CN112961117A - Application and preparation method of oxadiazole hydroxamic acid compound - Google Patents
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Abstract
The invention belongs to the field of biological medicines, and particularly relates to an application of oxadiazole hydroxamic acid anti-tumor metastasis compounds and a preparation method thereof. Histone Deacetylase (HDAC) and Histone Acetyltransferase (HAT) act synergistically to co-regulate the acetylation level of histone lysine residues. HDACi (histone deacetylase inhibitors) has been shown to play a role in the development of tumors through a variety of mechanisms. Oxadiazole hydroxamic acid derivatives have a variety of pharmacological properties, such as antitumor, antiinflammatory and antibacterial activity. The invention combines an oxadiazole structure as a CAP region with a hydroxamic acid structure to synthesize a novel anti-tumor metastasis histone deacetylase inhibitor, and performs an inhibition experiment on the activity of HDAC1 enzyme on the synthesized compound.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to application of an oxadiazole hydroxamic acid antitumor compound and a preparation method thereof.
Background
Tumors are second only to cardiovascular and cerebrovascular diseases and seriously threaten human life health, and the incidence of malignant tumors is increased at the rate of about 2.5% every year, and the mortality rate is increased every year.
Histone Deacetylases (HDACs) are a class of catalytic enzymes that catalyze the cleavage of terminal lysine residues in various substrates (e.g., nucleosome histones)A family of acyl-hydrolyzing proteases. Until now, human HDACs were found to comprise 18 subtypes of 4 subfamilies. The active sites of the three classes I (1, 2, 3, 8), II (4, 5, 6, 7, 9, 10) and IV (11) are zn-dependent2+While class III HDAC (SIRT 1-7) is NAD dependent+. They play a crucial role in regulating gene expression and in regulating various cellular processes. Histone tails with "naked" arginine or lysine residues (unmodified amine groups) are typically positively charged, which facilitates interaction of the histone tail with negatively charged phosphate groups on the DNA backbone. Histone deacetylation is involved in increasing binding affinity of histone to DNA, blocking gene transcription. Histone deacetylase mainly plays the following roles in the occurrence and development process of tumors: 1. promoting the proliferation, invasion and migration of tumor cells; 2. promoting the generation of new vessels of tumor tissues; 3. enhancing the drug resistance of tumor cells to radiotherapy and chemotherapy drugs; 4. inhibiting tumor cell differentiation and apoptosis.
The key role of HDACs in organisms has been demonstrated in studies using mice with members of HDAC subclass I knocked out. HDAC1 deficient mice die after birth and are generally slow growing, severely deficient in proliferation; HDAC2 deficient mice die after birth from cardiac malformations; HDAC3 deficient mice die after birth from a primitive intestinal malformation. Furthermore, HDAC1 deficient mice appear to be critical for gene expression. HDACs vary widely among cancer cells and are tumor type specific. HDAC1 is abundantly expressed in lung, prostate, stomach, colon, esophageal and breast cancers. HDAC2 was highly expressed in cervical, gastric and colorectal cancers. Furthermore, HDAC3 is highly expressed in breast and colon cancers, whereas HDAC6 is overexpressed in breast tumors. HDAC8 is abundantly expressed in neuroblastoma cells, HDAC11 is predominantly expressed in rhabdomyosarcoma. The expression level and/or histone acetylation level of different HDACs may be different, possibly affecting the function of single-target HDAC inhibitors.
HDACs have become a very promising target for cancer therapy and, in the past, a number of HDAC inhibitors have been developed, including SAHA, belinostat, panabiostat, valproic acid, and the like. HDACi has a common pharmacophore model: zinc Binding Group (ZBG), Linker region (Linker) and surface recognition group (CAP). Oxadiazole derivatives generally have specific and highly pharmacological properties, such as anti-inflammatory, antibacterial, anticonvulsant and anticancer properties. Due to the multiple applicability of 1,2, 4-oxadiazoles in medicinal chemistry, we focused mainly on 1,2, 4-oxadiazole derivatives.
Disclosure of Invention
Aiming at the problem that the existing histone deacetylase inhibitor has poor effect on solid tumors, the invention combines an oxadiazole structure as a CAP region with a hydroxamic acid structure to synthesize a novel histone deacetylase inhibitor.
In order to achieve the purpose, the invention adopts the following technical scheme.
An oxadiazole hydroxamic acid compound has a structural formula shown in formula (I):
I
wherein R is
The number of the carbon chain is a straight chain C above C3, and the substitution on the benzene ring is single substitution.
The number of C of the above C3 straight chain C is less than 6C; the monosubstituent on the benzene ring is a halogen substituent.
A single substituent on the phenyl ring; preferably, the substituents are independently selected from halogen.
The mono-substituent on the phenyl ring is a halogen substituent and its substitution position is changed.
The R is:
the compound can be obtained by adopting the following synthesis method:
compound 1 and bromoacetonitrile to produce compound 2; reacting the compound 2 with pimelic anhydride in a solvent A to obtain a compound 3; carrying out esterification reaction on the compound 3 and methanol to obtain a compound 4; reacting the compound 4 with hydroxylamine hydrochloride to obtain a compound 5; reacting the compound 5 with benzoyl chloride in a solvent B to obtain a compound 6; compound 6 is generated in a dichloromethane solution 7 of boron tribromide; reacting the compound 7 with a bromide of the R to generate a compound 8; and reacting the compound 8 with hydroxylamine hydrochloride in a solvent B, and separating and purifying to obtain a target product 9.
The synthetic route is as follows:
the solvent A is selected from absolute ethyl alcohol, dimethylformamide, toluene, benzene or tetrahydrofuran. The solvent B is selected from dioxane, dichloromethane, methanol, ethanol, dimethyl sulfoxide or toluene.
The pharmaceutically acceptable salts of the above compounds, preferably the salts are acid addition salts. More preferably, the acid is succinic acid, maleic acid, salicylic acid, hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, or pyruvic acid.
The compound and the pharmaceutically acceptable salt thereof are applied as histone deacetylase inhibitors. In particular, the compound can be used as a medicament for preventing and treating cancer, malignant tumor or inflammation caused by imbalance of histone acetylation regulation; can also be used as antitumor drug after chemotherapy failure caused by induced acquired drug resistance.
Preferably, the cancer or tumor is selected from breast cancer or non-small cell lung cancer.
A medicament comprising the above compound and pharmaceutically acceptable salts thereof.
The invention has the following advantages:
the hydroxamic acid histone deacetylase inhibitor containing the oxadiazole structure has good inhibition activity on HDAC1, and the inhibition activity is superior to SAHA; the series of compounds combine the advantages of oxadiazole and hydroxamic acid, and the obtained compounds as histone deacetylase inhibitors can be applied to medicines for preventing and treating cancers or inflammations; can also be used in the drugs for inducing the acquired drug resistance to cause the anti-tumor therapy after chemotherapy failure.
Detailed Description
The present invention will be further illustrated with reference to the following examples, but the present invention is not limited to the following examples.
Example 1 Synthesis and characterization of oxadiazole hydroxamic acids
In the present embodiment, the first and second electrodes are,1H-NMR was measured with a Bruker AVANCE III HD 600 Mm NMR spectrometer; MS is measured by an Agilent 6440 Triple Quad LC/MS type instrument and is in an ESI mode except for the indication; all solvents are redistilled before use, and the used anhydrous solvents are obtained by drying according to a standard method; all reactions were carried out under argon protection and followed by TLC except for the indication, and the post-treatment was carried out by washing with saturated saline and drying with anhydrous magnesium sulfate; purification of the product except for the indication silica gel 200 and 300 mesh) column chromatography; the silica gel used, including 200-300 mesh and GF254, was produced by Qingdao Seawa silica gel desiccant, Inc.
The specific synthesis steps are as follows:
(a) dissolving p-methoxyaniline (3600 mg and 30 mmol) and bromoacetonitrile in 4 mL of DMF (N-N dimethylformamide), stirring overnight at normal temperature, evaporating the solvent to dryness, and separating the target intermediate compound by silica gel column chromatography;
(b) reacting the compound 3240 mg and 20 mmol) obtained in the step (a) with pimelic anhydride in a dioxane solution, stirring and refluxing at 110 ℃ for 5 hours, evaporating the solvent, extracting with acid and base, evaporating the filtrate, and separating a target intermediate compound by a silica gel column chromatography;
(c) dissolving the compound (4300 mg, 14.2 mmol) obtained in the step (b) with 6 mL of methanol, adding two drops of thionyl chloride, refluxing and stirring at 70 ℃ for 4 h, evaporating the solvent, extracting with EtOAc, performing conventional treatment, and passing through a silica gel column;
(d) dissolving the compound (3000 mg, 9.4 mmol) obtained in the step (c) in a mixed system of ethanol and water, adding hydroxylamine hydrochloride, stirring at normal temperature overnight, evaporating the solvent to dryness, and then passing through a silica gel column to obtain a target intermediate compound;
(e) dissolving the compound (2070 mg and 5.89 mmol) obtained in the step (d) in a mixed system of dioxane and pyridine, slowly adding benzoyl chloride under the protection of nitrogen, stirring and refluxing at 110 ℃ for 4 hours, evaporating the solvent to dryness, extracting with ethyl acetate, evaporating the solvent to dryness again, and passing through a silica gel column;
(f) dissolving the compound (1650 mg, 3.77 mmol) obtained in the step (e) in 10 mL of dichloromethane, slowly adding boron tribromide in an ice bath, stirring at normal temperature for 6 h, adding methanol for inactivation, evaporating the solvent to dryness, and passing through a silica gel column to obtain a target intermediate compound;
g) dissolving the compound (300 mg, 0.71 mmol) obtained in the step (f) in 4 mLDMFN-N dimethylformamide, adding allyl bromide, stirring at 50 ℃ for 6 h, evaporating the solvent, extracting with ethyl acetate, evaporating the solvent again, and purifying with a silica gel column to obtain a target intermediate compound;
(h) reacting hydroxylamine hydrochloride with potassium hydroxide in methanol, filtering to obtain filtrate, dissolving the compound (153 mg, 0.33 mmol) obtained in the step (g) in the filtrate, stirring at 40 ℃ for 5 h, performing conventional treatment, and passing through a silica gel column to obtain a target compound QY 01;
replacing the allyl bromide of step (g) with a different bromine-substituted compound according to this method to produce the remaining compound QY02-QY 13;
the yield, purity and characterization of the compounds QY01-QY13 are as follows.
N1-hydroxy-N7- (4- (2-methoxyethoxy) phenyl) -N7- ((5-phenyl-1, 2, 4-oxadiazol-3-yl) methyl) pimelide (QY 01) yield: 34.9%
1H NMR (600 MHz, DMSO-d 6 ) δ 10.29 (br s, 1H), 8.63 (br s, 1H), 8.09 (d, J = 7.2 Hz, 2H), 7.72 (dd, J = 7.8 Hz, J = 7.2 Hz, 1H), 7.65-7.63 (m, 2H), 7.32-7.30 (m, 2H), 6.98 (d, J = 9.0 Hz, 2H), 4.97 (s, 2H), 4.09 (t, J = 7.2 Hz, 2H), 3.64 (t, J = 4.8 Hz, 2H), 3.29 (s, 3H), 2.03 (t, J = 7.8 Hz, 2H), 1.87 (t, J = 7.2 Hz, 2H), 1.47-1.35 (m, 4H), 1.15-1.10 (m, 2H).
N1-hydroxy-N7- (4- (3-methoxypropoxy) phenyl) -N7- ((5-phenyl-1, 2, 4-oxadiazol-3-yl) methyl) pimelide (QY 02) yield: 41%
1H NMR (600 MHz, DMSO-d 6 ) δ (10.32 br s, 1H), 8.67 (br s, 1H), 8.09 (d, J = 7.2 Hz, 2H), 7.73-7.64 (m, 3H), 7.31 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 4.97 (s, 2H), 4.09 (t, J = 7.2 Hz, 2H), 3.49-3.44 (m, 2H), 3.23 (s, 3H), 2.06-1.87 (m, 6H), 1.44-1.37 (m, 4H), 1.17-1.12(m, 2H).
3. N1- (4- (2-ethoxyethoxy) phenyl) -N7-hydroxy-N1- ((5-phenyl-1, 2, 4-oxadiazol-3-yl) methyl) pimelide (QY 03) yield: 36.5%
1H NMR (600 MHz, DMSO-d 6 ) δ 10.29 (br s, 1H), 8.63 (br s, 1H), 8.10(d, J = 7.2 Hz, 2H), 7.73-7.70 (m, 1H), 7.65-7.63 (m, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 4.98 (s, 2H), 4.11-4.08 (m, 2H), 3.64 (t, J = 4.8 Hz, 2H), 3.50-3.47( m, 2H), 3.17 (d, J = 5.4 Hz, 2H), 2.04 (t, J = 7.2 Hz, 2H), 1.88-1.86 (m, 2H), 1.47-1.35( m, 4H), 1.11 (t, J = 6.6 Hz, 3H).
4.N1-hydroxy-N7- ((5-phenyl-1, 2, 4-oxadiazol-3-yl) methyl) -N7- (4-propoxyphenyl) pimelinamide (QY 04) yield 42.1%
1H NMR (600 MHz, DMSO-d 6 ) δ 10.30( br s, 1H), 8.64 (br s, 1H), 8.10-7.99 (m, 2H), 7.73-7.56 (m, 3H), 7.37 (d, J = 9.0 Hz, 1H), 7.30(d, J = 9.0 Hz, 1H), 7.01-6.95 (m, 2H), 5.11 (s, 1H), 4.97 (s, 1H), 3.94-3.91 (m, 2H), 2.08-2.02 (m, 2H), 1.87 (t, J = 7.2 Hz, 2H), 1.75-1.69 (m, 2H), 1.47-1.35 (m, 4H), 1.16-1.10 (m, 2H), 0.98-0.95 (m, 3H).
5.N1- (4-butoxyphenyl) -N7-hydroxy-N1- ((5-phenyl-1, 2, 4-oxadiazol-3-yl) methyl) pimelide (QY 05) yield 38.6%
1H NMR (600 MHz, DMSO-d 6 ) δ 10.30(br s, 1H), 8.64 (br s, 1H), 8.09 (d, J = 7.8 Hz, 2H), 7.72-7.70 (m, 1H), 7.65-7.62 (m, 2H), 7.30 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 4.97 (s, 2H), 2.05-1.98 (m, 2H), 1.87 (t, J = 7.2 Hz, 2H), 1.70-1.65 (m, 2H), 1.47-1.35 (m, 6H), 1.18-1.11 (m, 2H). 0.91 (t, J = 7.2 Hz, 3H).
6.N1-hydroxy-N7- (4-isobutoxyphenyl) -N7- ((5-phenyl-1, 2, 4-oxadiazol-3-yl) methyl) pimelide (QY 06) yield: 43.5%
1H NMR (600 MHz, DMSO-d 6 ) δ 10.30 (br s, 1H), 8.64 (br s, 1H), 8.10 (d, J = 7.8 Hz, 2H), 7.72 (dd, J = 7.2 Hz, J = 7.2 Hz,1H), 7.64-7.58 (m, 2H), 7.31 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 4.98 (s, 2H), 3.76-3.73 (m, 2H), 2.08-1.99 (m, 3H), 1.88 (t, J = 7.2 Hz, 2H), 1.47-1.36 (m, 4H), 1.16-1.11 (m, 2H), 0.98-0.96 (m, 6H).
7.N1- (4- (allyloxy) phenyl) -N7-hydroxy-N1- ((5-phenyl-1, 2, 4-oxadiazol-3-yl) methyl) pimelide (QY 07) yield 28.4%
1H NMR (600 MHz, DMSO-d 6 ) δ 10.30 (br s, 1H), 8.64 (br s, 1H), 8.10 (d, J = 7.2 Hz, 2H), 7.73-7.70 (m, 1H), 7.65-7.62 (m, 2H), 7.32 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H), 6.06-6.00 (m, 1H), 5.39 (d, J = 10.2 Hz, 1H), 5.26 (d, J = 10.2 Hz, 1H), 4.97 (s, 2H), 4.57 (d, J = 5.4 Hz, 2H), 2.03 (t, J = 7.2 Hz, 2H), 1.87 (t, J = 7.2 Hz, 2H), 1.47-1.35 (m, 4H), 1.18-1.11 (m, 2H).
8. N1- (4- (cyclopropylmethoxy) phenyl) -N7-hydroxy-N1- ((5-phenyl-1, 2, 4-oxadiazol-3-yl) methyl) pimelide (QY 08) yield: 32.6%
1H NMR (600 MHz, DMSO-d 6 ) δ 10.30 (br s, 1H), 8.64 (br s, 1H), 8.09 (d, J = 7.8 Hz, 2H), 7.72-7.70 (m, 2H), 7.65-7.56 (m, 2H), 7.30 (d, J = 9.0 Hz, 2H), 6.96 (t, J = 9.0 Hz, 2H), 4.97 (s, 2H), 3.81 (d, J = 3.0 Hz, 2H), 2.08-2.02 (m, 2H), 1.87 (t, J = 7.2 Hz, 2H), 1.46-142 (m, 2H), 1.39-1.35 (m, 2H), 1.22-1.18 (m, 1H), 1.17-1.10 (m, 2H). 0.57-0.54 (m, 2H), 0.32-0.29 (m, 2H).
9. N1-hydroxy-N7- (4- (2-morpholinoethoxy) phenyl) -N7- ((5-phenyl-1, 2, 4-oxadiazol-3-yl) methyl) pimelide (QY 09) yield: 43.5%
1H NMR (600 MHz, DMSO-d 6 ) δ 10.29 (br s, 1H), 8.63 (br s, 1H), 8.10(d, J = 7.2 Hz, 2H), 7.73-7.70 (m, 1H), 7.65-7.63 (m, 2H), 7.31 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 4.97 (s, 2H), 4.10-4.07 (m, 2H), 3.56 (t, J = 4.2 Hz, 4H), 3.17 (d, J = 5.4 Hz, 1H), 2.67 (t, J = 5.4 Hz, 2H), 2.45 (s, 4H), 2.03 (t，J = 7.2 Hz, 2H), 1.87 (t, J = 7.2 Hz, 2H), 1.47-1.35 (m, 4H), 1.15-1.11 (m, 2H).
10.N1- (4- (cyclohexylmethoxy) phenyl) -N7-hydroxy-N1- ((5-phenyl-1, 2, 4-oxadiazol-3-yl) methyl) pimelide (QY 10) yield: 48.7%
1H NMR (600 MHz, DMSO-d 6 ) δ 10.30 (br s, 1H), 8.09 (d, J = 7.8 Hz, 2H), 7.72-7.70 (m, 1H),7.65-7.56 (m, 2H), 7.30 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz，2H), 4.97 (s, 2H), 3.78-3.75 (m, 2H), 2.08-2.02 (m, 2H), 1.91-1.86 (m，2H), 1.78 (d, J = 12.0 Hz, 2H), 1.69 (t, J = 9.6 Hz, 3H), 1.63 (d, J = 12.6 Hz, 1H), 1.47-1.35 (m, 4H), 1.26-1.10 (m, 5H), 1.09-0.99 (m, 2H).
11. N1-hydroxy-N7- (4- (((4-methylbenzyl) oxy) phenyl) -N7- ((5-phenyl-1, 2, 4-oxadiazol-3-yl) methyl) pimelinamide (QY 11) yield 39.1%
. 
1H NMR (600 MHz, DMSO-d 6 ) δ 10.31 (br s, 1H), 8.66 (br s, 1H), 8.09 (d, J = 7.2 Hz, 2H), 7.72-7.70 (m, 1H), 7.65-7.62(m, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.40-7.37 (m, 2H), 7.34-7.32 (m, 3H), 7.06 (d, J = 9.0 Hz, 2H), 5.09 (s, 2H), 4.98 (s, 2H), 2.04 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.47-1.42 (m, 2H), 1.40-1.35 (m, 2H), 1.15-1.10 (m, 2H).
12.N1-hydroxy-N7- (4- ((4-methylbenzyl) oxy) phenyl) -N7- ((5-phenyl-1, 2, 4-oxadiazol-3-yl) methyl) pimelide (QY 12) yield: 40.2%
1H NMR (600 MHz, DMSO-d 6 ) δ 10.32 (br s, 1H), 8.67 (br s, 1H), 8.09 (d, J = 7.2 Hz, 2H), 7.72-7.69 (m, 1H), 7.64-7.61 (m, 2H), 7.33-7.31 (m, 4H), 7.18 (d, J = 7.8 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 5.03 (s, 2H), 4.97 (s, 2H), 2.29 (s, 3H), 2.04 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.2 Hz, 2H), 1.47-1.36 (m, 4H), 1.18-1.10 (m, 2H).
13.N1- (4- ((3-bromobenzyl) oxy) phenyl) -N7-hydroxy-N1- ((5-phenyl-1, 2, 4-oxadiazol-3-yl) methyl) pimelide (QY 13) yield: 41.4%
1H NMR (600 MHz, DMSO-d 6 ) δ 10.30 (br s, 1H), 8.64 (br s, 1H), 8.09 (d, J = 7.2 Hz, 2H), 7.73-7.70 (m, 1H), 7.66-7.62 (m, 3H), 7.60-7.56 (m, 1H), 7.54-7.52 (m, 1H) ,7.46 (d, J = 7.8 Hz, 1H) , 7.41-7.33 (m, 3H), 7.07 (d, J = 9.0 Hz, 2H), 5.12 (d, J = 8.4 Hz, 2H), 4.98 (s, 2H), 2.09-2.03 (m, 2H), 1.89-1.86 (m, 2H), 1.47-1.35 (m, 4H), 1.17-1.10 (m, 2H)。
EXAMPLE 2 inhibition of HDAC1 enzymatic Activity by Compounds QY01-QY13
Using Ac-Lys-Tyr-LysAc) -AMC as a substrate, and adopting a fluorescence detection method to detect the enzyme activity in a 96-hole or 384-hole flat-bottom microplate: after deacetylation of substrate Ac-Lys-Tyr-LysAc) -AMC by HDAC1, product AMC obtained by hydrolysis with pancreatin emitted 460nm fluorescence under 355nm excitation by a fluorescence detector. The intensity of fluorescence is influenced after the inhibitor is added, the initial reaction speed is calculated by detecting the change of a fluorescence signal along with time, and IC is calculated50The results are shown in table 1, using SAHA as a positive control:
inhibition of HDAC1 by the compounds QY01-QY13 of Table 1
From table 1, it can be seen that the compound QY01-13 has certain inhibitory activity on HDAC1, and is significantly superior to SAHA, and particularly, the inhibitory activity of QY07 is 10 times higher than SAHA.
Claims (10)
1. An oxadiazole hydroxamic acid compound has a structural formula shown in formula (I):
I
wherein R =
2. A compound according to claim 1, wherein the number of carbon chains is C5The substitution on the benzene ring is disubstituted.
3. The compound of claim 1, wherein the substituents on the phenyl ring that vary are alkoxy substituents.
4. Compound according to claim 1, characterized in that the varying substituents on the phenyl ring are preferably independently selected from alkoxy compounds.
5. The compound of claim 1, wherein the substituents on the phenyl ring are alkoxy substituents and vary the length of the alkoxy chain.
6. The compound of claim 1, wherein R is:
7. a pharmaceutically acceptable salt of a compound as claimed in any one of claims 1 to 6.
8. The compound of claim 7, wherein the salt is an acid addition salt; preferably, the acid is succinic acid, maleic acid, salicylic acid, hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid or pyruvic acid.
9. Use of a compound according to any one of claims 1 to 8 as a histone deacetylase inhibitor; preferably, the compound is used as a medicament for preventing and treating cancers, malignant tumors or inflammations caused by imbalance of histone acetylation regulation or used as an anti-tumor medicament after chemotherapy failure caused by induced acquired resistance; the cancer or tumor is preferably breast cancer or non-small cell lung cancer.
10. A medicament comprising a compound as claimed in any one of claims 1 to 8.
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| CN103951649A (en) * | 2014-04-22 | 2014-07-30 | 华东师范大学 | Heterocycle substituted hydroxamate aromatic amide compound or pharmaceutical acceptable salt thereof, and preparation method and application thereof |
| CN108530378A (en) * | 2018-05-29 | 2018-09-14 | 济南大学 | The disubstituted hydroxamic acid compounds of nitrogen-atoms of a kind of Han You oxadiazole structures, purposes and preparation method thereof |
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2021
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| WO2006075888A1 (en) * | 2005-01-14 | 2006-07-20 | Sk Corporation | Oxazole hydroxamic acid derivatives and use thereof |
| CN102731343A (en) * | 2012-05-31 | 2012-10-17 | 华东师范大学 | Nitrogen atom-polysubstituted micro-molecular organic aryl amide compounds and derivatives thereof, and application and preparation method thereof |
| CN103951649A (en) * | 2014-04-22 | 2014-07-30 | 华东师范大学 | Heterocycle substituted hydroxamate aromatic amide compound or pharmaceutical acceptable salt thereof, and preparation method and application thereof |
| CN108530378A (en) * | 2018-05-29 | 2018-09-14 | 济南大学 | The disubstituted hydroxamic acid compounds of nitrogen-atoms of a kind of Han You oxadiazole structures, purposes and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114685496A (en) * | 2022-04-08 | 2022-07-01 | 佛山市晨康生物科技有限公司 | Synthesis and application of hydroxamic acid based HDAC6 inhibitor |
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