CN108299255A - Histone deacetylase 8 selective depressant and its preparation method and application - Google Patents
Histone deacetylase 8 selective depressant and its preparation method and application Download PDFInfo
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- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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Abstract
The invention discloses a kind of histone deacetylase 8 selective depressants and its preparation method and application.The histone deacetylase 8 selective depressant has structure shown in logical formula (I) as follows or (II).The present invention also provides the preparation method of such compound and preparing the application for preventing or treating with the drug of the abnormal relevant disease of HDAC8 activity.
Description
Technical field
The present invention relates to a kind of histone deacetylase 8 (HDAC8) selective depressant and its preparation method and application,
Belong to organic compound synthesis and medical applications technical field.
Background technology
Histon deacetylase (HDAC) (HDACs) is a kind of protease, can be catalyzed DNA methylase inhibitor, make its with it is negatively charged
The DNA of lotus combines closely, chromatin densification curling, to inhibit the transcription of related gene.Therefore, knots of the HDACs to chromosome
Structure is modified and gene expression regulation plays an important role.There are 18 members in the HDACs families found in human body at present, point
For four classes：I classes (HDAC1,2,3 and 8)；II classes (IIa：HDAC4,5,7 and 9；IIb：HDAC6,10)；Group III HDACs (SIRT
1-7) and IV classes (HDAC11).Wherein, I classes, II classes and IV classes rely on zinc ion and function, and Group III HDACs (SIRT 1-
7) NAD is then relied on+Function (Zagni, C.；Floresta,G.；Monciino,G.；Rescifina,A.,The Search
for Potent,Small-Molecule HDACIs in Cancer Treatment:A Decade After
Vorinostat.Med Res Rev 2017,37(6),1373-1428).More and more research shows that HDACs unconventionality expressions
It can lead to generation of various diseases, such as cancer, virus infection, inflammation and neurodegenerative disease etc..So far, 5 are shared
A HDACs inhibitor Vorinostat (SAHA), romidepsin (FK228), his (PXD101), pabishta (LBH589) of Baily department
Listing is gone through for treatment of cancer up to aniline (CS055) with west.However, the drug of this 5 listings that go through belongs to non-selection
Property HDACs inhibitor, there is more serious toxic side effects, such as：Tired, diarrhea, oligocythemia, leukopenia,
Thrombopenia and cardiac toxic (Alokta Chakrabarti, J.M., Fiona R Kolbinger, Ina Oehme,
Johanna Senger,Olaf Witt,Wolfgang Sippl&Manfred Jung,Targeting histone
deacetylase 8 as a therapeutic approach to cancer and neurodegenerative
diseases.Future Medicinal Chemistry 2016,8(13),1609-1634).And subtype-selective HDACs suppressions
Preparation is expected to avoid the toxic side effect of above-mentioned wide spectrum HDACs inhibitor.
HDAC8 is very unique in I classes HDACs, the protein that it is 42kDa by the molecular weight that 377 amino acid form,
It is mainly distributed in nucleus and cytoplasm, important role is played the part of in many physiology and pathologic process.Although histone is
No is that HDAC8 substrates still have dispute, but it is the bottom of HDAC8 that a large amount of nonhistones (such as SMC3, ERR α and p53), which is reported,
The ligand of object or its interaction.It to be essential for the expression of p53 that some researches show that HDAC8, and HDAC8 strikes
Low (knockdown) shows antiproliferative activity in the cell being mutated with p53, this indicates that HDAC8 inhibitor is possible to
As the adjuvant therapy medicaments with p53 mutated tumors.In addition, more and more evidences show HDAC8 activity or abnormal expression
In many diseases, especially in t cell lymphoma, children's neuroblastoma and Cornelia de Lange syndromes
(CdLS) (Chakrabarti, A. are played a crucial role in；Oehme,I.；Witt,O.；Oliveira,G.；Sippl,
W.；Romier,C.；Pierce,R.J.；Jung,M.,HDAC8:a multifaceted target for therapeutic
interventions.Trends Pharmacol Sci 2015,36(7),481-92).Currently, some researches show that HDAC8
Selective depressant, such as PCI-34051 have specific inhibitory effect to t cell lymphoma and neuroblastoma, are expected to
Develop into efficient, less toxic antitumor drug.
Invention content
In view of the deficiencies of the prior art, the present invention provides a kind of histone deacetylase 8 (HDAC8) selective depressants
And its preparation method and application.
Technical scheme is as follows：
One, histone deacetylase 8 (HDAC8) selective depressant
The present invention histone deacetylase 8 (HDAC8) selective depressant be have the following structure logical formula (I) or
(II) compound and its optical isomer of structure shown in, diastereoisomer and racemic mixture, it is pharmaceutically acceptable
Salt, solvate or prodrug：
Wherein：N=0-8；
R1It is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocyclic radical；
R2It is hydrogen, aliphatic group, aryl radical；
R3It is hydrogen, aliphatic group, aryl radical；
* it is S or R configurations or its raceme.
According to currently preferred, wherein：
N=0-3；
R1It is phenyl, substituted-phenyl；
R2It is-H ,-CH3,-CH(CH3)2,
R3It is
* it is S configurations.
According to the present invention it is further preferred that above compound is one of following：
Two, the preparation method of histone deacetylase 8 (HDAC8) selective depressant
The preparation of histone deacetylase 8 (HDAC8) selective depressant of the present invention includes the following steps：Raw material 1 with
Methanol occurs esterification and generates compound 2, and then key intermediate 3, intermediate is obtained by the reaction in compound 2 with thionyl chloride again
3 are condensed to yield compound 5a-5q with compound 4a-4q respectively again；Finally, compound 5a-5q in methanol solution with azanol potassium
Target compound 6a-6q is obtained by the reaction；
Synthetic route is as follows：
Wherein, n, R1, R2, R3Definition with described in logical formula (I) and logical formula (II)；
Reagent in said synthesis route and reaction condition：a:Methanol, hydrochloric acid, sodium bicarbonate；b:Thionyl chloride, N, N- bis-
Methylformamide；c:Triethylamine, toluene；d:Potassium hydroxide, hydroxylamine hydrochloride, methanol.
According to currently preferred, the system of histone deacetylase 8 (HDAC8) selective depression immunomodulator compounds 6a-6q
It is standby, by taking compound 6b as an example, it is as follows：
Intermediate 2：3- methoxycarbonyl benzene sulfonic acid sodium salts
By 11.2g raw material 3- carboxyl benzene sulfonates, 145mL absolute methanols, 34mL 12mol/L concentrated hydrochloric acids at 25 DEG C of room temperature
Back flow reaction 4-6h, reaction are finished, and filtering reacting liquid removes White residule, by filtrate and 10g anhydrous sodium bicarbonate normal-temperature reactions
1h filters out precipitation, washs filter residue with a small amount of methanol, merging filtrate adds 135mL methanol, place is evaporated after secondary filter again after concentration
Reason, it is spare to obtain intermediate 2；Obtain solid 9.8g, yield 82%；
Intermediate 3：Methyl -3- chlorosulfonyl benzoic ethers
It will flow back 4-6 hours at 10g intermediates 2,180mL thionyl chlorides, 80 DEG C of 0.2mL n,N-Dimethylformamide, instead
After answering, reaction solution is let cool, half solvent is evaporated off, is slowly added to mixture of ice and water thereto under clout ice bath stirring, waits for
Filtering, vacuum diaphragm pump are drained after being quenched completely, obtain 8 grams of compound as white solid, yield 85%；Since the intermediate 3 is unstable
Fixed, rapid input is reacted in next step；
Intermediate 5b:Methyl -3- (N- benzyls sulfonamide) benzoic ether
At 25 DEG C of room temperature, 4.2g raw materials benzylamine (4b) and 100mL toluene are put into 500mL round-bottomed flasks, by intermediate 3
It is dissolved in 100mL toluene, filters, instill filtrate in reaction bulb under stirring, drop finishes, the reaction was continued at 25 DEG C of room temperature 2-3h, TLC
After reaction, partial solvent is evaporated off in detection, filters, and uses water and a small amount of toluene to elute respectively filter cake, obtains white solid
4.2g, yield 65%.
The preparation method of compound 5a, 5c-5q are similar with compound 5b；
Target compound 6b：3- (N- benzyls sulfoamido)-N- hydroxybenzamides
1.5g intermediates 5b is dissolved in the freshly prepared azanol potassium solutions of 15mL, stirs 1-2h at 25 DEG C of room temperature, TLC is examined at any time
It surveys, reaction is terminated when until the reaction was complete and no coupling product generates, reaction solution pH to 5-6, filtering are adjusted with 1M aqueous hydrochloric acid solutions
Obtained precipitation, re-crystallizing in ethyl acetate obtain final product 6b, white solid 0.9g, yield 61%.
Three, the application of histone deacetylase 8 (HDAC8) selective depressant
The present invention also provides histone deacetylase 8 (HDAC8) selective depressant prepare prevent or treatment with
Application in the drug of HDAC8 activity or the relevant disease of abnormal expression；Described is relevant with HDAC8 activity or abnormal expression
Disease includes：Various blood tumors (such as t cell lymphoma), solid tumor (such as neuroblastoma), virus infection (such as influenza
Virus infection and human immunodeficiency virus infection etc.), parasitic disease (such as snail fever) etc..
In addition, being suitable for pharmaceutical composition administered orally or parenterally the invention also includes a kind of, comprising lead to formula (I) or
(II) compound and one or more pharmaceutically acceptable carriers described in or excipient.
Specific implementation mode
With reference to embodiment, the present invention is described further, but not limited to this.
The preparation of 1. compound 6a-6q of embodiment, by taking compound 6b as an example
Specific synthetic method and steps are as follows：
Intermediate 2：3- methoxycarbonyl benzene sulfonic acid sodium salts
By raw material 3- carboxyl benzene sulfonates (11.2g, 50mmol), absolute methanol (145mL), concentrated hydrochloric acid (34mL) under room temperature
Back flow reaction 4-6h, reaction are finished, and filtering reacting liquid removes White residule, by filtrate and 10g anhydrous sodium bicarbonate normal-temperature reactions
1h filters out precipitation, washs filter residue with a small amount of methanol, merging filtrate adds 135mL methanol, place is evaporated after secondary filter again after concentration
Reason, it is spare to obtain intermediate 2.Obtain solid 9.8g, yield 82%.
Intermediate 3：Methyl -3- chlorosulfonyl benzoic ethers
It will be at intermediate 2 (10g, 42.0mmol), thionyl chloride (180mL), 80 DEG C of n,N-Dimethylformamide (0.2mL)
Reflux 4-6 hours, after reaction, reaction solution is let cool, half solvent is evaporated off, is slowly added to thereto under clout ice bath stirring
Mixture of ice and water filters after being quenched completely, and vacuum diaphragm pump is drained, and 8 grams of compound as white solid, yield 85% are obtained.Due to
The intermediate 3 is unstable, and rapid input is reacted in next step.
Intermediate 5b:Methyl -3- (N- benzyls sulfonamide) benzoic ether
Under room temperature, by raw material benzylamine (4b, 4.2g, 40mmol) and 100mL toluene input 500mL round-bottomed flasks in, will in
Mesosome 3 is dissolved in 100mL toluene, filtering, instills filtrate in reaction bulb under stirring, and drop finishes, the reaction was continued at room temperature 2-3h,
TLC is detected after reaction, and partial solvent is evaporated off, and is filtered, and is used water and a small amount of toluene to elute respectively filter cake, is obtained white solid
4.2g, yield 65%.1H NMR(400MHz,DMSO-d6) δ 8.38 (s, 1H), 8.27 (t, J=1.7Hz, 1H), 8.15 (m,
1H), 8.06-7.99 (m, 1H), 7.71 (t, J=7.8Hz, 1H), 7.22 (m, 5H), 4.02 (s, 2H), 3.90 (s, 3H).
The preparation method of compound 5a, 5c-5q are similar with compound 5b.
Target compound 6b：3- (N- benzyls sulfoamido)-N- hydroxybenzamides
1.5g intermediates 5b is dissolved in the freshly prepared azanol potassium solutions of 15mL, stirs 1-2h at room temperature, TLC is detected at any time,
Reaction is terminated when until the reaction was complete and no coupling product generates, reaction solution pH to 5-6 is adjusted with 1M aqueous hydrochloric acid solutions, is obtained by filtration
Precipitation, re-crystallizing in ethyl acetate obtains final product 6b, white solid 0.9g, yield 61%.1H NMR(400MHz,DMSO-d6)δ
8.19 (d, J=1.8Hz, 1H), 7.96 (dd, J=7.8,1.5Hz, 1H), 7.91 (m, 1H), 7.65 (t, J=7.8Hz, 1H),
7.25(m,5H),4.01(s,2H)。13C NMR(101MHz,DMSO-d6)δ163.09,141.61,137.97,134.22,
130.80,129.93,129.29,128.69,128.03,127.64,125.65,46.56。HRMS(AP-ESI)m/z calcd
for C14H14N2O4S,[M+H]+307.0753,found 307.0750。
The preparation method of compound 6a, 6c-6q are similar with compound 6b.
The external HeLa nucleus extractions object of 2. target compound of embodiment (including mainly HDAC1 and HDAC2) inhibitory activity
Evaluation experimental
Experimental procedure：Blank group and control group are set：Three multiple holes are arranged in each concentration, and buffer solution 60 is added in blank group
Microlitre, then 37 DEG C of incubation 5min are added 40 microlitres of substrate, continue to be incubated 30min at 37 DEG C, 100 microlitres of ends are then added
Only liquid continues to be incubated 20min, the fluorescence intensity measured under 390nm/460nm is taken out, as blank fluorescence value.100% control group
It takes 50 microlitres of buffer solutions to be mixed with 10 microlitres of HDACs enzyme solutions, and sets three multiple holes, after being incubated 5min, it is micro- that substrate 40 is added per hole
It rises, continues to be incubated 30min, be eventually adding 100 microlitres of terminate liquid, act on and terminating after incubation 20min, measure fluorescent value.Compound
50 microlitres of prepared each concentration solution to be measured, each concentration of each compound is taken all to set three multiple holes with positive drug group, with
After 10 microlitres of HDACs enzyme solutions mixing, it is incubated 5min, the same control group of subsequent operation finally measures fluorescence at 390nm/460nm
Intensity calculates the inhibiting rate under respective concentration, and carries out S curve the Fitting Calculation using Origin softwares, obtains the half of compound
Number inhibition concentration, that is, IC50。
Inhibiting rate calculation formula：
Test the Vorinostat (SAHA) of approved listing according to the above method, he is (PXD101) and of the invention for Baily department
The inhibitory activity of the external HeLa nucleus extractions objects of 6a-6q (main includes HDAC1 and HDAC2).
Test result (table 1) shows non-selective HDACs inhibitor SAHA and PXD101 to HeLa nucleus extraction object tables
Reveal stronger inhibiting effect.In contrast, the compound of the present invention 6a-6q under 20 μM of concentration to HeLa nucleus extractions
Object does not have significant inhibiting effect, prompts compound 6a-6q weaker to HDAC1 and HDAC2 inhibitory activity.
1. external HeLa nucleus extractions object inhibitory activity evaluation result of tablea
aNumerical value is indicated with independent repeated trials mean value formation three times.
The external HDACs subtype-selectives evaluation experimental of 3. target compound of embodiment
HDACs subtype-selectives experimental procedure is consistent with 2 experimental procedure of embodiment.Test result (table 2) shows non-selection
Property HDACs inhibitor SAHA to HDAC2 and HDAC6 have very strong inhibitory activity (IC50Respectively 0.22 μM and 0.09 μM), but
(IC weaker to HDAC8 inhibitory activity505 μM of ＞)；In contrast, compound 6a-6c, 6e-6g, 6k-6l and 6p-6q are shown not
With the HDAC8 inhibitory activity and selectivity of degree, wherein compound 6a-6c is stronger to the inhibitory activity of HDAC8, IC50Value difference
It it is 0.05 μM, 0.08 μM and 0.06 μM, and the hypotype of the HDAC6 to HDAC2 the and class IIb subtribes of class I subtribes
Selectivity is up to 180 times and 30 times respectively.
The external HDACs subtype-selectives evaluation experimental of the representative target compound of table 2.a
aNumerical value is indicated with independent repeated trials mean value formation three times.
The external antiproliferative experiment of 4. target compound of embodiment
Experimental principle：The measurement of micromolecular compound extracorporeal anti-tumor cell-proliferation activity mostly uses mtt assay.MTT (thiazoles
It is blue) entitled 3- (4,5- dimethylthiazoles-the 2) -2,5- diphenyltetrazolium bromide bromides (3- (4,5- of its chemistry
Dimethylthiazol-2-yl) -2,5-diphenylterazolium bromide), it is a kind of dye that can act on colour developing
Material is usually used in detecting cell viability.The MTT and succinate dehydrogenase (Succinate in living cells Mitochondria
Dehydrogenase, SDH) effect so that the MTT of yellow is restored, and royal purple color substance formazan (formazan) is generated.It should
Substance is not soluble in water, but can be dissolved in DMSO, and after experiment, with DMSO Rong Xie formazans, extinction is measured at microplate reader 540nm
Degree.Due to the number positive correlation of living cells in the production quantity and culture solution of formazan, the Er absorbances of formazan solution are dense Yu formazan
Spend it is directly proportional, so measure formazan absorbance can clear cell quantity, You formazan absorbances calculate resisting for untested compound
Tumor cell proliferation effect.
Experimental procedure：Take increased logarithmic phase cell, suspension cell per 7000/100 microlitres of hole, attached cell 3500/
It 100 microlitres, is inoculated into 96 porocyte culture plates, at 37 DEG C, 5%CO2After cultivating 6h in incubator, prepared difference is added
100 microlitres of concentration gradient compound, each concentration set three multiple holes.After cultivating 48 or 72h, 20 microlitres of Fresh are added per hole
MTT storing solutions, at 37 DEG C, 5%CO2Continue to be incubated 4h in incubator, be then centrifuged for discarding culture medium, it is micro- that 200 are added per hole
It rises DMSO and measures absorbance at 540nm, according to the inhibitory activity of the numerical computations compound on intracellular of absorbance.
S curve the Fitting Calculation is carried out using Origin softwares, obtains the half-inhibition concentration i.e. IC of compound50。
Experimental result (table 3) shows that compound 6a, 6b and 6c are to T similar to HDAC8 selective depressant PCI-34051
Cell leukemia cell Jurkat, acute lymphoblastic leukemia cell Molt-4 and neuroblastoma cells SK-N-
BE- (2) shows stronger selecting cell toxicity.However, not having in non-selective hdac inhibitor SAHA and PXD101
Observe this selecting cell toxicity.It is worth noting that, ICs of the compound 6c to Jurkat and Molt-4 cell lines50Value point
Wei not be 7.9 μM and 6.2 μM, it is suitable with PCI-34051, it is expected to be developed further into the antitumor drug for HDAC8 selectivity.
The external antiproliferative experiment of 3. representative compound of tablea
aNumerical value is indicated with independent repeated trials mean value formation three times.
bUndetermined.
Claims (9)
1. histone deacetylase 8 selective depressant is the chemical combination for having the following structure structure shown in logical formula (I) or (II)
Object and its optical isomer, diastereoisomer and racemic mixture, pharmaceutically acceptable salt, solvate or preceding
Medicine：
Wherein：N=0-8；
R1It is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocyclic radical；
R2It is hydrogen, aliphatic group, aryl radical；
R3It is hydrogen, aliphatic group, aryl radical；
* it is S or R configurations or its raceme.
2. histone deacetylase 8 selective depressant as described in claim 1, it is characterised in that：
Wherein：N=0-3；
R1It is phenyl, substituted-phenyl；
R2It is-H ,-CH3,-CH(CH3)2,
R3It is
* it is S configurations.
3. histone deacetylase 8 selective depressant as claimed in claim 1 or 2, it is characterised in that be following chemical combination
One of object：
4. the preparation method of histone deacetylase 8 selective depressant as claimed in claim 1 or 2, including following step
Suddenly：Raw material 1 occurs esterification with methanol and generates compound 2, and then compound 2 is obtained by the reaction with thionyl chloride among key again
Body 3, intermediate 3 are condensed to yield compound 5a-5q with compound 4a-4q respectively again；Finally, compound 5a-5q is in methanol solution
In with azanol potassium target compound 6a-6q is obtained by the reaction；
Synthetic route is as follows：
Wherein, n, R1, R2, R3Definition with described in claims 1 or 2 formula of (I) or logical formula (II)；
Reagent in said synthesis route and reaction condition：a:Methanol, hydrochloric acid, sodium bicarbonate；b:Thionyl chloride, N, N- dimethyl
Formamide；c:Triethylamine, toluene；d:Potassium hydroxide, hydroxylamine hydrochloride, methanol.
5. the preparation method of histone deacetylase 8 selective depressant as claimed in claim 4, wherein compound 6b's
Preparation method includes step：
Intermediate 2：3- methoxycarbonyl benzene sulfonic acid sodium salts
By 11.2g raw material 3- carboxyl benzene sulfonates, 145mL absolute methanols, the reflux of 34mL 12mol/L concentrated hydrochloric acids at 25 DEG C of room temperature
4-6h is reacted, reaction is finished, and filtering reacting liquid removes White residule, filtrate is reacted for 25 DEG C with 10g anhydrous sodium bicarbonates room temperature
1h filters out precipitation, washs filter residue with a small amount of methanol, merging filtrate adds 135mL methanol, place is evaporated after secondary filter again after concentration
Reason, it is spare to obtain intermediate 2；Obtain solid 9.8g, yield 82%；
Intermediate 3：Methyl 3- chlorosulfonyl benzoic ethers
It will flow back 4-6 hours at 10g intermediates 2,180mL thionyl chlorides, 80 DEG C of 0.2mL n,N-Dimethylformamide, reaction knot
Shu Hou lets cool reaction solution, and half solvent is evaporated off, mixture of ice and water is slowly added to thereto under clout ice bath stirring, waits being quenched
Filtering, vacuum diaphragm pump are drained after completely, obtain 8 grams of compound as white solid, yield 85%；It is fast since the intermediate 3 is unstable
Speed input is reacted in next step；
Intermediate 5b:Methyl -3- (N- benzyls sulfonamide) benzoic ether
At 25 DEG C of room temperature, by 4.2g raw materials benzylamine (4b) and 100mL toluene input 500mL round-bottomed flasks, intermediate 3 is dissolved in
In 100mL toluene, filtering instills filtrate in reaction bulb under stirring, and drop finishes, the reaction was continued at 25 DEG C of room temperature 2-3h, TLC detections
After reaction, partial solvent is evaporated off, filters, uses water and a small amount of toluene to elute respectively filter cake, obtains white solid 4.2g, produce
Rate 65%；
The preparation method of compound 5a, 5c-5q are similar with compound 5b；
Target compound 6b：3- (N- benzyls sulfoamido)-N- hydroxybenzamides
1.5g intermediates 5b is dissolved in the freshly prepared azanol potassium solutions of 15mL, 1-2h is stirred at 25 DEG C of room temperature, TLC is detected at any time,
Reaction is terminated when until the reaction was complete and no coupling product generates, reaction solution pH to 5-6 is adjusted with 1M aqueous hydrochloric acid solutions, is obtained by filtration
Precipitation, re-crystallizing in ethyl acetate obtains final product 6b, white solid 0.9g, yield 61%.
6. histone deacetylase 8 selective depressant as described in any one of claims 1-3 prepare prevent or treatment with
Application in the drug of HDAC8 activity or the relevant disease of abnormal expression.
7. application as claimed in claim 6, which is characterized in that described with HDAC8 activity or the relevant disease of abnormal expression
For various blood tumors, solid tumor, virus infection, parasitic disease.
8. the use as claimed in claim 7, which is characterized in that the blood tumor is t cell lymphoma；The solid tumor
For neuroblastoma；The virus infection is influenza infection and human immunodeficiency virus infection；The parasite
Disease is snail fever.
9. a kind of pharmaceutical composition being suitable for administered orally or parenterally, including any histones of claim 1-3 are gone
8 selective depressant of acetylase and one or more pharmaceutically acceptable carriers or excipient.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111278805A (en) * | 2017-08-25 | 2020-06-12 | 路易斯安娜州立大学监测委员会农业和机械学院 | Compositions and methods for ameliorating pain |
| CN113912560A (en) * | 2020-12-07 | 2022-01-11 | 五邑大学 | Oxazole histone deacetylase inhibitor and preparation method and application thereof |
| CN114409638A (en) * | 2022-02-09 | 2022-04-29 | 深圳大学 | Histone deacetylase 8 selective degradation agent, preparation method and application thereof in antitumor activity |
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| CN111278805A (en) * | 2017-08-25 | 2020-06-12 | 路易斯安娜州立大学监测委员会农业和机械学院 | Compositions and methods for ameliorating pain |
| US11458142B2 (en) | 2017-08-25 | 2022-10-04 | The Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Compositions and methods for ameliorating pain |
| US11529355B2 (en) | 2017-08-25 | 2022-12-20 | The Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Compositions and methods for ameliorating pain and reducing fever |
| CN111278805B (en) * | 2017-08-25 | 2023-04-18 | 路易斯安娜州立大学监测委员会农业和机械学院 | Compositions and methods for ameliorating pain |
| CN113912560A (en) * | 2020-12-07 | 2022-01-11 | 五邑大学 | Oxazole histone deacetylase inhibitor and preparation method and application thereof |
| CN114409638A (en) * | 2022-02-09 | 2022-04-29 | 深圳大学 | Histone deacetylase 8 selective degradation agent, preparation method and application thereof in antitumor activity |
| CN114409638B (en) * | 2022-02-09 | 2023-02-14 | 深圳大学 | Histone deacetylase 8 selective degradation agent, preparation method and application thereof in antitumor activity |
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