CN107556349B - Palladium-carbon-based vorinostat derivative and preparation method and application thereof - Google Patents
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Abstract
The invention provides a palladium-carbon-based vorinostat derivative, and a preparation method and application thereof. The palladium-carbon-based vorinostat derivative provided by the invention takes vorinostat as a parent compound, and improves the water solubility of the vorinostat by connecting water-soluble groups, so that the inconvenience of the vorinostat raw drug in use and the side effects in the medication process are effectively improved. Meanwhile, the preparation method is simple and convenient in process, simple in operation steps and suitable for large-scale production.
Description
Technical Field
The invention relates to the field of preparation of antitumor drugs, and particularly relates to a palladium-carbon-based vorinostat derivative, and a preparation method and application thereof.
Background
Vorinostat (vorinostat), chemically known as "N-hydroxy-N' -phenylsuberamide" or "suberoylanilide hydroxamic acid (SAHA)" is the first Histone Deacetylase (HDAC) inhibitor antineoplastic agent developed by Merck, usa. Vorinostat is used for treating tumor patients with cancer cells that are continuously proliferating, and is also clinically mainly used for treating cutaneous T-cell lymphoma (CTCL: a non-hodgkin lymphoma, a T-cell cancer affecting skin leukocyte types) which is aggravated, sustained and recurrent or ineffective after treatment with two systemic drugs, because vorinostat can selectively induce late differentiation of tumor cells to inhibit proliferation of such cells under appropriate conditions.
VorinostatApproved for marketing in the us in 2006, with clear antitumor efficacy, but nevertheless, due to its poor water solubility, the development and application of vorinostat is limited.
The low water solubility of vorinostat at defined concentrations or physiological pH makes it difficult to formulate for administration as water for injection (Kelly, w.k. et al, Phase I clinical tertiary of hormone deacetylase inhibitor: suberoyl lanilide hydrate administered orally in ravenousous. clin. cancer Res2003, 9, 3578-. Various adverse reactions such as diarrhea, fatigue, nausea, dysgeusia, anorexia nervosa, anemia, and thrombocytopenia are generated to maintain the drug concentration in vivo (Krug, l.m. et al, [ J ]. clin.lung Cancer 2006, 7, 257). In particular, when people face patients who cannot swallow, such as infants, critical patients, paralyzed patients or coma patients, oral administration cannot be realized, and the problem of the non-injectable administration of the medicine becomes more prominent (US 20100240601A).
Therefore, improving the water solubility of vorinostat and reducing adverse reactions become the key to ensure the continuation of the anti-tumor chemotherapy.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The first object of the present invention is to provide a palladium-carbon-based vorinostat derivative having good water solubility and being capable of effectively preventing adverse reactions.
The second purpose of the invention is to provide a preparation method of the palladium-carbon-based vorinostat derivative, which has the advantages of less preparation method process, simple and convenient operation and the like.
A third object of the present invention is to provide an application of the palladium-carbon-based vorinostat derivative.
A fourth object of the present invention is to provide a medicament or pharmaceutical composition comprising the palladium on carbon based vorinostat derivative of the invention.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
a palladium on carbon based vorinostat derivative having the structure:
in the formula (I), R1-R4Each independently is hydrogen, hydroxy, or carboxy; r5、R7Each independently is a substituted or unsubstituted alkylene group of C0-C20; r6、R8Each independently is hydrogen, substituted or unsubstituted alkyl of C1-C20; wherein R is1-R4Wherein at least one hydroxyl or carboxyl group is present.
Preferably, in the palladium-carbon-based vorinostat derivative of the invention, R is shown in formula (I)1-R4Each independently is hydroxyl or carboxyl; r5、R7Each independently is a substituted or unsubstituted alkylene group of C1-C12; r6、R8Independently represents hydrogen, C1-C12 substituted or unsubstituted alkyl.
Preferably, in the palladium-carbon-based vorinostat derivative of the invention, R is shown in formula (I)1-R4Wherein at least one hydroxyl group and one carboxyl group are present; r5、R7Each independently is a substituted or unsubstituted alkylene group of C1-C6; r6、R8Independently represents hydrogen, C1-C6 substituted or unsubstituted alkyl.
Preferably, in the palladium-carbon-based vorinostat derivative according to the present invention, the structure of the vorinostat derivative is as follows:
meanwhile, the invention also provides a preparation method of the palladium-carbon-based vorinostat derivative, which comprises the following steps:
will be provided withCarrying out condensation reaction with vorinostat, and then carrying out deprotection and reduction reaction to obtain the vorinostat derivative; wherein, in the formula (i), R9-R12Each independently is hydrogen, a protected hydroxyl group, or a protected carboxyl group; wherein R is9-R12At least one protected hydroxyl group or protected carboxyl group; r5、R7Each independently is a substituted or unsubstituted alkylene group of C0-C20; r6、R8Each independently is hydrogen, substituted or unsubstituted alkyl of C1-C20; x1Is halogen.
Preferably, in the preparation method of the present invention, in the formula (i), R is9-R12Independently is a protected hydroxyl group or a protected carboxyl group; r5、R7Each independently is a substituted or unsubstituted alkylene group of C1-C12; r6、R8Each independently is hydrogen, substituted or unsubstituted alkyl of C1-C12; x1Is chlorine or bromine.
Preferably, in the preparation method of the present invention, in the formula (i), R is9-R12Wherein at least one protected hydroxyl group and one protected carboxyl group are present; r5、R7Each independently is a substituted or unsubstituted alkylene group of C1-C6; r6、R8Each independently is hydrogen, substituted or unsubstituted alkyl of C1-C6;
X1is chlorine.
Preferably, in the preparation method of the present invention, the structure of formula (i) is as follows:
meanwhile, the invention also provides the application of the vorinostat derivative in preparing a tumor treatment medicament; preferably, the tumor is a cutaneous T cell lymphoma.
More preferably, the present invention also provides a medicament or pharmaceutical composition comprising the vorinostat derivative of the invention.
Compared with the prior art, the invention has the beneficial effects that:
(1) in the invention, the active vorinostat is used as a parent structure to be structurally modified by introducing a water-soluble group, so that the obtained vorinostat derivative has good water solubility, and the problems of side effects, incapability of injection administration and the like in actual medicine caused by poor water solubility of the vorinostat can be effectively solved;
meanwhile, the vorinostat derivative provided by the invention can achieve a tumor inhibition effect equivalent to that of a vorinostat original drug in the presence of enzyme, so that the vorinostat derivative is suitable for being used as a prodrug of a tumor inhibition drug.
(2) In the preparation method, the used raw materials are simple and easy to obtain, the steps of the preparation method are simple and convenient, the operation is simple, meanwhile, large-scale instruments are not needed, the method is suitable for preparing the vorinostat derivative in an industrial scale, the cost control can be effectively realized, and the burden of patients is reduced.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows a process for the preparation of vorinostat derivatives according to the invention.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
In view of the problems of limited use, side effects and the like of vorinostat raw drug due to poor water solubility, the invention particularly provides a novel vorinostat derivative, and the structure of the vorinostat parent drug is modified by introducing a water-soluble group, so that the novel vorinostat derivative which has good water solubility and practicability and can achieve the tumor inhibition activity equivalent to that of the vorinostat raw drug is provided.
Specifically, the vorinostat derivative provided by the invention has the following structure:
wherein, in the formula (I), R1-R4Each independently is hydrogen, hydroxy, or carboxy, and R1-R4Wherein at least one hydroxyl or carboxyl group is present; preferably, R1-R4Each independently is hydroxyl or carboxyl; more preferably, R1-R4At least one hydroxyl group and one carboxyl group, for example: can be R1Is carboxyl, R2-R4Is a hydroxyl group; or, R may be4Is carboxyl, R1-R3Is a hydroxyl group; or alternatively, R may be1Is hydroxy, R2-R4Is a carboxyl group; or also, R4Is hydroxy, R1-R3Is a carboxyl group; or alternatively, R1、R4Is carboxyl, R2、R3Is a hydroxyl group; or also, R1、R4Is hydroxy, R2、R3Is a carboxyl group, etc.;
R5、R7each independently is a substituted or unsubstituted alkylene group of C0-C20; preferably, R5、R7Each independently is a substituted or unsubstituted alkylene group of C1-C12; more preferably, R5、R7Each independently is a substituted or unsubstituted alkylene group of C1-C6; further preferably, R5、R7Each independently being a C1-C6 unsubstituted alkylene group, e.g. R5、R7Each independently can be methylene, ethylene, propylene, isopropylene, butylene, isobutylene, pentylene, isopentylene, neopentylene, hexylene, etc.;
R6、R8each independently is hydrogen, substituted or unsubstituted alkyl of C1-C20; preferably, R6、R8Each independently is hydrogen, substituted or unsubstituted alkyl of C1-C12; more preferably, R6、R8Each independently is hydrogen, substituted or unsubstituted alkyl of C1-C6; further preferably, R6、R8Each independently is C1-C6 unsubstituted alkyl, e.g. R6、R8Respectively can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, neopentyl and hexylAnd the like.
In the vorinostat derivative with the structure shown in the formula (I), provided by the invention, the hydroxyhydroxamic acid position of the vorinostat parent nucleus is modified, and a water-soluble group is added, so that the water solubility of the vorinostat original drug is improved.
More preferably, the vorinostat derivative provided by the invention has the following structure:
in the more preferable compounds, the water solubility of the vorinostat derivative obtained by modifying the parent ring of vorinostat with a glucuronyl group as a water-soluble group is about 600 times that of vorinostat;
meanwhile, the compound of the formula (II) can release vorinostat under the action of beta-D-glucuronidase and play a role in tumor inhibition, so that the vorinostat derivative can be used as a prodrug compound of vorinostat;
further, β -D-glucuronidase catalyzing the decomposition of the compound of the above formula (II) plays an important role in tumorigenesis, tumor growth, infiltration and metastasis, and particularly it causes degradation of extracellular matrix and cell basement membrane to destroy the barrier of cancer cell metastasis, and by inhibiting the activity of the enzyme or consuming the enzyme, the metastasis of tumor cells can be inhibited to exert antitumor activity.
That is, the palladium-carbon-based vorinostat derivative provided by the invention not only can play a role in inhibiting tumors by decomposing and releasing vorinostat, but also can play a further role in adjuvant therapy of tumors by consuming beta-D-glucuronidase in the catalytic decomposition process.
The preparation method of the palladium-carbon-based vorinostat derivative can be referred to as follows: will be provided with
Condensation reaction with vorinostat, and then deprotectionProtecting and reducing to obtain the vorinostat derivative;
in the formula (i), R9-R12Each independently is hydrogen, protected hydroxy, or protected carboxy, wherein R is9-R12At least one protected hydroxyl group or protected carboxyl group; preferably, R9-R12Independently is a protected hydroxyl group or a protected carboxyl group; more preferably, R9-R12In which at least one protected hydroxy group and one protected carboxy group, e.g. R9For a protected carboxyl group, R10-R12Is a protected hydroxyl group; or, R may be12For a protected carboxyl group, R9-R11Is a protected hydroxyl group; or alternatively, R may be9For protected hydroxy, R10-R12Is a protected carboxyl group; or also, R12For protected hydroxy, R9-R11Is a protected carboxyl group; or alternatively, R9、R12For a protected carboxyl group, R10、R11Is a protected hydroxyl group; or also, R9、R12Is a protected hydroxy group, R10、R11Protected carboxy, and the like;
the protected hydroxyl group is a hydroxyl group after reaction with a protecting group as described above, and the hydroxyl protecting group may be t-butyldimethylsilyl, acetyl, benzyl, pivaloyl, or the like; meanwhile, the carboxyl group protected as described above is a carboxyl group after reaction with a protecting group, and the protecting group for the carboxyl group may be benzyl, allyl, or the like;
the starting compound of formula (i) may be purchased from a source supplier or may be synthesized as desired, as is known in the art (Bouvier E. et al First enzyme activated Taxotere products for ADEPT and PMT. bioorganic & Medicinal Chemistry, 2004,12, 969-);
when the raw material compound of formula (i) contains at least one protected hydroxyl and at least one protected carboxyl, in the preparation process, firstly removing the hydroxyl protecting group, and then removing the carboxyl protecting group while reducing the nitro;
R5、R7each independently is a substituted or unsubstituted alkylene group of C0-C20; preferably, R5、R7Each independently is a substituted or unsubstituted alkylene group of C1-C12; more preferably, R5、R7Each independently is a substituted or unsubstituted alkylene group of C1-C6; further preferably, R5、R7Each independently being a C1-C6 unsubstituted alkylene group, e.g. R5、R7Each independently can be methylene, ethylene, propylene, isopropylene, butylene, isobutylene, pentylene, isopentylene, neopentylene, hexylene, etc.;
X1is halogen; preferably, X1Is chlorine or bromine; more preferably, X1Is chlorine.
R6、R8Each independently is hydrogen, substituted or unsubstituted alkyl of C1-C20; preferably, R6、R8Each independently is hydrogen, substituted or unsubstituted alkyl of C1-C12; more preferably, R6、R8Each independently is hydrogen, substituted or unsubstituted alkyl of C1-C6; further preferably, R6、R8Each independently is C1-C6 unsubstituted alkyl, e.g., R6Can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl and the like, R8Can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, etc.;
still more preferably, in the preparation method of the present invention, the structure of the raw material compound is as follows:
when the compound represented by the above formula (II) is used as a starting material, the process for preparing the target compound (II) of the present invention can be specifically referred to as follows: (a) condensation of a compound of formula (ii) with vorinostat gives an intermediate compound (iii) having the following structure:
preferably, in the step (a), the raw material compound of the formula (ii) is mixed with vorinostat and solvent pyridine at 0 ℃, and then condensation reaction is carried out for 5 hours at 25 ℃;
(b) deprotecting the hydroxy group of the compound of formula (iii) obtained in step (a) to give an intermediate compound of formula (iv) having the structure shown below:
in step (b), the preferred solvent is tetrahydrofuran, and the reaction temperature is preferably controlled to be 50 ℃;
(c) carrying out carboxyl deprotection and reduction on the intermediate compound of the formula (iv) obtained in the step (b) under the hydrogen condition and the action of a catalyst to obtain a target product (II), namely obtaining the target product (II)
Preferably, in step (c), the catalyst used is a palladium on carbon catalyst;
preferably, step (c) is carried out in an ethanol solution.
The above preparation scheme can be further specifically referred to in FIG. 1.
Further preferably, in the above-mentioned preparation process, the prepared intermediate compound (II) is purified by column chromatography, and then the reaction of step (b) is carried out, and the obtained product compound (II) is also preferably purified by column chromatography;
meanwhile, preferably, the intermediate compound (iv) obtained in step (b) may be used in the reaction of step (c) without purification.
The palladium-carbon-based vorinostat derivative prepared by the invention has good water solubility and can release vorinostat through reaction, so that the palladium-carbon-based vorinostat derivative can be used for treating tumors, and is preferably used for treating cutaneous T cell lymphoma.
Furthermore, the palladium-carbon-based vorinostat derivative has good water solubility, so that the palladium-carbon-based vorinostat derivative can be further mixed with auxiliary materials and additives to prepare tablets for administration, and can also be dissolved in normal saline or glucose for injection;
in the actual process of tumor treatment, the palladium-carbon-based vorinostat derivative can be used alone or in combination with other medicines for treating tumors.
EXAMPLE 1 preparation of O- [ NN-dimethyl-N-4- (2, 3, 4-tri-O-tert-butyldimethylsilyl-6-benzyl-beta-D-glucopyranosyloxy-1-yl) -3-nitrobenzyloxycarbonylethylenediamine ] -formyl-vorinostat (iii)
Vorinostat 913mg (3.46mmol) was dissolved in 20mL pyridine and cooled at 0 ℃ for 5 minutes. To the above solution was added 3g (3.14mmol) of the compound (ii) at 0 ℃ to give a red suspension. The suspension was warmed to 25 ℃ and stirred for 5 hours under constant temperature, after which 100mL of water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (50mL × 3 times), the organic layers were combined, extracted with 0.5M HCl (30mL × 4 times) and saturated brine (30mL × 2 times) in this order, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to obtain 3.4g of intermediate iii, which was isolated by preparative chromatography (dichloromethane: methanol ═ 50: 1) with a yield of 92%.
Characterization of the product:1HNMR(400MHz,CDCl3)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)。
EXAMPLE 2 preparation of O- [ NN-dimethyl-N-4- (6-benzyl-. beta. -D-glucopyranosyloxy-1-yl) -3-nitrobenzyloxycarbonylethylenediamine ] -formyl-vorinostat (iv)
3.4g (2.87mmol) of intermediate iii are dissolved in 18mL of tetrahydrofuran, 4.63g (28.7mmol) of triethylamine trihydrofluoride salt is added at 25 ℃ and the reaction is warmed to 50 ℃ and maintained for 16 hours. After the reaction, the reaction mixture was concentrated by a rotary evaporator, 50mL of water was added to the concentrated solution, extraction was performed with ethyl acetate/acetonitrile (3/1) (20mL × 4 times), organic layers were combined, washed with saturated brine 2 times, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated by a rotary evaporator, and preparative chromatography (dichloromethane: methanol ═ 50: 1) was performed to separate crude iv 5.0g, yield was 74%, and the crude product was directly fed to the next reaction.
EXAMPLE 3 preparation of O- [ NN-dimethyl-N-4- (. beta. -D-glucopyranosyloxy-1-yl) -3-aminobenzyloxycarbonylethylenediamine ] -formyl-vorinostat (II)
84mg (0.1mmol) of the crude iv are dissolved in 20mL of an ethanol solution containing 240mg of 10% Pd/C and stirred under hydrogen pressure (1bar) for 5 hours. Filtration through Celite (Celite 545), concentration of the filtrate and isolation by preparative chromatography (acetonitrile: water-9: 1) gave 42mg of solid product II in 58% yield.
Characterization of the product:1HNMR:(400MHz,DMSO-d6)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)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]。
example 4 solubility of Vorinostat derivatives in Water (Unit: μ g/mL)
1. Experimental methods
Respectively dissolving the vorinostat derivative (II) prepared by the method of the present invention in an excess amount in 2 aqueous microcentrifuge tubes (eppendorf tubes), each tube containing 1mL of purified water; vortexed at 25 ℃ for 20 min, centrifuged again to remove the suspension (20000rpm, 15 min), and finally analyzed quantitatively by HPLC to obtain the initial solubility of the prodrug in water.
2. The results of the experiments are shown in Table 1
The results of the experimental tests are shown in table 1 below:
table 1 vorinostat and vorinostat derivative solubility test of the present application
Drug to be tested | Vorinostat | Vorinostat derivative (II) |
Solubility in water | 20-50μmol/L | 25-28mmol/L |
Wherein, in Table 1, the vorinostat water solubility data can refer to the prior art ((a) Marks, P.A. discovery and depletion of SAHA as an anticancer agent. oncogene.2007, 26, 1351-;
as can be seen from the control test results in table 1, the water solubility of vorinostat derivative (II) of the present invention is significantly improved compared to vorinostat, and the water solubility is about 560 times that of vorinostat.
Example 5 in vitro inhibition of Water-soluble Vorinostat derivatives II on different tumor cells with and without β -D-glucuronidase
1. Experimental Material
Cell lines: HT-29, Hut-78,
Culture medium: the culture medium for Hut-78 and HT-29 are IMDM medium containing 20% fetal calf serum and McCoy's 5A medium containing 10% fetal calf serum
The preparation of the medicine comprises the following steps: vorinostat (Vorinostat), a water-soluble Vorinostat derivative II prepared by the method of the embodiment of the present invention;
t cell lymphoma cells;
2. experimental methods
Digesting cells from a cell culture dish using pancreatin, measuring cell density after suspending the cells using a culture medium, diluting the cells to a solution containing an optimized number of cells per ml, adding 50. mu.l/well of the cell solution after adjusting the density to a cell assay plate, placing the plated cell culture plate in an incubator at 37 ℃ in 5% CO2For 24 hours under humid conditions.
A200-fold concentration of the reference compound and the test compound solution was prepared according to the experimental template, and 2.5. mu.l of the compound solution and 2.5. mu.l of the enzyme were diluted in 245. mu.l of the medium. Adding 50 microliter of the diluted compound solution into the cell culture plate prepared the day before, and putting the cell culture plate added with the compound back into the incubator at 37 ℃ under 5% CO2For 72 hours under humid conditions.
The detection reagents were allowed to equilibrate at room temperature 30 minutes prior to the experiment. 30 microliter of detection reagent is added into each hole of the cell culture plate, and the plate is shaken for 10 minutes to induce cell lysis. After 10 minutes, the cell culture plates were incubated at room temperature for 2 minutes to stabilize the luminescence signal. Envision read plates were used with time set to 0.5 seconds per well.
Data processing, using XLfit software.
The inhibition ratio is (maximum signal value-compound signal value)/(maximum signal value-minimum signal value) × 100%.
The maximum signal value was obtained from cells treated with dmso for 72 hours, and the minimum signal value was obtained from medium alone (cell number zero).
3. Results of the experiment
The results of the experiment are shown in table 2 below:
TABLE 2 Vorinostat and Vorinostat derivatives (II) tumor suppressive ability under different conditions
From the comparative test data as in table 2 above, it can be seen that: in the absence of beta-D-glucuronidase, the IC50 of the vorinostat derivative (II) is more than 10 mu M for tumor cell strains HT-29 and Hut-78;
under the condition of the existence of beta-D-glucuronidase, the inhibition effect of the vorinostat derivative (II) on the tumor is close to that of the original drug vorinostat. The vorinostat derivative is supposed to release vorinostat under the action of beta-D-glucuronidase to play a role in inhibiting tumors, and the vorinostat derivative provided by the invention can be used as a prodrug of a tumor inhibitor.
While particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
Claims (7)
2. a process for the preparation of vorinostat derivatives as claimed in claim 1, characterized in that it comprises the following steps:
will be provided with(i) Carrying out condensation reaction with vorinostat, and then carrying out deprotection and reduction reaction to obtain the vorinostat derivative;
in the formula (i), R9For a protected carboxyl group, R10-R12Is a protected hydroxyl group; r5Is methylene, R7Is ethylene, R6、R8Each independently is methyl; x1Is halogen.
3. The process according to claim 2, wherein in the formula (i), R is9For a protected carboxyl group, R10-R12Is a protected hydroxyl group; r5Is methylene, R7Is ethylene, R6、R8Each independently is methyl; x1Is chlorine or bromine.
4. The process according to claim 2, wherein in the formula (i), R is9For a protected carboxyl group, R10-R12Is a protected hydroxyl group; r5Is methylene, R7Is ethylene, R6、R8Each independently is methyl; x1Is chlorine.
6. use of the vorinostat derivative according to claim 1 for preparing a medicament for treating tumors;
the tumor is cutaneous T cell lymphoma.
7. A pharmaceutical composition comprising the vorinostat derivative of claim 1.
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