g(3.33mmol); suberic acid mono-methyl 0.63g (3.33mmol), boric acid 0.10g (1.67mmol) is placed in tri-mouthfuls of round-bottomed flasks of 100ml, adds 30ml toluene; nitrogen protection; magnetic agitation, oil bath is heated to refluxing toluene, separates the water generating in reaction process with water trap; before reaction, in water trap, fill it up with toluene; reaction times is 20h, during by thin layer chromatography board, follow the tracks of reaction, developping agent is ether: sherwood oil=1:1.After having reacted, reaction solution poured in the 300ml sherwood oil in stirring, stirred after 0.5h, with sand core funnel vacuumizing filtration, obtain solid, and water cleans to remove catalyzer boric acid to solid, after draining again with sherwood oil cleaning solid and solid is drained.The final solid 1.11g that obtains, productive rate is: 81.2%;
Step (2): weigh KOH1.21g (21.6mmol) and be dissolved in 10ml methyl alcohol, add NH 2oHHCl1.58g(22.8mmol), mix rear 40 degrees Celsius of magnetic agitation 0.5h, cool to room temperature, the product 0.50g (1.2mmol) that adds again the first step reaction to obtain, by thin layer chromatography board, follow the tracks of reaction during this time, after 0.5h, reaction finishes, and reaction solution is poured in the 300ml frozen water in magnetic agitation, separates out solid, filter, with 20ml distillation washing solid twice, each 10ml, vacuum is drained and with 20ml ether, is washed twice afterwards, each 10ml, drain and with acetonitrile recrystallization, obtain B123 solid 0.21g afterwards, productive rate is: 41.2%, MS(ES +) m/z:411.0527 (M+H) +, 1hNMR (DMSO-d 6, 400MHz): δ=10.36 (s, 1H), 10.33 (s, 1H), 8.66 (s, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 2.34 (t, J=7.3Hz, 2H), (1.95 t, J=7.4Hz, 2H), 1.54 (m, 4H), 1.29 (m, 4H).
Other compounds process for production thereof is similar to above example.
Hydroxamic acid B101:MS (ES +) m/z:315.1113 (M+H) +; 1hNMR (DMSO-d 6, 400MHz): δ=10.33 (s, 1H), 9.18 (s, 1H), 7.96 (s, 1H), 6.95 (d, J=8.6Hz, 1H), 6.85 (d, J=8.6Hz, 1H), 2.40 (t, J=7.6Hz, 2H), (1.94 t, J=7.0Hz, 2H), 1.53 (m, 4H), 1.28 (m, 4H).
Hydroxamic acid B105MS (ES +) m/z:329.1265 (M+H) +; 1hNMR (DMSO-d 6, 400MHz): δ=10.33 (s, 1H), 9.86 (s, 1H), 8.66 (s, 1H), 7.79 (s, 1H), 7.42 (d, J=8.9Hz, 1H), 7.09 (d, J=8.9Hz, 1H), (3.81 s, 3H), 2.26 (t, J=7.4Hz, 2H), 1.94 (t, J=7.2Hz, 2H), 1.53 (m, 4H), 1.28 (m, 4H).
Hydroxamic acid B107:MS (ES +) m/z:295.1655 (M+H) +; 1hNMR (DMSO-d 6, 400MHz): δ=10.33 (s, 1H), 9.62 (s, 1H), 9.23 (s, 1H), 8.65 (s, 1H), 7.46 (d, J=8.0Hz, 1H), 6.67 (s, 1H), 6.57 (d, J=8.2Hz, 1H), 2.36 (t, J=7.3Hz, 2H), 2.20 (s, 3H), 1.94 (d, J=7.2Hz, 2H), 1.53 (m, 4H), 1.28 (m, 4H).
Hydroxamic acid B109:MS (ES +) m/z:315.1118 (M+H) +; 1hNMR (DMSO-d 6, 400MHz): δ=10.33 (s, 1H), 9.73 (s, 1H), 9.20 (s, 1H), 8.75 (s, 1H), 7.78 (d, J=8.5Hz, 1H), 6.87 (s, 1H), 6.81 (d, J=8.5Hz, 1H), 2.37 (t, J=7.4Hz, 2H), 1.94 (t, J=7.3Hz, 2H), 1.52 (m, 4H), 1.28 (m, 4H).
Hydroxamic acid B110:MS (ES +) m/z:334.0821 (M+H) +; 1hNMR (DMSO-d 6, 400MHz): δ=10.33 (s, 1H), 10.16 (s, 1H), 8.65 (s, 1H), 8.00 (s, 1H), (7.55 d, J=8.8Hz, 1H), 7.48 (d, J=8.8Hz, 1H), 2.31 (t, J=7.4Hz, 2H), 1.94 (t, J=7.4Hz, 2H), 1.53 (m, 4H), 1.28 (m, 4H).
Hydroxamic acid B112:MS (ES +) m/z:329.1270 (M+H) +; 1hNMR (DMSO-d 6, 400MHz): δ=10.33 (s, 1H), 9.86 (s, 1H), 8.65 (s, 1H), 7.78 (s, 1H), 7.42 (d, J=9.0Hz, 1H), 7.09 (d, J=9.0Hz, 1H), (3.81 s, 3H), 2.26 (t, J=7.5Hz, 2H), 1.94 (t, J=7.4Hz, 2H), 1.53 (m, 4H), 1.28 (m, 4H).
Hydroxamic acid B113:MS (ES +) m/z:293.1866 (M+H) +; 1hNMR (DMSO-d 6, 400MHz): δ=10.32 (s, 1H), 9.67 (s, 1H), 8.65 (s, 1H), 7.36 (s, 1H), 7.30 (d, J=8.0Hz, 1H), 7.02 (d, J=8.0Hz, 1H), 2.26 (t, J=7.4Hz, 2H), 2.18 (s, 3H), 2.16 (s, 3H), 1.94 (t, J=7.4Hz, 2H), 1.53 (m, 4H), 1.28 (m, 4H).
Hydroxamic acid B114:MS (ES +) m/z:334.0807 (M+H) +; 1hNMR (DMSO-d 6, 400MHz): δ=10.33 (s, 1H), 9.53 (s, 1H), (8.65 s, 1H), 7.72 (d, J=8.8Hz, 1H), 7.66 (s, 1H), 7.41 (d, J=8.8Hz, 1H), 2.37 (t, J=7.3Hz, 2H), 1.95 (t, J=7.4Hz, 2H), 1.54 (m, 4H), 1.29 (m, 4H).
Hydroxamic acid B115:MS (ES +) m/z:317.1068 (M+H) +; 1hNMR (DMSO-d 6, 400MHz): δ=10.33 (s, 1H), 10.08 (s, 1H), (8.65 s, 1H), 7.94 (d, J=7.0Hz, 1H), 7.46 (m, 1H), 7.35 (t, J=9.1Hz, 1H), 2.30 (t, J=7.4Hz, 2H), 1.94 (t, J=7.3Hz, 2H), 1.53 (m, 4H), 1.28 (m, 4H).
Hydroxamic acid B116:MS (ES +) m/z:361.0571,363.0548; 1hNMR (DMSO-d 6, 400MHz): δ=10.32 (s, 1H), 10.20 (s, 1H), 8.65 (s, 1H), 7.77 (d, J=11.6Hz, 1H), (7.61 t, J=8.5Hz, 1H), 7.28 (d, J=8.8Hz, 1H), 2.31 (t, J=7.4Hz, 2H), 1.94 (t, J=7.3Hz, 2H), 1.53 (m, 4H), 1.28 (m, 4H).
Hydroxamic acid B117:MS (ES +) m/z:295.1656 (M+H) +; 1hNMR (DMSO-d 6, 400MHz): δ=10.33 (s, 1H), 9.45 (s, 1H), 9.21 (s, 1H), 8.65 (s, 1H), 7.48 (s, 1H), 6.74 (m, 2H), (2.37 t, J=7.3Hz, 2H), 2.19 (s, 3H), 1.95 (t, J=7.3Hz, 2H), 1.53 (m, 4H), 1.28 (m, 4H).
Hydroxamic acid B119:MS (ES +) m/z:360.0638 (M+H) +; 1hNMR (DMSO-d 6, 400MHz): δ=10.33 (s, 1H), 10.28 (s, 1H), 9.19 (s, 1H), 8.65 (s, 1H), 7.74 (d, J=8.5Hz, 1H), 7.01 (s, 1H), 6.94 (d, J=8.5Hz, 1H), 2.38 (t, J=7.3Hz, 2H), 1.94 (t, J=7.4Hz, 2H), 1.53 (m, 4H), 1.28 (m, 4H).
Hydroxamic acid B123:MS (ES +) m/z:412.0558 (M+H) +; 1hNMR (DMSO-d 6, 400MHz): δ=10.36 (s, 1H), 10.33 (s, 1H), 8.66 (s, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 2.34 (t, J=7.3Hz, 2H), (1.95 t, J=7.4Hz, 2H), 1.54 (m, 4H), 1.29 (m, 4H).
Embodiment 4:
(1) experimental cell system, select five kinds of cancer cells: Human skin melanoma cell (A375), human lung carcinoma cell (A549), gastric carcinoma cells (MGC80-3), human liver cancer cell (HepG2) or human esophagus cancer cell (TE-1), wherein Human skin melanoma cell (A375) and human liver cancer cell (HepG2), containing in the DMEM substratum of 10% foetal calf serum, go down to posterity after digesting with 0.25% trypsinase is conventional.Human lung carcinoma cell (A549), gastric carcinoma cells (MGC80-3), and human esophagus cancer cell (TE-1) is containing in RPMI-1640 (HyClone) substratum of 10% foetal calf serum, after digesting, goes down to posterity with 0.25% trypsinase is conventional.
(2) cancer cells of logarithmic phase is digested to after individual cells, with 4 * 10 4the density of individual/ml is inoculated in 96 orifice plates, every hole adds the cell suspension of 0.1ml, containing in 37 ℃ of incubators of 5%CO2, cultivating 12 hours, hydroxamic acid of the present invention and contrast medicine Vorinostat (SAHA) are all acted on to same cell, each concentration arranges 3 multiple holes, after cell attachment, adding hydroxamic acid or SAHA processes, medicine for cancer cells to different concns, after 48h, suck nutrient solution, each hole adds MTT solution 20 μ L to hatch after 4 hours, abandon substratum, every hole adds 150 μ LDMSO, even 10 minutes of shake, after the crystallization of first a ceremonial jade-ladle, used in libation is fully dissolved, by microplate reader, detect the absorbance at 490nm place and calculate IC 50value.
Table II: the inhibition degree of hydroxamic acid to different carcinoma cell
The result of table II shows: the hydroxamic acid of different structure is different to the inhibition ability of different carcinoma cell proliferation.
(1) restraining effect for Human skin melanoma cell: B101, B105, B110, B112, B113, B115, B116, B117 and B123 is better than positive control compound Vorinostat (SAHA) (U.S. Patent number 5369108).Especially B105, B110, B113 and B123, its inhibition is obviously better than Vorinostat (SAHA).
(2) for human lung carcinoma cell: the restraining effect of B105, B110, B112, B113, B115, B116 and B123 is better than positive control compound S AHA, as above-mentioned B105, B110, B113 and B123 Human skin melanoma cell to obvious inhibition, this class hydroxamic acid is equally all obviously better than control compound Vorinostat (SAHA) to the inhibition of human lung carcinoma cell simultaneously.
(3) for stomach cancer cell: for gastric carcinoma cells MGC80-3, the restraining effect of B101, B105, B107, B109, B110, B112, B113, B115, B116, B117 and B123 is better than positive control compound S AHA, simultaneously as above-mentioned B105, B110, B113 and B123 Human skin melanoma cell and human lung carcinoma cell all to obvious inhibition, the inhibition for gastric carcinoma cells MGC80-3 is all obviously better than control compound Vorinostat (SAHA) similarly.
According to the result of table II, in hydroxamic acid compound provided by the invention, be no lack of Human skin melanoma cell (A375), the restraining effect of human lung carcinoma cell (A549) and gastric carcinoma cells (MGC80-3) is all better than the hydroxamic acid of control compound Vorinostat (SAHA), the present invention is B110 particularly preferably, B112, B116, five hydroxamic acid compounds such as B117 and B123 are done the cancer cells administration experiment of human esophagus cancer (TE-1) and people's liver cancer (HepG2), the results are shown in Table III
Table III: the inhibition degree of hydroxamic acid to different carcinoma cell
Table III result shows, selected five hydroxamic acid are all better than positive control compound Vorinostat (SAHA) to its restraining effect of esophageal carcinoma TE-1.But to the restraining effect of liver cancer cell HepG2 because the structure of hydroxamic acid is different.Liver cancer cell HepG2 has different susceptibilitys to different hydroxamic acid, and wherein the restraining effect of B112 and B116 is better than Vorinostat (SAHA).

Claims (10)

1. a hydroxamic acid compound, is characterized in that the structure shown in following logical formula I:
Wherein n is 4 to 8; R is alkyl or substituted alkyl;
A is selected from: hydrogen, chlorine, bromine, iodine, hydroxyl, alkyl, alkane cyclic group, cycloalkyl, fluorine substituted alkyl, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, fragrant cyclic group, heterocyclic radical, benzo cyclic group, heterocycle phenyl, cycloalkyloxy or alkane epoxy group(ing);
B is selected from: hydrogen, bromine, iodine, hydroxyl, alkyl, alkane cyclic group, cycloalkyl, fluorine substituted alkyl, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, fragrant cyclic group, heterocyclic radical, benzo cyclic group, heterocycle phenyl, cycloalkyloxy or alkane epoxy group(ing);
X is selected from: hydrogen, chlorine, bromine, iodine, hydroxyl, alkyl, alkane cyclic group, cycloalkyl, fluorine substituted alkyl, alkoxyl group, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, fragrant cyclic group, heterocyclic radical, benzo cyclic group, heterocycle phenyl, cycloalkyloxy or alkane epoxy group(ing);
Y is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, alkyl, alkane cyclic group, cycloalkyl, fluorine substituted alkyl, alkoxyl group, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, fragrant cyclic group, heterocyclic radical, benzo cyclic group, heterocycle phenyl, cycloalkyloxy or alkane epoxy group(ing);
Z is selected from: hydrogen, bromine, iodine, hydroxyl, alkyl, alkane cyclic group, cycloalkyl, fluorine substituted alkyl, alkoxyl group, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, fragrant cyclic group, heterocyclic radical, benzo cyclic group, heterocycle phenyl, cycloalkyloxy or alkane epoxy group(ing);
When wherein A is different from X, being hydrogen, is chlorine when A is different from X, is chlorine when A is different from Y.
2. hydroxamic acid compound according to claim 1, it is characterized in that, the formed salt of described hydroxamic acid compound and mineral acid, organic acid, mineral alkali or organic bases, forms hydrate or solvate and pharmaceutically acceptable carrier and/or additive with water or applicable solvent.
3. hydroxamic acid compound according to claim 1 and 2, wherein the fragrant cyclic group in logical formula I is selected from:
4. hydroxamic acid compound according to claim 1 and 2, is characterized in that, described hydroxamic acid compound is selected from:
5. the application of the hydroxamic acid compound described in any one in preparing anticancer propagation or treatment cancer drug in claim 1 to 4.
6. application according to claim 5, wherein cancer cells or cancer comprise human melanoma cell A375, human lung cancer cell A549, gastric carcinoma cells MGC80-3, human esophagus cancer cell TE-1, the cell lung cancer cell H460 of the National People's Congress, human liver cancer cell HepG2, human breast cancer cell MCF-7, human pancreatic cancer cell PANC-1, colorectal carcinoma, the rectum cancer, cervical cancer, ovarian cancer.
7. application according to claim 6, wherein cancer cells is or/and cancer is people's Human melanoma cell line A375, human lung cancer cell A549, gastric carcinoma cells MGC80-3, human liver cancer cell HepG2 or human esophagus cancer cell TE-1.
8. a method of preparing hydroxamic acid compound claimed in claim 1 (general formula I):
Above-claimed cpd (I) is prepared from by the following step
Step (1):
Step (2):
Intermediate (IV)+NH 2oHHCl+M-OH (or M-OR ")
Wherein R is the alkyl of alkyl or replacement, and n is 4 to 8; M is basic metal; R ' is methyl, ethyl, n-propyl, sec.-propyl, the butyl of butyl or replacement, the amyl group of amyl group or replacement; R " be methyl, ethyl, propyl group, the tertiary butyl; A, B, X, Y and Z be independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, alkyl, alkane cyclic group, cycloalkyl, fluorine substituted alkyl, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, fragrant cyclic group, heterocyclic radical, benzo cyclic group, heterocycle phenyl, alkoxyl group, cycloalkyloxy, or alkane epoxy group(ing);
Step (1): under boric acid catalysis, will lead to formula II compound and as solvent, react with hydrocarbon polymer with logical formula III compound, thus preparation amide product (IV); Wherein compound (II) and boric acid mole ratio be 1:(0.01～1.00); Wherein said compound (II) is 1:(1～1.2 with the mol ratio of compound (III)); Wherein said hydrocarbon cosolvent is selected from pentane, hexane, heptane, octane, toluene, dimethylbenzene, trimethylbenzene or their mixture; Reaction times is 1 to 24 hour, and temperature is 20 ℃ to 145 ℃;
Step (2): by NH 2oHHCl be dissolved in the alkali metal hydrogen oxygen compound M-OH of organic solvent or an alkali metal salt MOR of alcohol " mix; at 20 ℃ to 60 ℃, stir 0.5 to 3 hour; add after the product (IV) of step (1); at 20 ℃ to 60 ℃, continue to stir 1 to 5 hour; separation; purifying, obtains required hydroxamic acid compound (I); The mol ratio of the product (IV) of wherein said NH2OHHCl and metal hydroxides and step (1) is (19～3): (18～2): 1.
9. method according to claim 8, wherein said alkali metal hydrogen oxygen compound is sodium hydroxide, potassium hydroxide or cesium hydroxide.
10. method according to claim 8, wherein an alkali metal salt of wherein said alcohol is sodium methylate, sodium ethylate or potassium tert.-butoxide.
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CN106397102A (en) * 2016-08-29 2017-02-15 山东同成医药股份有限公司 Halogenated hydrocarbon product and sealed heat insulation pressurized production method thereof
CN106905191A (en) * 2017-03-05 2017-06-30 北京化工大学 A kind of nitrogen mustards compound containing hydroxamic acid group and its production and use
CN114315778A (en) * 2020-10-12 2022-04-12 北京化工大学 Trichoderma harzianum acid A compound and trichoderma harzianum mutant strain producing same

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WO2015158244A1 (en) * 2014-04-15 2015-10-22 北京化工大学 Hydroxamic acid compound and use thereof in preparing medications for inhibiting cancer cell proliferation and/or treating cancers
CN106397102A (en) * 2016-08-29 2017-02-15 山东同成医药股份有限公司 Halogenated hydrocarbon product and sealed heat insulation pressurized production method thereof
CN106905191A (en) * 2017-03-05 2017-06-30 北京化工大学 A kind of nitrogen mustards compound containing hydroxamic acid group and its production and use
CN106905191B (en) * 2017-03-05 2019-03-29 北京化工大学 A kind of nitrogen mustards compound and its preparation method and application containing hydroxamic acid group
CN114315778A (en) * 2020-10-12 2022-04-12 北京化工大学 Trichoderma harzianum acid A compound and trichoderma harzianum mutant strain producing same
CN114315778B (en) * 2020-10-12 2023-06-20 北京化工大学 Trichoderma harzianum acid A compound and trichoderma harzianum mutant strain for producing same

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