CN107556349A - A kind of Vorinostat derivative based on palladium carbon and its preparation method and application - Google Patents
A kind of Vorinostat derivative based on palladium carbon and its preparation method and application Download PDFInfo
- Publication number
- CN107556349A CN107556349A CN201710945266.7A CN201710945266A CN107556349A CN 107556349 A CN107556349 A CN 107556349A CN 201710945266 A CN201710945266 A CN 201710945266A CN 107556349 A CN107556349 A CN 107556349A
- Authority
- CN
- China
- Prior art keywords
- vorinostat
- independently
- derivative
- substituted
- palladium carbon
- 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.)
- Granted
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of Vorinostat derivative based on palladium carbon and its preparation method and application.Vorinostat derivative provided by the present invention based on palladium carbon is using Vorinostat as parent compound, and it is water-soluble to improve it by connecting water soluble group, so as to effectively improve the side effect existing during using upper inconvenience and medication of Vorinostat active compound.Meanwhile preparation method simple process of the present invention and operating procedure it is simple, suitable for large-scale production.
Description
Technical field
The present invention relates to antineoplastic preparation field, derives in particular to a kind of Vorinostat based on palladium carbon
Thing and its preparation method and application.
Background technology
Vorinostat (vorinostat), chemical entitled " Vorinostat " or " suberoylanilide is different
Hydroximic acid (SAHA) ", it is first histone deacetylase (HDAC) inhibitors antitumor drugs of Merck companies of U.S. research and development.
Because Vorinostat is capable of the late differentiation of the induced tumor cell of selectivity, so as to suppress such cell under appropriate conditions
Propagation, thus, Vorinostat be used to treat the tumor patient constantly bred of cancer cell, and clinically also bed is mainly used in controlling
Treat skin T cell lymphoma (CTCL invalid after aggravating, continue and recur or being treated with two kinds of systemic medications:One kind is non-suddenly
Strange golden lymthoma, it is a kind of T cell cancer for influenceing skin leukocyte cell types).
VorinostatWent through to list in the U.S. in 2006, there is clear and definite antitumor curative effect, to the greatest extent
Pipe limits the development and application of Vorinostat in this way, because its water solubility is poor.
Under the conditions of defined concentration or physiological pH, the low aqueous solubility of Vorinostat make it difficult to be configured to water for injection to
Medicine (Kelly, W.K. etc., Phase I clinical trial of histone deacetylase inhibitor:
Suberoy lanilide hydroxamic acid administered intravenously.Clin.Cancer Res
2003,9,3578-3588), thus, current formulation with capsule oral be administered based on (FDA (2006) Available at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfmFuseaction=
Search.DrugDetails).To maintain vivo medicine concentration to generate diarrhoea, fatigue, nausea, dysgeusia, nerve
A variety of adverse reactions such as apositia, anemia, decrease of platelet (Krug, L.M. etc., [J] .Clin.Lung Cancer 2006,
7,257).Especially, when we face the patient that can not swallow, such as baby, critically ill patient, can not when paralysis or coma patient
Realize be administered orally, at this time medicine can not drug administration by injection problem just become especially prominent (US20100240601A).
Therefore, it is water-soluble to improve Vorinostat, reduces adverse reaction, turns into and ensures that its antitumor chemotherapy is continued
Key.
In view of this, it is special to propose the present invention.
The content of the invention
The first object of the present invention is to provide a kind of Vorinostat derivative based on palladium carbon, and described Vorinostat spreads out
Biology has good water solubility, can effectively prevent adverse reaction.
The second object of the present invention is to provide a kind of preparation method of the described Vorinostat derivative based on palladium carbon,
This method has the advantages that preparation method flow is few, easy to operate.
The third object of the present invention is to provide a kind of application of the Vorinostat derivative based on palladium carbon.
The fourth object of the present invention is to provide a kind of medicine for including the Vorinostat derivative of the invention based on palladium carbon
Or pharmaceutical composition.
In order to realize the above-mentioned purpose of the present invention, spy uses following technical scheme:
A kind of Vorinostat derivative based on palladium carbon, the Vorinostat derived structure based on palladium carbon are as follows:
In formula (I), R1-R4Independently for hydrogen, hydroxyl, or carboxyl;R5、R7The substitution for C0-C20 independently
Or unsubstituted alkylidene;R6、R8Independently for hydrogen, C1-C20 substituted or unsubstituted alkyl;Wherein, R1-R4In extremely
Rare a hydroxyl or carboxyl.
Preferably, in the Vorinostat derivative formula (I) of the present invention based on palladium carbon, R1-R4Independently for hydroxyl
Base or carboxyl;R5、R7The substituted or unsubstituted alkylidene for C1-C12 independently;R6、R8Independently for hydrogen, C1-
C12 substituted or unsubstituted alkyl.
Preferably, in the Vorinostat derivative formula (I) of the present invention based on palladium carbon, R1-R4In at least one hydroxyl
Base and a carboxyl;R5、R7The substituted or unsubstituted alkylidene for C1-C6 independently;R6、R8Independently for hydrogen,
C1-C6 substituted or unsubstituted alkyl.
Preferably, in the Vorinostat derivative of the present invention based on palladium carbon, the knot of the Vorinostat derivative
Structure is as follows:
Meanwhile present invention also offers the preparation method of the Vorinostat derivative based on palladium carbon, it is included such as
Lower step:
WillWith Vorinostat condensation reaction,
Then it is deprotected and reduction reaction, produces the Vorinostat derivative;Wherein, in formula (i), R9-R12Independently
For hydrogen, protected hydroxyl, or protected carboxyl;Wherein, R9-R12In at least one protected hydroxyl or protected carboxyl;R5、
R7The substituted or unsubstituted alkylidene for C0-C20 independently;R6、R8Independently for hydrogen, C1-C20 substitution or
Unsubstituted alkyl;X1For halogen.
Preferably, in preparation method of the present invention, in the formula (i), R9-R12Independently for protected hydroxyl or
Protected carboxyl;R5、R7The substituted or unsubstituted alkylidene for C1-C12 independently;R6、R8Independently for hydrogen,
C1-C12 substituted or unsubstituted alkyl;X1For chlorine or bromine.
Preferably, in preparation method of the present invention, in the formula (i), R9-R12In at least one protected hydroxyl and
One protected carboxyl;R5、R7The substituted or unsubstituted alkylidene for C1-C6 independently;R6、R8Independently be
The substituted or unsubstituted alkyl of hydrogen, C1-C6;
X1For chlorine.
Preferably, in preparation method of the present invention, formula (i) structure is as follows:
Meanwhile the application present invention also offers described Vorinostat derivative in anti-tumor medicine is prepared;It is excellent
Choosing, the tumour is skin T cell lymphoma.
It is furthermore preferred that present invention also offers the medicine or pharmaceutical composition for including Vorinostat derivative of the present invention.
Compared with prior art, beneficial effects of the present invention are:
(1) it is that precursor structure carries out structure to active Vorinostat by introducing water soluble group in the present invention
It is modified, so that gained Vorinostat derivative has good water solubility, and can effectively solve the problem that due to Vorinostat water
Side effect in the presence of reality caused by dissolubility difference is medicinal and can not drug administration by injection the problems such as;
Meanwhile Vorinostat derivative provided by the present invention is under the conditions of existing for enzyme, can reach and Vorinostat
The suitable tumor inhibition effect of active compound, thus, it is adapted as the use of tumor suppression prodrug.
(2) in preparation method of the present invention, raw materials used simplicity is easy to get, and preparation method step is easy, simple to operate, together
When without using large-scale instrument, prepare Vorinostat derivative suitable for industrially scalable, and effectively cost of implementation can control,
Mitigate patient burden.
Brief description of the drawings
In order to illustrate more clearly about the embodiment of the present invention or technical scheme of the prior art, below will be to embodiment or existing
There is the required accompanying drawing used in technology description to be briefly described.
Fig. 1 is Vorinostat derivative preparation flow of the present invention.
Embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the present invention.It is unreceipted specific in embodiment
Condition person, the condition suggested according to normal condition or manufacturer are carried out.Agents useful for same or the unreceipted production firm person of instrument, it is
The conventional products that can be obtained by commercially available purchase.
In view of Vorinostat active compound is the use caused by poorly water-soluble is limited and the problems such as side effect, spy of the present invention carries
A kind of new Vorinostat derivative has been supplied, and Vorinostat precursor structure has been modified by introducing water soluble group, from
And offer one kind is new, has good aqueous solubility and practicality, and the tumour suppression suitable with Vorinostat active compound can be reached
Make the Vorinostat derivative of activity.
Specifically, the structure of Vorinostat derivative provided by the present invention is as follows:
Wherein, in formula (I), R1-R4Independently for hydrogen, hydroxyl, or carboxyl, and R1-R4In at least one hydroxyl or
Carboxyl;Preferably, R1-R4Independently for hydroxyl or carboxyl;It is furthermore preferred that R1-R4In at least one hydroxyl and a carboxylic
Base, such as:Can be with R1For carboxyl, R2-R4For hydroxyl;Or can be with R4For carboxyl, R1-R3For hydroxyl;Or can be with R1For
Hydroxyl, R2-R4For carboxyl;Also or, R4For hydroxyl, R1-R3For carboxyl;Or R1、R4For carboxyl, R2、R3For hydroxyl;Also or
Person, R1、R4For hydroxyl, R2、R3For carboxyl etc.;
R5、R7The substituted or unsubstituted alkylidene for C0-C20 independently;Preferably, R5、R7Independently be
C1-C12 substituted or unsubstituted alkylidene;It is furthermore preferred that R5、R7The substituted or unsubstituted Asia for C1-C6 independently
Alkyl;It is further preferred that R5、R7The unsubstituted alkylidene for C1-C6 independently, for example, R5、R7Independently
Can be methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isoamylidene, sub- neopentyl,
Hexylidene etc.;
R6、R8Independently for hydrogen, C1-C20 substituted or unsubstituted alkyl;Preferably, R6、R8Independently
For hydrogen, C1-C12 substituted or unsubstituted alkyl;It is furthermore preferred that R6、R8Independently for hydrogen, C1-C6 substitution or do not take
The alkyl in generation;It is further preferred that R6、R8The unsubstituted alkyl for C1-C6 independently, such as R6、R8Can be respectively
Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, amyl group, isopentyl, neopentyl, hexyl etc..
In Vorinostat derivative provided by the present invention such as above formula (I) structure, in the hydroxyoxime of Vorinostat parent nucleus
It is modified on sour position, and accesses water soluble group, so as to improves the water solubility of Vorinostat active compound.
It is furthermore preferred that Vorinostat derivant structure provided by the present invention is as follows:
As above it is using glucuronic acid group as water soluble group, and to Vorinostat in further preferred compound
Female ring is modified resulting Vorinostat derivative, and its water solubility can reach 600 times of Vorinostat or so;
Meanwhile if above formula (II) compound is under β-D-Glucose aldehydic acid enzyme effect, Vorinostat can be discharged, concurrently
The effect of tumor suppression is waved, thus, the Vorinostat derivative can turn into the prodrug compound of Vorinostat;
Further, catalysis β-D-Glucose aldehydic acid enzyme that such as above formula (II) compound is decomposed is in tumour generation, tumour life
Played an important role in long, infiltration and transfer, especially it can cause the degraded of extracellular matrix and cell basilar memebrane, so as to destroy
The barrier of cancer metastasis, by suppressing the activity of the enzyme or consuming the enzyme, the transfer of tumour cell can be suppressed, played antitumor
Activity.
That is, the Vorinostat derivative provided by the present invention based on palladium carbon can not only be by decomposing release volt
Li Nuota and play a part of suppress tumour, at the same time it can also pass through in catalytic decomposition process consume β-D-Glucose aldehydic acid
Enzyme, so as to play further tumor aid treatment effect.
The preparation method of Vorinostat derivative of the invention based on palladium carbon refers to as follows:Will
With Vorinostat condensation reaction, so
After be deprotected and reduction reaction, produce the Vorinostat derivative;
In formula (i), R9-R12Independently for hydrogen, protected hydroxyl, or protected carboxyl, wherein, R9-R12In at least
There are a protected hydroxyl or protected carboxyl;Preferably, R9-R12Independently for protected hydroxyl or protected carboxyl;
It is furthermore preferred that R9-R12In at least one protected hydroxyl and a protected carboxyl, such as can be with R9For protected carboxyl,
R10-R12For protected hydroxyl;Or can be with R12For protected carboxyl, R9-R11For protected hydroxyl;Or can be with R9For
Protected hydroxyl, R10-R12For protected carboxyl;Also or, R12For protected hydroxyl, R9-R11For protected carboxyl;Or
R9、R12For protected carboxyl, R10、R11For protected hydroxyl;Also or, R9、R12For protected hydroxyl, R10、R11For protected carboxylic
Base etc.;
Protected hydroxyl as described above be with the reacted hydroxyl of protection group, and hydroxyl protecting group can be tert-butyl group diformazan
Base silicon substrate, acetyl group, benzyl, valeryl etc.;Meanwhile shielded carboxyl is and the reacted carboxylic of protection group as described above
Base, and carboxyl-protecting group can be benzyl, pi-allyl etc.;
Starting materials of formulae (i) compound is purchased from raw material supplier, or can also be synthesized as needed, its synthetic method
Refer to prior art (the First enzymatically activated Taxotere such as Bouvier E. prodrugs
Designed for ADEPT and PMT.Bioorganic&Medicinal Chemistry, 2004,12,969-977);
And when including at least one protected hydroxyl and at least one protected carboxyl in starting materials of formulae (i) compound,
In preparation process, eliminating hydroxide protection group first, then, while nitro is reduced, carboxyl-protecting group is removed;
R5、R7The substituted or unsubstituted alkylidene for C0-C20 independently;Preferably, R5、R7Independently be
C1-C12 substituted or unsubstituted alkylidene;It is furthermore preferred that R5、R7The substituted or unsubstituted Asia for C1-C6 independently
Alkyl;It is further preferred that R5、R7The unsubstituted alkylidene for C1-C6 independently, for example, R5、R7Independently
Can be methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isoamylidene, sub- neopentyl,
Hexylidene etc.;
X1For halogen;Preferably, X1For chlorine or bromine;It is furthermore preferred that X1For chlorine.
R6、R8Independently for hydrogen, C1-C20 substituted or unsubstituted alkyl;Preferably, R6、R8Independently
For hydrogen, C1-C12 substituted or unsubstituted alkyl;It is furthermore preferred that R6、R8Independently for hydrogen, C1-C6 substitution or do not take
The alkyl in generation;It is further preferred that R6、R8The unsubstituted alkyl for C1-C6 independently, for example, R6Can be methyl,
Ethyl, propyl group, isopropyl, butyl, isobutyl group, amyl group, isopentyl, neopentyl, hexyl etc., R8It can be methyl, ethyl, third
Base, isopropyl, butyl, isobutyl group, amyl group, isopentyl, neopentyl, hexyl etc.;
Still more preferably, in preparation method of the present invention, raw materials used compound structure is as follows:
And when using compound is raw material as shown in above formula (ii) when, the preparation method of target compound (II) of the present invention can have
Body is with reference to as follows:(a) formula (ii) compound obtains midbody compound (iii), the intermediate with Vorinostat condensation reaction
The structure of compound (iii) is as follows:
Preferably, in step (a), fed under the conditions of 0 DEG C, and by starting materials of formulae (ii) compound and Vorinostat and molten
Agent pyridine mixes, then the condensation reaction 5h under the conditions of 25 DEG C again;
(b) gained formula (iii) compound carries out hydroxyl deprotection in step (a), obtains the formula that structure is as follows
(iv) midbody compound:
In step (b), preferable solvent is tetrahydrofuran, and the temperature of reaction preferably controls to be carried out at 50 DEG C;
(c) gained formula (iv) midbody compound under hydrogen atmosphere and catalyst action, carries out carboxyl in step (b)
Deprotection and reduction, obtain target product (II), that is, obtain
Preferably, in step (c), used catalyst is palladium carbon catalyst;
Preferably, step (c) is reacted in ethanol solution.
Flow produced above can be further with specific reference to Fig. 1.
It is by obtained midbody compound (ii) column chromatography it is further preferred that in preparation flow as described above
After purification, then carry out the reaction of step (b), and products therefrom compound (II) it is also preferred that purified by column chromatography;
Likewise it is preferred that, midbody compound (iv) can not be purified obtained by step (b), is directly used in step (c)
In reaction.
As the Vorinostat derivative based on palladium carbon prepared by the present invention due to good water solubility, but also can
It to discharge Vorinostat by reaction, thus can use it in oncotherapy, and be preferably used in cutaneous T-cell lymph
The treatment of knurl.
Further, because Vorinostat derivative of the present invention based on palladium carbon has good water solubility, thus both may be used
After it further to be mixed with auxiliary material and auxiliary agent, tablets are made, can also be dissolved in physiological saline or glucose
Injection uses;
And during actual oncotherapy use, Vorinostat derivative of the present invention based on palladium carbon can individually be made
With, or itself and other drugs be used cooperatively, and it is provided commonly for the treatment of tumour.
The O- of embodiment 1 [NN- dimethyl-N -s 4- (2,3,4- tri--O- t-Butyldimethylsilyl -6- benzyl-β-D-- pyrroles
Mutter glucuronic acid -1- bases) -3- nitrobenzyloxycarbonyls ethylenediamine]-formoxyl-Vorinostat (iii) preparation
Vorinostat 913mg (3.46mmol) is dissolved in 20mL pyridines, cooled down 5 minutes at 0 DEG C.At 0 DEG C, to above-mentioned
Compound (ii) 3g (3.14mmol) is added in solution, turns into red suspension.The suspension is warming up to 25 DEG C, insulated and stirred
5 hours, 100mL water quenchings were added afterwards and are gone out reaction.Reaction solution is extracted with ethyl acetate (50mL × 3 time), merges organic layer, successively
Extracted with 0.5M HCl (30mL × 4 time), saturated aqueous common salt (30mL × 2 time), anhydrous sodium sulfate drying is dense with Rotary Evaporators
Contracting, preparative chromatography (dichloromethane:Methanol=50:1) isolated intermediate iii 3.4g, yield 92%.
To the sign of product:1HNMR (400MHz, CDCl3) δ 7.45-7.87 (m, 5H), 7.29-7.32 (m, 5H), 7.07-
7.27 (m, 2H), 5.59 (d, J=5.6Hz, 1H), 5.01-5.17 (m, 4H), 4.52 (s, 1H), 4.41 (s, 1H), 4.05 (d, J
=5.6Hz, 1H), 3.85 (d, J=3.6Hz, 1H), 3.46 (m, 4H), 2.89-3.03 (m, 6H), 2.35 (d, J=6.8Hz,
2H), 2.22-2.25 (m, 2H), 1.67-1.73 (m, 5H), 1.26 (m, 2H), 0.84-0.94 (m, 27H), 0.01-0.16 (m,
18H)。
The O- of embodiment 2 [NN- dimethyl-N -s 4- (6- benzyl-β-D-- glucopyra aldehydic acid -1- bases) -3- nitro benzyloxy carbonyls
Base ethylenediamine]-formoxyl-Vorinostat (iv) preparation
Intermediate iii 3.4g (2.87mmol) are dissolved in 18mL tetrahydrofurans, the hydrogen fluorine of triethylamine three is added at 25 DEG C
Hydrochlorate 4.63g (28.7mmol), 50 DEG C are heated to, insulation reaction 16 hours.Reaction is finished, and reaction solution is concentrated with Rotary Evaporators,
50mL water is added in concentrate, (20mL × 4 time) is extracted with ethylacetate/acetonitrile (3/1), merges organic layer, saturated aqueous common salt
Wash 2 times, anhydrous sodium sulfate drying, filter, filtrate is concentrated with Rotary Evaporators, preparative chromatography (dichloromethane:Methanol=50:1)
Isolated crude product iv 5.0g, yield 74%, direct plunge into and react in next step.
The O- of embodiment 3 [NN- dimethyl-N -s 4- (β-D-- glucopyra aldehydic acid -1- bases) -3- aminobenzyloxycarbonyls second two
Amine]-formoxyl-Vorinostat (II) preparation
Crude product iv 84mg (0.1mmol) are dissolved in the ethanol solution that 20mL contains 240mg10%Pd/C, in hydrogen pressure
Stirred 5 hours under power (1bar).Filtered with diatomite (Celite 545), filtrate concentration, preparative chromatography (acetonitrile:Water=9:1)
Isolated solid product II 42mg, yield 58%.
To the sign of product:1HNMR:(400MHz, DMSO-d6) δ 12.32 (s, 1H), 10.42 (s, 1H), 7.83 (s,
1H), 7.56 (d, J=8.8Hz, 1H), 7.46 (d, J=8.4Hz, 2H), 7.34 (d, J=8.8Hz, 1H), 7.24 (t, J=
8Hz, 2H), 7.00 (t, J=7.2Hz, 1H), 5.64 (d, J=6.8Hz, 1H), 5.28 (s, 2H), 5.04 (s, 2H), 4.02 (d,
J=9.6Hz, 1H), 3.70-3.86 (m, 3H), 3.22-3.27 (m, 4H), 3.07 (m, 6H), 2.30 (t, J=7.6Hz, 2H),
1.96 (t, J=7.2Hz, 2H), 1.53-1.60 (m, 4H), 1.35 (m, 4H);
13C NMR (400MHz, DMSO-d6) δ 179.80,173.02,169.97,156.40,156.01,143.21,
140.35,136.70,134.03,133.83,131.69,131.54,128.63,124.69,124.51,122.24,119.30,
119.08,117.21,106.87,78.65,74.41,73.23,72.61,55.57,55.27,38.26,32.64,29.56,
28.02,25.66,25.30.
LCMS:720[M+H]+, 742 [M+Na].
Solubility (unit of the Vorinostat derivative of embodiment 4 in water:μg/mL)
1st, experimental method
By the Vorinostat derivative (II) prepared by present invention method respectively it is excessive be dissolved in 2 it is aqueous micro-
Measure in centrifuge tube (eppendorf pipes), often manage respectively pure water containing 1mL;It is vortexed 20 minutes under the conditions of 25 DEG C respectively, then centrifuges and remove
Suspension (20000rpm, 15 minutes) is removed, finally obtains initial dissolution degree of the prodrug in water with HPLC quantitative analyses.
2nd, experimental result is referring to table 1
Experimental results are as shown in table 1 below:
The Vorinostat of table 1 and the application Vorinostat derivative solubility test
Medicine to be tested | Vorinostat | Vorinostat derivative (II) |
Solubility | 20-50μmol/L | 25-28mmol/L |
Wherein, in table 1, Vorinostat water solubility data refers to prior art ((a) Marks, P.A.Discovery
And development of SAHA as an anticancer agent.Oncogene.2007,26,1351-1356;(b)
The .Selective induction of apoptosisby histone deacety lase such as Zhang inhibitor
SAHA in cutaneous T-cell lymphoma cells:relevance to mechanism of therapeutic
Action. [J] .J Invest Dermatol.2005,125,1045-1052;(c) Cang etc., New clinical
developments in histone deacetylase inhibitors for epigenetic therapy of
Cancer. [J] .J Hematol Oncol.2009,2:22;(d)http://bpsbioscience.com/saha-
vorinostat-27006.);
From the control test result of table 1, relative to Vorinostat, Vorinostat derivative (II) of the present invention is water-soluble
It is significantly increased, water solubility is approximately 560 times of Vorinostat.
The Vorinostat soluble derivative II of embodiment 5 is swollen to difference under the conditions of with or without β-D-Glucose aldehydic acid enzyme
The In-vitro Inhibitory Effect of oncocyte
1st, experiment material
Cell line:HT-29、Hut-78、
Culture medium:Hut-78 uses the IMDM culture mediums containing 20% hyclone, and HT-29 is used containing 10% hyclone
McCoy's 5A culture mediums
Medicine and preparation:The Vorinostat soluble derivative II prepared by present invention method, Vorinostat
(Vorinostat);
T cell lymphoma cell;
2nd, experimental method
Under cell is digested from cell culture using pancreatin, cell density is determined after being resuspended using culture medium, will be thin
Born of the same parents are diluted to the solution of every milliliter of quantity cell containing optimization, by the cell solution after adjustment density with every 50 microlitres of addition cells in hole
In brassboard, the Tissue Culture Plate completed is put into incubator, at 37 degrees Celsius, 5% CO2Wet condition under be incubated it is 24 small
When.
According to the reference compound of experiment pattern 200 times of concentration of preparation and compound solution to be tested, 2.5 microlitres of chemical combination are taken
Thing solution and 2.5 microlitres of enzymes are diluted into 245 microlitres of culture mediums.The compound solution after 50 microlitres of dilutions is taken to add previous
In its ready Tissue Culture Plate, the Tissue Culture Plate for adding compound places back in incubator, at 37 degrees Celsius, 5% CO2
Wet condition under be incubated 72 hours.
Detection reagent is positioned over room temperature in 30 minutes before experiment and is balanced.Tissue Culture Plate adds 30 microlitres of detections per hole
Reagent, rocker 10 minutes, inducing cell lysis.Tissue Culture Plate is incubated 2 minutes with stabilized illumination at room temperature after 10 minutes
Signal.Using Envision read plates, during read plate the time be set as 0.5 second per hole.
Data processing, use XLfit softwares.
Inhibiting rate=(maximum signal level-compound signal value)/(maximum signal level-minimum signal value) × 100%.
The signal value of maximum is obtained from the dmso treatment cell of 72 hours, (cell number is from single culture medium
Zero) minimum signal value is obtained.
3rd, experimental result
Experimental result is as shown in table 2 below:
Vorinostat and Vorinostat derivative (II) tumor suppression ability under the different condition of table 2
From the contrast test data of such as upper table 2:In the presence of without β-D-Glucose aldehydic acid enzyme, Vorinostat of the present invention
IC50 > 10 μM of the derivative (II) for tumor cell line HT-29 and Hut-78;
And in the case where there is β-D-Glucose aldehydic acid enzyme existence condition, suppression of the Vorinostat derivative (II) of the present invention for tumour
Making is approached with active compound Vorinostat.It is vertical to speculate that Vorinostat derivative discharges the ending of the dog days under β-D-Glucose aldehydic acid enzyme effect
Promise he, play tumor inhibition effect, Vorinostat derivative provided by the present invention has as the possibility of tumor inhibitor prodrug.
Although illustrate and describing the present invention with specific embodiment, but will be appreciated that without departing substantially from the present invention's
Many other change and modification can be made in the case of spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
- A kind of 1. Vorinostat derivative based on palladium carbon, it is characterised in that the Vorinostat derived structure based on palladium carbon It is as follows:In formula (I), R1-R4Independently for hydrogen, hydroxyl, or carboxyl;R5、R7The substituted or unsubstituted alkylidene for C0-C20 independently;R6、R8Independently for hydrogen, C1-C20 substituted or unsubstituted alkyl;Wherein, R1-R4In at least one hydroxyl or carboxyl.
- 2. the Vorinostat derivative according to claim 1 based on palladium carbon, it is characterised in that in the formula (I), R1-R4 Independently for hydroxyl or carboxyl;R5、R7The substituted or unsubstituted alkylidene for C1-C12 independently;R6、R8Independently for hydrogen, C1-C12 substituted or unsubstituted alkyl.
- 3. the Vorinostat derivative according to claim 2 based on palladium carbon, it is characterised in that in the formula (I), R1-R4 In at least one hydroxyl and a carboxyl;R5、R7The substituted or unsubstituted alkylidene for C1-C6 independently;R6、R8Independently for hydrogen, C1-C6 substituted or unsubstituted alkyl.
- 4. the Vorinostat derivative according to claim 3 based on palladium carbon, it is characterised in that the Vorinostat derives The structure of thing is as follows:
- 5. the preparation method of the Vorinostat derivative based on palladium carbon any one of claim 1-4, it is characterised in that The preparation method comprises the following steps:WillWith Vorinostat condensation reaction, then It is deprotected and reduction reaction, produces the Vorinostat derivative;Wherein, in formula (i), R9-R12Independently for hydrogen, protected hydroxyl, or protected carboxyl;Wherein, R9-R12In at least There are a protected hydroxyl or protected carboxyl;R5、R7The substituted or unsubstituted alkylidene for C0-C20 independently;R6、R8Independently for hydrogen, C1-C20 substituted or unsubstituted alkyl;X1For halogen.
- 6. preparation method according to claim 5, it is characterised in that in the formula (i), R9-R12Independently be by Protect hydroxyl or protected carboxyl;R5、R7The substituted or unsubstituted alkylidene for C1-C12 independently;R6、R8It is only respectively It is vertical for hydrogen, C1-C12 substituted or unsubstituted alkyl;X1For chlorine or bromine.
- 7. preparation method according to claim 6, it is characterised in that in the formula (i), R9-R12In at least one by Protect hydroxyl and a protected carboxyl;R5、R7The substituted or unsubstituted alkylidene for C1-C6 independently;R6、R8Point It is not independently hydrogen, C1-C6 substituted or unsubstituted alkyl;X1For chlorine.
- 8. preparation method according to claim 7, it is characterised in that formula (i) structure is as follows:
- 9. the Vorinostat derivative based on palladium carbon any one of claim 1-4 is in anti-tumor medicine is prepared Using;Preferably, the tumour is skin T cell lymphoma.
- 10. include the medicine or drug regimen of the Vorinostat derivative based on palladium carbon any one of claim 1-4 Thing.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710945266.7A CN107556349B (en) | 2017-10-12 | 2017-10-12 | Palladium-carbon-based vorinostat derivative and preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710945266.7A CN107556349B (en) | 2017-10-12 | 2017-10-12 | Palladium-carbon-based vorinostat derivative and preparation method and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107556349A true CN107556349A (en) | 2018-01-09 |
CN107556349B CN107556349B (en) | 2020-11-06 |
Family
ID=60983994
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710945266.7A Active CN107556349B (en) | 2017-10-12 | 2017-10-12 | Palladium-carbon-based vorinostat derivative and preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107556349B (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009005673A1 (en) * | 2007-06-28 | 2009-01-08 | Schering Corporation | Anti-igf1r |
CN102260190A (en) * | 2011-03-08 | 2011-11-30 | 华东理工大学 | N-benzyl-N'-(terminal carboxylic acid substituted acyloxy)octanediamide compounds with anti-tumor effect and pharmaceutical salts thereof |
CN102516124A (en) * | 2011-11-11 | 2012-06-27 | 华东理工大学 | Antitumor dicarboxylic acid di-(hydroxamic acid) ester and preparation method thereof |
-
2017
- 2017-10-12 CN CN201710945266.7A patent/CN107556349B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009005673A1 (en) * | 2007-06-28 | 2009-01-08 | Schering Corporation | Anti-igf1r |
CN102260190A (en) * | 2011-03-08 | 2011-11-30 | 华东理工大学 | N-benzyl-N'-(terminal carboxylic acid substituted acyloxy)octanediamide compounds with anti-tumor effect and pharmaceutical salts thereof |
CN102516124A (en) * | 2011-11-11 | 2012-06-27 | 华东理工大学 | Antitumor dicarboxylic acid di-(hydroxamic acid) ester and preparation method thereof |
Non-Patent Citations (1)
Title |
---|
EMMANUEL BOUVIER,ET AL: "First enzymatically activated Taxotere prodrugs designed for ADEPT and PMT", 《BIOORGANIC AND MEDICINAL CHEMISTRY》 * |
Also Published As
Publication number | Publication date |
---|---|
CN107556349B (en) | 2020-11-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2951153B1 (en) | Selective hdac3 inhibitors | |
CN104024227A (en) | Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof | |
CN112979528B (en) | Tegaserod water-soluble organic acid salt and preparation method and application thereof | |
WO2012142615A2 (en) | Auranofin and auranofin analogs useful to treat proliferative disease and disorders | |
CN103420917A (en) | Benzamide compounds containing fused ring structure and applications thereof as antitumor medicaments | |
Li et al. | Design, synthesis, and biological evaluation of target water‐soluble hydroxamic acid‐based HDACi derivatives as prodrugs | |
CN110551102B (en) | ALK covalent inhibitors and uses thereof | |
CN106995449A (en) | Podophyllotoxin vitamin A acid heterocomplex synthetic method and applied to prevention, treatment tumour medicine | |
CN107556349A (en) | A kind of Vorinostat derivative based on palladium carbon and its preparation method and application | |
CN108358894B (en) | Compound for inhibiting histone acetyltransferase as well as preparation method and application thereof | |
CN109369620B (en) | Pyridine compound, preparation method thereof and application thereof in resisting gastric cancer | |
CN113929681A (en) | Tetracyclic derivative and preparation method and application thereof | |
CN107698631A (en) | A kind of Vorinostat derivative based on lithium hydroxide and its preparation method and application | |
CN116444501A (en) | Quinazoline derivative, preparation method thereof, pharmaceutical composition and application | |
CN107698632B (en) | Acetic acid-based belinostat derivative and preparation method and application thereof | |
CN106397407B (en) | The preparation method of antitumor drug AZD9291 derivatives | |
EP4154884A1 (en) | Anti-sars-cov-2 durg | |
CN114031523A (en) | Synthesis method and application of histone deacetylase and microtubule dual-target inhibitor | |
Li et al. | Synthesis and tumor cytotoxicity of novel 1, 2, 3-triazole-substituted 3-oxo-oleanolic acid derivatives | |
CN108440556A (en) | A kind of tablet adm derivative and its application | |
CN113292554A (en) | Dihydronaphtho [2,1-d ] isoxazole amide derivatives and application thereof in antitumor drugs | |
CN107474084B (en) | Belinostat derivative based on formic acid and preparation method and application thereof | |
CN103113353A (en) | Triazole compounds, medical composition thereof and preparation and application of triazole compounds | |
US11970464B1 (en) | Multi-target drug candidates for the treatment of triple-negative breast cancer | |
Qiu et al. | Novel chiral matrine derivatives as potential antitumor agents: design, synthesis and biological evaluation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |