CN103922967B - A kind of hydroxamic acid compound and the application in the medicine preparing anticancer propagation and/or Therapeutic cancer thereof - Google Patents
A kind of hydroxamic acid compound and the application in the medicine preparing anticancer propagation and/or Therapeutic cancer thereof Download PDFInfo
- Publication number
- CN103922967B CN103922967B CN201410151843.1A CN201410151843A CN103922967B CN 103922967 B CN103922967 B CN 103922967B CN 201410151843 A CN201410151843 A CN 201410151843A CN 103922967 B CN103922967 B CN 103922967B
- Authority
- CN
- China
- Prior art keywords
- hydroxamic acid
- acid
- acid compound
- cell
- cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 CC(CCC1CC(*C*CCCC[C@](C)*)C1)NC Chemical compound CC(CCC1CC(*C*CCCC[C@](C)*)C1)NC 0.000 description 2
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Pain & Pain Management (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to medicinal chemistry art, a kind of hydroxamic acid compound and the application in the medicine preparing anticancer propagation and/or Therapeutic cancer thereof. Hydroxamic acid compound provided by the present invention has the ability of anticancer propagation, thus reaches the object of Therapeutic cancer. Especially to suppression Human skin melanoma cell (A375), human lung carcinoma cell (A549), gastric carcinoma cells (MGC80-3), human esophagus cancer cell (TE-1) and human liver cancer cell (HepG2) have the activity of excellent anticancer propagation.
Description
Technical field
The present invention relates to class hydroxamic acid compound and its production and use.
Background technology
Histon deacetylase (HDAC) (histonedeacetylase; and histone acetyltransferase (histoneacetyltransferase HDAC); HAT) for eukaryotic cell extensively exists the mutual anti-proteolytic enzyme short of money of class; they regulate and control the acetylize of histone terminal amino acid residue jointly, make it to be 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 is by affecting the structure of chromatin and then affects the expression of gene. Acetylation of histone state is diversity, and specific gene position carries out the acetylize of histone in site-specific mode. The generation of tumour and the acetylize of lysine residue and the unbalance of deacetylation of nucleosome core histones nitrogen end have substantial connection, and histon deacetylase (HDAC) and histone acetyltransferase co-controlling the acetylize of histone in body and be 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 then 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; thus cause the generation of tumour, research NSC 630176 for probe into tumour mechanism and development of new antitumor drug significant.
In cancer cells; the deacetylation of histone can be promoted when histon deacetylase (HDAC) is excessive; and then make histone and thymus nucleic acid (deoxyribonucleicacid; DNA) reactive force between increases; nucleosome becomes tight by lax; finally inhibit the expression of specific gene, especially some cancer suppressor gene. NSC 630176 then by the acetylize of the active raising karyomit(e) particular group albumen of inhibition of histone deacetylase, and then can promote 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 restraining effect, and some normal cells does not cause cessation of growth cessation or withers and die. NSC 630176 is the antitumor drug that a class has the poison novel, efficient, low of very big development potentiality, has huge researching value.
Studying comparatively successfully representative in NSC 630176 is SAHA.
Vorinostat (SAHA) is the first medicine being used for the treatment of transitivity cutaneous T cell lymphoma by U.S. FDA approval listing, but it is poor to find that in research in recent years SAHA still exists bioavailability, the defect that the selectivity of anticancer propagation is not strong. Therefore, seek that structurally to have more compared with the hydroxamic acid compound of high resistance cancer cell multiplication activity than SAHA be the important scientific research project of this field worker. If success, the real exploitation to cancer therapy drug has profound and significance, brings huge national economy simultaneously and is worth.
The present invention provides the hydroxamic acid compound as shown in logical formula I, and experiment proves its ability that multiple cancer cells all has powerful Inhibit proliferaton, and the patient suffering from cancer can be had excellent result for the treatment of. Chinese patent application (publication number CN103159646A) discloses the effect that multiple cancer cells is had Inhibit proliferaton by a kind of compound N-(2,5-Dimethoxyphenyl)-N '-hydroxyl suberamide, but fails to reach preferably effect. United States Patent (USP) (US5369108) discloses a series of hydroxamic acid compounds, also that the propagation of cancer cells is inhibited. The present invention provides a series of novel hydroxamic acid compounds, and the hydroxamic acid compound with excellent antitumor cell proliferation provided by the present invention is never mentioned in above-mentioned patent or is disclosed.
United States Patent (USP) (US5369108) first describes and adopts acid chloride intermediate to prepare the method for Vorinostat (SAHA), and not only product rate is low brings serious environmental pollution simultaneously for this method, produces a large amount of refuse. Chinese patent application (publication number CN102264694A and CN103159646A) and J.Med.Chem.2005,48,5047-5051 also reports the preparation method of SAHA, they all adopt card special other condensing agent and the N such as condensing agent BOP or dicyclohexylcarbodiimide (DCC), the auxiliarys such as N-diisopropylethylamine (DIEA), promote the synthesis of the intermediate (IV) of first step. Condensing agent described in literary composition and auxiliary are not only expensive, produce the condensing agent of two molar equivalents and the waste byproduct of auxiliary, cause the severe contamination of environment after simultaneous reactions. And their purifying hydroxamic acid compounds need to adopt silicagel column separating treatment, except the time is longer, also waste silica gel and a large amount of eluents.
It is catalyzer taking boric acid that the present invention provides a kind of, in addition to water and the novel method of efficient synthesis Vorinostat (SAHA) that produces of no waste. This reaction not only has height atom economy, is also green and the reaction of low carbon geochemistry simultaneously.
Document, works, patent and the patent application publication book quoted from the present invention, wherein all or local all clearly with independent ground all in present patent application incorporated by reference.
Summary of the invention
The present invention relates to the Design and synthesis of a class hydroxamic acid, in order to overcome the above-mentioned deficiency of prior art, the hydroxamic acid compound that the present invention provides a kind of drug activity more excellent. 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 solve the problem is realize by the following technical programs:
A kind of hydroxamic acid compound, it is characterised in that the structure shown in general formula (I):
Wherein n is 4 to 8; The alkyl that R is alkyl or is replaced.
A is selected from: hydrogen, chlorine, bromine, iodine, hydroxyl, alkyl, alkane ring base, cycloalkyl, fluorine substituted alkyl, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, aromatic nucleus base, heterocyclic radical, benzo ring base, heterocycle phenyl, ring alkoxyl group or alkane epoxy group(ing).
B is selected from: hydrogen, bromine, iodine, hydroxyl, alkyl, alkane ring base, cycloalkyl, fluorine substituted alkyl, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, aromatic nucleus base, heterocyclic radical, benzo ring base, heterocycle phenyl, ring alkoxyl group or alkane epoxy group(ing).
X is selected from: hydrogen, chlorine, bromine, iodine, hydroxyl, alkyl, alkane ring base, cycloalkyl, fluorine substituted alkyl, alkoxyl group, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, aromatic nucleus base, heterocyclic radical, benzo ring base, heterocycle phenyl, ring alkoxyl group or alkane epoxy group(ing).
Y is selected from: fluorine, chlorine, bromine, iodine, hydroxyl, alkyl, alkane ring base, cycloalkyl, fluorine substituted alkyl, alkoxyl group, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, aromatic nucleus base, heterocyclic radical, benzo ring base, heterocycle phenyl, ring alkoxyl group or alkane epoxy group(ing).
Z is selected from: hydrogen, bromine, iodine, hydroxyl, alkyl, alkane ring base, cycloalkyl, fluorine substituted alkyl, alkoxyl group, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, aromatic nucleus base, heterocyclic radical, benzo ring base, heterocycle phenyl, ring alkoxyl group or alkane epoxy group(ing).
It is hydrogen when wherein A and X is different, it is chlorine when A and X is different, be chlorine when A and Y is different.
As a kind of preferred version, the hydroxamic acid compound of the present invention is selected from down the structure of the fragrant phenyl ring base being listed 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 are formed by chemical reaction, form hydrate or solvate with water or solvent.
As one 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, ��-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 one most preferably scheme, described solvate refers to that described hydroxamic acid compound closes, with covalent linkage, hydrogen bond, ionic linkage, Van der Waals force, complexing power or bag, the stable material formed with chemically conventional solvent, and solvent wherein is selected from: methyl alcohol, ethanol, propyl alcohol, butanols, ethylene glycol, propylene glycol, polyoxyethylene glycol or acetone.
The invention also discloses a kind of method 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)+NH2OH HCl+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 the amyl group of the butyl of methyl, ethyl, n-propyl, sec.-propyl, butyl or replacement, amyl group or replacement. R " it is methyl, ethyl, propyl group, the tertiary butyl. A, B, X, Y and Z independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, alkyl, alkane ring base, cycloalkyl, fluorine substituted alkyl, fluorine substituted alkoxy, amino, alkyl amine group, alkyl-carbonyl, alkoxy carbonyl, alkyl amide, alkylthio, nitro, cyano group, aromatic nucleus base, heterocyclic radical, benzo ring base, heterocycle phenyl, alkoxyl group, ring alkoxyl group, or alkane epoxy group(ing).
Above-claimed cpd (I) be prepared from by the following step.
Step (1): under boric acid catalysis, reacts logical formula II compound and logical formula III compound under hydrocarbon polymer makes solvent case, thus prepares amide product (IV), and the reaction times is 1 to 24 hour, and temperature is 20 DEG C to 145 DEG C.
Step (2): by NH2OH HCl mixes with an alkali metal salt of the metal hydroxides or alcohol that are dissolved in organic solvent, stir 0.5 to 3 hour at 20 DEG C to 60 DEG C, after adding the product IV of step (1), continue to stir 1 to 5 hour at 20 DEG C to 60 DEG C, separation, purifying, thus the hydroxamic acid compound (I) needed for obtaining.
Compound of the present invention (II) is 1 to 0.01��1.00 with the mol ratio of boric acid, it is preferable that 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, it is preferable that than being 1 to 1.03.
The hydrocarbon polymer being used 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 invention2The product (IV) of an alkali metal salt of OH HCl 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, it is preferable that person is sodium methylate.
Following compounds is the hydroxamic acid that the present invention synthesizes a wherein part:
The hydroxamic acid that Table I the present invention synthesis is wherein a part of
Embodiment
By following embodiment, the foregoing of the present invention is done further detailed explanation again and exhibition is stated, the those of ordinary skill of this area is enable to understand the present invention more easily, but this should not being interpreted as, the scope of theme of the present invention is only limitted to following example and any or all right of restriction the present invention, more should not deviate from the spirit of the present invention.
Hydroxamic acid embodiment 1:
The preparation that N-(3,4-3,5-dimethylphenyl)-N-hydroxyl suberamide (is 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 100ml tri-mouthfuls of round-bottomed flasks; add 30ml toluene; nitrogen protection; magnetic agitation; oil bath is heated to refluxing toluene; separating in reaction process the water generated with water trap, fill it up with toluene before reaction in water trap, the reaction times is 10h; period follows the tracks of reaction by thin layer chromatography board, and developping agent is ethyl acetate: sherwood oil=1:1. After having reacted, reaction solution is poured in the 300ml sherwood oil in stirring, after stirring 0.5h, obtain solid by sand core funnel vacuumizing filtration, and clean to remove catalyzer boric acid to solid with water, clean solid with sherwood oil again after draining and solid is drained. Final solid 2.27g, product rate is: 78.0%;
Step (2): weigh KOH2.08g (37.08mmol) and be dissolved in 10ml methyl alcohol, add NH2OH HCl2.72g(39.14mmol), mixed even rear 40 degrees Celsius of magnetic agitation 0.5h, cool to room temperature, add the product 0.60g (2.06mmol) that the first step is obtained by reacting again, period follows the tracks of reaction by thin layer chromatography board, in the 300ml frozen water that reaction solution is poured in magnetic agitation after terminating by reaction 0.5h, precipitate out solid, filter, wash solid twice with 20ml distillation, each 10ml, vacuum washes twice with 20ml ether, each 10ml after draining, then obtains B113 solid 0.30g with recrystallized from acetonitrile after draining, product rate is: 49.7%, MS (ES+)m/z:293.1866(M+H)+,1HNMR(DMSO-d6,400MHz):��=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 acidEmbodiment 2:
The preparation that N-(the chloro-4-fluorophenyl of 3-)-N '-hydroxyl suberamide (hydroxamic acid) (is called for short B115).
Step (1): weigh the chloro-4-fluoroaniline 1.46g(10mmol of 3-); suberic acid mono-methyl 1.88g (10mmol), boric acid 0.31g (5mmol) is placed in 100ml tri-mouthfuls of round-bottomed flasks, adds 30ml toluene; nitrogen protection; magnetic agitation, oil bath is heated to refluxing toluene, separates in reaction process the water generated with water trap; before reaction, toluene filled it up with by water trap; reaction times is 12h, and period follows the tracks of reaction by thin layer chromatography board, and developping agent is ether: sherwood oil=1:1. After having reacted, reaction solution is poured in the 300ml sherwood oil in stirring, after stirring 0.5h, obtain solid by sand core funnel vacuumizing filtration, and clean to remove catalyzer boric acid to solid with water, clean solid with sherwood oil again after draining and solid is drained. Final solid 1.57g, product rate is: 49.7%;
Step (2): weigh KOH2.02g (36mmol) and be dissolved in 10ml methyl alcohol, add NH2OH HCl2.64g(38mmol), mixed even rear 40 degrees Celsius of magnetic agitation 0.5h, cool to room temperature, add the product 0.63g (2mmol) that the first step is obtained by reacting again, period follows the tracks of reaction by thin layer chromatography board, in the 300ml frozen water that after 0.5h, reaction solution is poured in magnetic agitation after terminating by reaction, precipitate out solid, filter, wash solid twice with 20ml distillation, each 10ml, vacuum washes twice with 20ml ether, each 10ml after draining, then obtains B115 solid 0.25g with recrystallized from acetonitrile after draining, product rate is: 39.7%, MS(ES+) m/z:317.1068 (M+H)+,1HNMR(DMSO-d6,400MHz):��=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 that N-(the bromo-5-trifluoromethyl of 3-)-N-hydroxyl suberamide (is called for short B123).
Step (1): weigh the bromo-5-5-trifluoromethylaniline 0.8g(3.33mmol of 3-); suberic acid mono-methyl 0.63g (3.33mmol); boric acid 0.10g (1.67mmol) is placed in 100ml tri-mouthfuls of round-bottomed flasks; add 30ml toluene; nitrogen protection; magnetic agitation; oil bath is heated to refluxing toluene; the water generated is separated in reaction process with water trap; before reaction, toluene filled it up with by water trap; reaction times is 20h, and period follows the tracks of reaction by thin layer chromatography board, and developping agent is ether: sherwood oil=1:1. After having reacted, reaction solution is poured in the 300ml sherwood oil in stirring, after stirring 0.5h, obtain solid by sand core funnel vacuumizing filtration, and clean to remove catalyzer boric acid to solid with water, clean solid with sherwood oil again after draining and solid is drained. Final solid 1.11g, product rate is: 81.2%;
Step (2): weigh KOH1.21g (21.6mmol) and be dissolved in 10ml methyl alcohol, add NH2OH HCl1.58g(22.8mmol), mixed even rear 40 degrees Celsius of magnetic agitation 0.5h, cool to room temperature, add the product 0.50g (1.2mmol) that the first step is obtained by reacting again, period follows the tracks of reaction by thin layer chromatography board, after 0.5h, reaction terminates, and is poured into by reaction solution in the 300ml frozen water in magnetic agitation, precipitates out solid, filter, with 20ml distillation washing solid twice, each 10ml, vacuum washes twice with 20ml ether after draining, each 10ml, obtaining B123 solid 0.21g with recrystallized from acetonitrile after draining, product rate is: 41.2%, MS(ES again+) m/z:411.0527 (M+H)+,1HNMR(DMSO-d6,400MHz):��=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-d6,400MHz):��=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-d6,400MHz):��=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-d6,400MHz):��=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-d6,400MHz):��=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-d6,400MHz):��=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-d6,400MHz):��=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-d6,400MHz):��=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-d6,400MHz):��=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-d6,400MHz):��=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-d6,400MHz):��=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-d6,400MHz):��=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-d6,400MHz):��=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-d6,400MHz):��=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) are containing, in the DMEM substratum of 10% foetal calf serum, going down to posterity with after 0.25% trypsinase routine digestion. Human lung carcinoma cell (A549), gastric carcinoma cells (MGC80-3), and human esophagus cancer cell (TE-1) are containing, in RPMI-1640 (HyClone) substratum of 10% foetal calf serum, going down to posterity with after 0.25% trypsinase routine digestion.
(2) after the cancer cells of logarithmic phase being digested to individual cells, with 4 �� 104The density of individual/ml is inoculated in 96 orifice plates, every hole adds the cell suspension of 0.1ml, cultivate 12 hours in containing 37 DEG C of incubators of 5%CO2, the hydroxamic acid of the present invention and comparison medicine Vorinostat (SAHA) are all acted on same cell, each concentration arranges 3 multiple holes, after cell attachment, add hydroxamic acid or SAHA process, for cancer cells to the medicine of different concns, after 48h, suck nutrient solution, each hole adds after MTT solution 20 �� L hatches 4 hours, abandon substratum, every hole adds 150 �� LDMSO, shake and shake even 10 minutes, after first a ceremonial jade-ladle, used in libation crystallization is fully dissolved, detect the absorbance at 490nm place by microplate reader and calculate IC50Value.
Table II: hydroxamic acid is to the degree of suppression of different carcinoma cell
The result of table II shows: the hydroxamic acid of different structure is different to the rejection ability of different carcinoma cell proliferation.
(1) for Human skin melanoma cell: the restraining effect of B101, B105, B110, B112, B113, B115, B116, B117 and B123 is better than positive reference 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 reference compound SAHA, simultaneously such as above-mentioned B105, B110, B113 and B123 that Human skin melanoma cell has obvious inhibition, the inhibition of human lung carcinoma cell is equally all obviously better than control compound Vorinostat (SAHA) by this kind of hydroxamic acid.
(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 reference compound SAHA, simultaneously such as above-mentioned B105, B110, B113 and B123 that Human skin melanoma cell and human lung carcinoma cell all have obvious inhibition, the inhibition for gastric carcinoma cells MGC80-3 is all obviously better than control compound Vorinostat (SAHA) similarly.
Result according to table II, hydroxamic acid compound provided by the invention is no lack of to 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, five hydroxamic acid compounds such as B116, B117 and B123 do 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: hydroxamic acid is to the degree of suppression of different carcinoma cell
Table III result shows, its restraining effect of esophageal carcinoma TE-1 is all better than positive reference compound Vorinostat (SAHA) by five selected hydroxamic acid. But the restraining effect of hepatocellular carcinoma H22 is then different because of the structure of hydroxamic acid. Different hydroxamic acid is had different susceptibilitys by hepatocellular carcinoma H22, and wherein the restraining effect of B112 and B116 is then better than Vorinostat (SAHA).
Claims (2)
1. a hydroxamic acid compound, it is characterised in that it is characterized in that, described hydroxamic acid compound is selected from:
��
2. the hydroxamic acid compound described in claim 1 is in the application prepared in anticancer propagation or Therapeutic cancer medicine, 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.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410151843.1A CN103922967B (en) | 2014-04-15 | 2014-04-15 | A kind of hydroxamic acid compound and the application in the medicine preparing anticancer propagation and/or Therapeutic cancer thereof |
| PCT/CN2015/076519 WO2015158244A1 (en) | 2014-04-15 | 2015-04-14 | Hydroxamic acid compound and use thereof in preparing medications for inhibiting cancer cell proliferation and/or treating cancers |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410151843.1A CN103922967B (en) | 2014-04-15 | 2014-04-15 | A kind of hydroxamic acid compound and the application in the medicine preparing anticancer propagation and/or Therapeutic cancer thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103922967A CN103922967A (en) | 2014-07-16 |
| CN103922967B true CN103922967B (en) | 2016-06-01 |
Family
ID=51141394
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410151843.1A Active CN103922967B (en) | 2014-04-15 | 2014-04-15 | A kind of hydroxamic acid compound and the application in the medicine preparing anticancer propagation and/or Therapeutic cancer thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN103922967B (en) |
| WO (1) | WO2015158244A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103922967B (en) * | 2014-04-15 | 2016-06-01 | 北京化工大学 | A kind of hydroxamic acid compound and the application in the medicine preparing anticancer propagation and/or Therapeutic cancer thereof |
| 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 |
| 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 |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5369108A (en) * | 1991-10-04 | 1994-11-29 | Sloan-Kettering Institute For Cancer Research | Potent inducers of terminal differentiation and methods of use thereof |
| WO2009098515A1 (en) * | 2008-02-07 | 2009-08-13 | Generics [Uk] Limited | Novel process for the preparation of vorinostat |
| CN102264694A (en) * | 2008-10-15 | 2011-11-30 | 基因里克斯(英国)有限公司 | Process for preparing vorinostat |
| CN103159646A (en) * | 2013-03-19 | 2013-06-19 | 广东药学院 | Hydroxamic acid compound, and preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5700811A (en) * | 1991-10-04 | 1997-12-23 | Sloan-Kettering Institute For Cancer Research | Potent inducers of terminal differentiation and method of use thereof |
| CN103922967B (en) * | 2014-04-15 | 2016-06-01 | 北京化工大学 | A kind of hydroxamic acid compound and the application in the medicine preparing anticancer propagation and/or Therapeutic cancer thereof |
-
2014
- 2014-04-15 CN CN201410151843.1A patent/CN103922967B/en active Active
-
2015
- 2015-04-14 WO PCT/CN2015/076519 patent/WO2015158244A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5369108A (en) * | 1991-10-04 | 1994-11-29 | Sloan-Kettering Institute For Cancer Research | Potent inducers of terminal differentiation and methods of use thereof |
| WO2009098515A1 (en) * | 2008-02-07 | 2009-08-13 | Generics [Uk] Limited | Novel process for the preparation of vorinostat |
| CN102264694A (en) * | 2008-10-15 | 2011-11-30 | 基因里克斯(英国)有限公司 | Process for preparing vorinostat |
| CN103159646A (en) * | 2013-03-19 | 2013-06-19 | 广东药学院 | Hydroxamic acid compound, and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2015158244A1 (en) | 2015-10-22 |
| CN103922967A (en) | 2014-07-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111448189A (en) | Biaryl derivative, preparation method and pharmaceutical application thereof | |
| CN104447743B (en) | The preparation method of Pa Boxini | |
| CN103922967B (en) | A kind of hydroxamic acid compound and the application in the medicine preparing anticancer propagation and/or Therapeutic cancer thereof | |
| US11702399B2 (en) | Quinazolinone derivative, preparation method therefor, pharmaceutical composition, and applications | |
| US10793548B2 (en) | Method for preparing tyrosine kinase inhibitor and derivative thereof | |
| GB2398565A (en) | Imatinib preparation and salts | |
| EP1959944A1 (en) | A pharmaceutical composition comprising an amide derivative | |
| CN105254589B (en) | A method of preparing heart failure drugs intermediate | |
| CN103608341A (en) | N-aryl unsaturated fused ring tertiary amine compound, preparation method thereof and antitumor application thereof | |
| CN103965133B (en) | It is a kind of to contain N, S heterocyclic compound and its preparation and use with DHODH inhibitory activity | |
| CN106749259A (en) | A kind of synthetic method of cyclopenta pyrimido azoles | |
| CN103910671A (en) | Preparation method for vismodegib and intermediate of vismodegib | |
| US20230192619A1 (en) | Processes for the Preparation of a Kinase Inhibitor | |
| KR100595117B1 (en) | Process for Preparing 4-[2-DimethylaminoEthoxy]Benzylamine of Itopride·HCl Mediates | |
| CN110804059B (en) | Carbamate compound, pharmaceutical composition and application thereof | |
| EP0532530A4 (en) | Derivatives of 6-aminooctahydroindolizinetriol | |
| CN105541705B (en) | A kind of synthetic method of flupirtine maleate compound | |
| CN104771392B (en) | Class I histone deacetylase inhibitor and application | |
| CN106749045A (en) | A kind of new D amino acid oxidase inhibitors and its preparation method and application | |
| CN104116728A (en) | Pharmaceutical composition composed of hydroxamic acid compounds and vitamin A compounds and application thereof | |
| CN112250682B (en) | Aromatic heterocycle modified naphthalimide derivative and preparation method and application thereof | |
| WO2018223122A1 (en) | Hdac3-selective inhibitors | |
| JP2013529687A5 (en) | ||
| CN105541810A (en) | Coumarin NEDD8 activating enzyme inhibitor and preparation method and application thereof | |
| CN103242321A (en) | Benzylpiperazine compound and anti-tumor application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |