CN107474084B

CN107474084B - Belinostat derivative based on formic acid and preparation method and application thereof

Info

Publication number: CN107474084B
Application number: CN201710944782.8A
Authority: CN
Inventors: 杜文婷; 李军; 黄文海; 林素
Original assignee: Hangzhou Medical College
Current assignee: Hangzhou Medical College
Priority date: 2017-10-12
Filing date: 2017-10-12
Publication date: 2020-04-07
Anticipated expiration: 2037-10-12
Also published as: CN107474084A

Abstract

The invention provides a belinostat derivative based on formic acid and a preparation method and application thereof. The formic acid-based belinostat derivative provided by the invention takes belinostat with tumor inhibition activity as a parent drug, and is connected with a water-soluble substituent through reaction to improve the solubility of the belinostat, so that the obtained formic acid-based belinostat derivative has good water solubility, and the side effect of the belinostat caused by poor water solubility can be effectively solved. Meanwhile, the preparation method provided by the invention has the advantages of few preparation processes and simple and convenient operation steps, and is suitable for large-scale production.

Description

Belinostat derivative based on formic acid and preparation method and application thereof

Technical Field

The invention relates to the field of antitumor drugs, and particularly relates to a formic acid-based belinostat derivative and a preparation method and application thereof.

Background

Belinostat

Belongs to a hydroximic acid histone deacetylase inhibitor (HDACI). Due to overexpression or abnormal regulation of Histone Deacetylase (HDAC), histone is over-deacetylated, and chromatin is remodeled into a transcription inhibiting configuration, so that the expression of corresponding genes is reduced, and canceration is caused. Thus, inhibition of HDACs is considered to be a promising target for anticancer drugs. The belinostat can directly act on the link of gene abnormal expression so as to inhibit and correct the excessive proliferation and abnormal differentiation of tumor cells, and can also be used together with medicaments with other action mechanisms aiming at the common problem of medicament resistance. The belinostat can effectively inhibit proliferation of solid tumor cells such as colon cancer, lung cancer, ovarian cancer, myeloma and the like, and has a therapeutic effect on malignant tumors of blood systems such as leukemia, lymphoma and the like.

Belinostat was approved by the FDA for marketing in 2014 as a therapeutic drug for relapsed and refractory peripheral T-cell lymphomas. Despite the wide acceptance of cancer treatment, belinostat is limited in its practical application and development by low water solubility (0.14 mg/mL). Under the condition of a specified concentration or physiological pH, the lyophilized injection of belinostat prepared for maintaining the in vivo drug concentration can cause adverse reactions such as nausea, vomiting, hypodynamia, fever, anemia and the like when in use, and can even cause serious side effects such as liver failure, thrombocytopenia, creatinine rise, gastrointestinal toxicity, pneumonia, tumor lysis syndrome, multiple organ failure and the like (specifically, refer to www.accessdata.fda.gov/drug of fdda _ docs/label/2014/206256lbl. Therefore, the improvement of the water solubility of the belinostat and the reduction of 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

A first object of the present invention is to provide a formic acid-based belinostat derivative which has good water solubility and does not cause side effects under the concentration conditions to be used.

The second purpose of the invention is to provide a preparation method of the formic acid-based belinostat derivative, which has the advantages of few operation steps, simple process, suitability for large-scale production and the like.

The third purpose of the invention is to provide the application of the formic acid-based belinostat derivative in preparing a tumor treatment medicine.

The fourth object of the present invention is to provide a medicament or pharmaceutical composition comprising the formic acid-based belinostat derivative.

In order to achieve the above purpose of the present invention, the following technical solutions are adopted:

a formic acid-based belinostat derivative having the structure:

wherein, in the formula (I), R₁-R₄Each independently is hydrogen, hydroxy or carboxy, and R₁-R₄At least one of them is hydroxyl or carboxyl; r₅Is hydrogen, or a substituted or unsubstituted alkyl group of C1-C20; x₁、X₂Independently represent a substituted or unsubstituted alkylene group having from C1 to C20.

Preferably, in the formic acid-based belinostat derivatives of the invention of formula (I), R₁-R₄Each independently is hydroxyl or carboxyl; r₅Is hydrogen, or a substituted or unsubstituted alkyl group of C1-C12; x₁、X₂Independently represent a substituted or unsubstituted alkylene group having from C1 to C12.

Preferably, in the formic acid-based belinostat derivatives of the invention of formula (I), R₁-R₄Wherein at least one hydroxyl group and one carboxyl group are present; r₅Is a substituted or unsubstituted alkyl group of C1 to C6; x₁、X₂Independently represent a substituted or unsubstituted alkylene group having from C1 to C6.

Preferably, the structure of the formic acid-based belinostat derivative of the invention is as follows:

meanwhile, the invention also provides a preparation method of the belinostat derivative based on formic acid, which comprises the following steps:

will be provided with

Carrying out condensation reaction with belinostat, then removing a protective group and reducing to obtain the belinostat derivative;

wherein, in the formula (i), R₆-R₉Each independently is hydrogen, protected hydroxy or protected carboxy, and R₆-R₉At least one of which is protectedA hydroxy or protected carboxy group of (a); r₅Is hydrogen, or a substituted or unsubstituted alkyl group of C1-C20; x₁、X₂Each independently is a substituted or unsubstituted alkylene group of C1-C20; x₃Is a succinimidyl group.

Preferably, in the preparation method of the invention, R₆-R₉Independently of each other, a protected hydroxyl group or a protected carboxyl group; r₅Is hydrogen, or a substituted or unsubstituted alkyl group of C1-C12; x₁、X₂Each independently is a substituted or unsubstituted alkylene group of C1-C12; x₃Is a succinimidyl group.

Preferably, in the preparation method of the present invention, R is₆-R₉Each independently is a protected hydroxy or protected carboxy group, and R₆-R₉Wherein at least one protected hydroxyl group and one protected carboxyl group are present; r₅Is optionally substituted or unsubstituted alkyl of C1-C6; x₁、X₂Each independently is a substituted or unsubstituted alkylene group of C1-C6; x₃Is a succinimidyl group.

Preferably, in the preparation method of the present invention, the structure of formula (i) is specifically as follows:

furthermore, the invention also provides the application of the formic acid-based belinostat derivative in preparing antitumor drugs; preferably, the tumor is a cutaneous T cell lymphoma.

Likewise, the invention also provides a medicament or a pharmaceutical composition containing the formic acid-based belinostat derivative.

Compared with the prior art, the invention has the beneficial effects that:

(1) according to the invention, the structure of the belinostat is modified by the water-soluble group, so that the water solubility of the belinostat is effectively improved, and the obtained belinostat derivative has good solubility while maintaining the original tumor inhibition activity; meanwhile, the tumor inhibition activity of the belinostat derivative is not influenced by enzyme, the belinostat derivative can play a role in effectively inhibiting the activity of tumor cells, and simultaneously can solve the problem of drug side effects caused by poor water solubility of belinostat;

(2) in the preparation method, the used raw materials are simple and easily obtained, the steps and the flow are few, the operation is simple and convenient, large-scale instruments and equipment are not needed, the production cost can be effectively controlled, and the treatment burden of patients can be further realized.

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 is a schematic diagram of the preparation process of the formic acid-based belinostat derivatives of the present 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 practical problems of side effects and the like caused by poor water solubility of the belinostat in practical application, the invention particularly provides a novel formic acid-based belinostat derivative, so as to improve the water solubility of the original drug of the belinostat.

Specifically, the structure of the formic acid-based belinostat derivative provided by the invention is as follows:

according to the structure of the formic acid-based belinostat derivative shown in the formula (I), the formic acid-based belinostat derivative is a belinostat compound with a novel structure obtained by introducing a water-soluble group to a hydroximic acid position on a belinostat mother ring;

wherein, in the formula (I), R₁-R₄Independently of each other is hydrogen, hydroxy, or carboxy, and R is₁-R₄Wherein at least one hydroxyl or carboxyl group is present; preferably, R₁-R₄Each independently is hydroxyl or carboxyl; more preferably, R₁-R₄In which at least one hydroxyl group and one carboxyl group, e.g. 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.;

R₅is hydrogen, substituted or unsubstituted alkyl of C1-C20; preferably, R₅Is hydrogen, substituted or unsubstituted alkyl of C1-C12; more preferably, R₅Is a substituted or unsubstituted alkyl group of C1 to C6; further preferably, R₅Is unsubstituted alkyl of C1 to C6, e.g., R₅Can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, etc.;

X₁、X₂each independently is a substituted or unsubstituted alkylene group of C1-C20; preferably, X₁、X₂Each independently is a substituted or unsubstituted alkylene group of C1-C12; more preferably, X₁、X₂Each independently is a substituted or unsubstituted alkylene group of C1-C6; further preferably, X₁、X₂Each independently being an unsubstituted alkylene radical of C1 to C6, e.g. X₁Can be methylene, ethylene, propylene, isopropylene, butylene, isobutylene, pentylene, isopentylene, neopentyleneRadicals, hexylene radicals and the like, X₂May be methylene, ethylene, propylene, isopropylene, butylene, isobutylene, pentylene, isopentylene, neopentylene, hexylene, etc.

Still more preferably, the structure of the formic acid-based belinostat derivative provided by the invention is as follows:

as can be seen from the structure of the above formula (II), the formic acid-based belinostat derivative compound preferably provided by the present invention is a belinostat derivative having a water-soluble glucuronic acid derivative as a substituent and having substitution linkage at the position of a hydroximic acid on the belinostat ring, and the compound has a water solubility of 750 times that of belinostat.

Meanwhile, although the compound structurally has a glucuronyl group structure, the tumor inhibition activity of the compound is not influenced by β -D-glucuronidase.

β -D-glucuronidase, as described above, plays an important role in tumorigenesis, Tumor growth, infiltration and metastasis, and in particular, it can cause degradation of extracellular matrix and Cell basement membrane, thereby disrupting the barrier to metastasis of Cancer cells. metastasis of Tumor cells can be inhibited by inhibiting the activity of or consuming the enzyme, and anti-Tumor activity can be exerted (see (a) Parish, C.R. et al. Heparanase: a key enzyme involved in Cell invasion [ J ]. Biochim Biophys acta,2001,1471, M99-M108.(b) Poon, I.K.H. et al. Histidine-rich binding enzymes involved in activity and Regulation genes interaction and Cell proliferation [ J.Int. J. Cell B.2010,42, 1506, 1508. fig. 12. J. (see, see also No. 7. Cell) No. 7. see, No. 5. Cell kinase, No. 35. 7. origin, No. 11. Cell, No. 7. origin, 11. 7. origin, No. 7, 5. Cell, No. 7, 5, No. 7, animal origin, protein.

Further, the preparation method of the belinostat derivative can be referred to as follows:

will be provided with

Carrying out condensation reaction with belinostat, then removing a protective group and reducing to obtain the belinostat derivative based on formic acid;

wherein, in the formula (i), R₆-R₉Each independently is hydrogen, protected hydroxy, or protected carboxy, wherein R is₆-R₉At least one protected hydroxyl group or protected carboxyl group; preferably, in the formula (i), R₆-R₉Independently is a protected hydroxyl group or a protected carboxyl group; more preferably, in formula (i), R₆-R₉In which at least one protected hydroxy group and one protected carboxy group, e.g. R₆For a protected carboxyl group, R₇-R₉Is a protected hydroxyl group; or, R may be₉For a protected carboxyl group, R₆-R₈Is a protected hydroxyl group; or alternatively, R may be₆For protected hydroxy, R₇-R₉Is a protected carboxyl group; or also, R₉For protected hydroxy, R₆-R₈Is a protected carboxyl group; or alternatively, R₆、R₉For a protected carboxyl group, R₇、R₈Is a protected hydroxyl group; or also, R₆、R₉Is a protected hydroxy group, R₇、R₈Protected 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 protected carboxyl group is a carboxyl group after reaction with a protecting group as described above, and the protecting group for the carboxyl group may be benzyl, allyl, or the like;

when the starting compound of formula (i) contains at least one protected hydroxyl group and at least one protected carboxyl group, the step of removing the protecting group is preferably performed in two steps during the preparation process, i.e., the hydroxyl protecting group is removed first, then the carboxyl protecting group is removed, and the nitro group is reduced to amino group while the carboxyl protecting group is removed;

X₁、X₂each independently is a substituted or unsubstituted alkylene group of C1-C20; preferably, X₁、X₂Each independently is a substituted or unsubstituted alkylene group of C1-C12; more preferably, X₁、X₂Each independently is a substituted or unsubstituted alkylene group of C1-C6; further preferably, X₁、X₂Each independently being an unsubstituted alkylene radical of C1 to C6, e.g. X₁May be methylene, ethylene, propylene, isopropylene, butylene, isobutylene, pentylene, isopentylene, neopentylene, hexylene, etc., and X₂May be methylene, ethylene, propylene, isopropylene, butylene, isobutylene, pentylene, isopentylene, neopentylene, hexylene, etc.;

X₃is a succinimidyl group; .

Meanwhile, the compound of formula (i) as a reaction raw material may be purchased from a raw material supplier, or may be synthesized as needed, and the synthesis method thereof may be referred to the prior art (AlaouiA. E. et al, New Taxol (paclitaxel) pro-drug design for ADEPT and strategies in cancer chemistry [ J ]. bioorg. Med. chem.2006,14, 5012-.

Further preferably, in the preparation method of the present invention, the structure of the raw material of formula (i) is as follows:

when the reaction is carried out by using the compound of the above formula (ii) as a raw material, the preparation method of the present invention may specifically refer to the following steps:

(a) dissolving the belinostat, adding the compound of the formula (ii), and carrying out condensation reaction to obtain the compound

Preferably, the belinostat is dissolved at 0 ℃, and the solvent is preferably a mixed solution of tetrahydrofuran and pyridine; then, after preferably raising the temperature to 25 ℃, adding the compound of the formula (ii) for condensation reaction, and preferably reacting for 16 hours under the condition of keeping the temperature at 25 ℃;

(b) then, the compound of formula (iii) obtained in step (a) is subjected to a first deprotection reaction, in which the compound of formula (iii) is mixed with hydrofluoric acid, preferably at 0 ℃, and then, preferably, the temperature is raised to 20 ℃, and the reaction is carried out for 2d, so as to remove the tert-butyldimethylsilyl (TBS) protecting group, and obtain an intermediate having the structure of formula (iv);

(c) finally, carrying out secondary deprotection reaction on the compound shown in the formula (iv), namely removing the allyl carboxyl protecting group on the structure shown in the formula (iv) to obtain a final product shown in the following formula (II);

preferably, the step is carried out in the presence of triethylamine and formic acid under the catalysis condition of palladium tetratriphenylphosphine after the compound of the formula (iv) is dissolved;

preferably, the solvent used is tetrahydrofuran; the reaction is preferably carried out under the protection of gas, such as argon, the temperature of the reaction is preferably controlled at room temperature, and the time of the reaction is controlled at about half an hour;

the overall reaction preparation scheme as above can be referred to as the following FIG. 1.

Furthermore, the belinostat derivative based on formic acid has good water solubility, so that the belinostat derivative can be further mixed with an auxiliary agent and an auxiliary material to prepare tablets for administration, and can also be dissolved in normal saline or glucose for injection;

in the actual process of treating the tumor, the formic acid-based belinostat derivative can be used alone or matched with other medicines for treating the tumor.

EXAMPLE 1 preparation of O- { [ N-methyl-N-4- (2,3, 4-tri-O-tert-butyldimethylsilyl-6-allyl- β -D-glucopyranosyloxy-1-yl) -3-nitrobenzyloxycarbonyl ] -2-aminoethyl } -formyl-belinostat (iii)

Belinostat (469mg,1.47mmol) was dissolved in 6.4mL tetrahydrofuran and the system was cooled to 0 ℃; then slowly dropwise adding 1.6mL of pyridine; the mixture was stirred at 25 ℃ for 5 minutes and then compound ii (1.3g,1.34mmol) was added. The reaction solution was stirred for 16 hours while maintaining 25 ℃. Then diluted with 20mL of water and quenched, extracted with ethyl acetate (20 mL. times.2); the organic layers were combined, washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator. Preparative chromatography of the residue (petroleum ether: ethyl acetate 3:1to1:1) gave the following white solid iii (1.035g, 65.9%);

characterization of the product: LCMS 1285[ M- + TFA]^-。

Example 2 preparation of O- { [ N-methyl-N-4- (6-allyl- β -D-glucopyranosyloxy-1-yl) -3-nitrobenzyloxycarbonyl ] -2-aminoethyl } -formyl-belinostat (iv)

Compound iii (400mg,0.34mmol) was dissolved in a mixed solvent of tetrahydrofuran (20mL) and acetonitrile (20 mL);

hydrofluoric acid (4.8mL, 40% in H)₂O) is dissolved in acetonitrile (15.2mL) to prepare a solution, and the solution is added to the solution containing the compound iii at the temperature of 0 ℃; the reaction solution is stirred for 2 days at 20 ℃, then the reaction solution is concentrated to about 8mL, and the white solid iv is obtained by high performance liquid phase separation(130mg,30.7％)。

Characterization of the product:¹H NMR(400MHz,DMSO-d6):δ12.39(brs,1H),10.35(brs,1H),7.99(s,1H),7.89-7.86(m,2H),7.74(d,J＝7.6Hz,1H),7.68-7.58(m,3H),7.46(d,J＝8.8Hz,1H),7.23(t,J＝7.6Hz,2H),7.09(d,J＝7.6Hz,2H),7.03(t,J＝7.6Hz,1H),6.60(d,J＝16.0Hz,1H),5.93-5.85(m,1H),5.56-5.51(m,2H),5.34-5.28(m,3H),5.18(d,J＝10.8Hz,1H),5.08(s,2H),4.61(d,J＝4.0Hz,2H),4.36(t,J＝4.8Hz,2H),4.16(d,J＝9.6Hz,1H),3.58-3.56(m,2H),3.45-3.28(m,3H),2.93-2.89(m,3H).

LCMS:829[M-H]⁺

example 3 preparation of O- { [ N-methyl-N-4- (β -D-glucopyranosyloxy-1-yl) -3-aminobenzyloxycarbonyl ] -2-aminoethyl } -formyl-belinostat (II)

Compound iv (183mg, 0.22mmol) was dissolved in 12mL of tetrahydrofuran;

dissolving 95. mu.L of triethylamine and 7. mu.L of formic acid in 190. mu.L of tetrahydrofuran, and adding the solution dropwise to the tetrahydrofuran solution of the compound iv;

introducing argon for 10 minutes, adding a little tetrakistriphenylphosphine palladium, stirring at room temperature for about 30 minutes until the raw material disappears, concentrating by using a rotary evaporator, and separating the residue by preparative chromatography (acetonitrile: water-20: 1) to obtain a white target product II (134mg, 80%);

characterization of the product:¹H NMR(400MHz,DMSO-d₆):δ12.59(brs,1H),10.41(brs,1H),7.93-7.89(m,1H),7.66(s,1H),7.80-7.78(m,1H),7.51-7.49(m,1H),7.45(d,J＝16.0Hz,1H),7.16(m,2H),7.05-7.02(m,1H),6.97-6.95(m,5H),6.92(d,J＝16.0Hz,1H),6.82-6.78(m,6H),5.18-5.14(m,2H),4.76(m,1H),4.39(t,J＝4.8Hz,2H),4.02-3.94(m,2H),3.74-3.68(m,2H),3.40-3.33(m,2H),2.79-2.76(m,3H)；

¹³C NMR(400MHz,DMSO-d₆.)δ173.1,162.4,154.9,154.6,150.8,142.1,140.9,138.9,136.1,135.9,133.1,130.8,129.3,128.7,125.7,123.9,121.8,118.9,118.7,117.9,113.5,111.5,81.7,74.6,73.1,72.6,65.9,64.2,51.9,37.1；

LCMS:761[M+H]⁺,783[M+Na]⁺。

example 4 Water solubility experiments with belinostat and formic acid-based belinostat derivatives

1. Experimental methods

Respectively dissolving the belinostat derivative II based on formic acid provided by the embodiment of the invention in 2 aqueous microcentrifuge tubes (eppendorf tubes) in an excessive amount, wherein each tube contains 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. Results of the experiment

The water solubility data for belinostat and the formic acid-based belinostat derivative II of the invention are shown in table 1 below:

TABLE 1 Water solubility of belinostat and belinostat derivatives II based on formic acid

Drug to be tested	Belinostat	Belinostat derivatives II
			Solubility (mg/mL)	0.14mg/ml	100-105mg/ml

Wherein, in table 1, the belinostat solubility data can be found in the prior art: www.accessdata.fda.gov/drug atfda _ docs/label/2014/206256 lbl.pdf;

as can be seen from the comparison of the data, the water solubility of the belinostat derivative II provided by the present invention is significantly improved compared to belinostat, and the solubility is about 750 times higher than that of belinostat.

Example 5 in vitro inhibition of different tumor cells by formic acid-based Bellistat derivative II with or 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: the embodiment of the invention provides a formic acid-based belinostat derivative II, belinostat (Vorinostat);

t cell lymphoma cells.

2. Experimental methods

Digesting the cells from the cell culture dish with pancreatin, measuring the cell density after suspending the cells with a culture medium, diluting the cells to a solution containing an optimized number of cells per ml, adding the cell solution after the cell density adjustment to a cell assay plate at 50. mu.l/well, placing the plated cell culture plate in an incubator at 37 ℃ and 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 μ l of the diluted compound solution to the cell culture plate prepared the day before, and placing the cell culture plate with the compound back into the incubator at 37 deg.C and 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 rate 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 Belinostat and Belinostat derivative II tumor suppressive ability under different conditions

As can be seen from a comparison of the data in the table of Table 2 above, the IC50 of belinostat on both HT-29 and Hut-78 cell lines was > 10. mu.M, and toxicity was not affected by β -D-glucuronidase;

in the absence of β -D-glucuronidase, the IC50 of the belinostat derivative II on a cell line HT29 is about 10 mu M, the IC50 on Hut-78 is about 1.3 mu M, the toxicity of the two cell lines is greatly different, but the IC50 is almost unchanged in the presence of β -D-glucuronidase;

the results of the above tests may be due to the fact that the belinostat derivative II could not be obtained by hydrolysis with β -D-glucuronidase, and the results of the hydrolysis with β -D-glucuronidase of belinostat derivative II were consistent with the toxicity of belinostat derivative II.

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

1. A formic acid-based belinostat derivative having the structure:

2. the method for preparing a formic acid-based belinostat derivative according to claim 1, comprising the steps of:

will be provided with

And carrying out condensation reaction with the belinostat, then removing a protective group and reducing to obtain the belinostat derivative.

3. Use of the formic acid-based belinostat derivative of claim 1 for the preparation of an antitumor medicament.

4. The use according to claim 3, wherein the tumor is cutaneous T-cell lymphoma.

5. A medicament or pharmaceutical composition comprising the formic acid-based belinostat derivative of claim 1.