KR101536050B1 - Novel Isatin-Based Hydroxamic Acids and Anti-Cancer Composition Comprising the Same As Active Ingredient - Google Patents

Abstract

The present invention relates to novel isatin-based hydroxamic acid and an anticancer composition comprising the same as an active ingredient. The hydroxamic acid compound of the present invention has an inhibitory activity against histone deacetylase (HDAC), exhibits cytotoxicity in various cancer cells and exhibits anticancer efficacy, and thus can be developed as an active ingredient of a potent anticancer drug.

Description

[0001] The present invention relates to a new actin-based hydroxamic acid and an anticancer composition comprising the hydroxamic acid as an active ingredient. [0002]

The present invention relates to novel isatin-based hydroxamic acid and an anticancer composition comprising the same as an active ingredient.

Histone acetylases (HATs) and histone deacetylases (HDACs) are two enzymes that catalyze the acetylation and deacetylation of specific lysine residues in the tail portion of the histone, respectively. These enzymes play a very important role in gene transcription because acetylation is involved in opening the chromosomal structure and making the gene transcribable [1]. Recent studies have shown that these two enzymes regulate chromosome structure and gene expression as well as cell cycle progression and carcinogenesis [2]. In humans, 18 HDAC enzymes have been identified and are divided into four classes based on homology with yeast HDAC. Class I includes HDACs 1, 2, 3, and 8, and Class II includes HDACs 4, 5, 6, 7, 9, and 10. Class III HDACs, known as Sirtuins, contain the NAD ⁺ -dependent enzyme Sirt1-7. Class IV contains only one enzyme, HDAC11, which exhibits the characteristics of both Class I and Class II HDACs [2]. It is known that inhibition of HDACs in some cancer cell lines and in vivo pre-clinical models induces cell differentiation, apoptosis and cell cycle arrest. Therefore, HDAC inhibitors are currently attracting attention as anticancer drugs [3-6]. Based on the therapeutic potential for the treatment of cellular proliferative disorders, a variety of new HDAC inhibitors such as trichostatin A, SAHA (Vorinostat), MS-27-275 (Entinostat), LBH-589 (Panobinostat), PXD- And oxamflatin have been developed [7-12] (see Figure 1). Of these, SAHA was approved in 2006 as a treatment for several types of lymphoma.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

Korea Patent Publication No. 2009-0094383 Korean Patent No. 10-1261305 Korea Patent Publication No. 2007-0043978

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The present inventors have made efforts to develop a novel hydroxamic acid having a strong inhibitory effect on histone deacetylase (HDAC). As a result, we succeeded in synthesizing a novel hydroxyacetic acid based on Isatin, and the fact that the synthesized hydroxamic acid compounds not only inhibited the activity of histone deacetylase, but also had anticancer activity against various kinds of cancer cell lines The present invention has been completed.

It is therefore an object of the present invention to provide novel isatin-based hydroxamic acid compounds.

It is another object of the present invention to provide an anticancer pharmaceutical composition comprising the novel isatin-based hydroxamic acid compound as an active ingredient.

The objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, there is provided a isostene-based hydroxamic acid compound represented by the following formula (1) or (2).

[Chemical Formula 1]

Wherein R is hydrogen, halogen, C ₁ -C ₅ alkyl, or nitro.

(2)

In Formula 2, R is hydrogen, halogen, C ₁ -C ₅ alkyl, or nitro.

According to a preferred embodiment of the present invention, in the above formula (1) or (2), the substituent R is present at carbon number 5 or 7 of the adamantine ring.

According to another preferred embodiment of the present invention, the halogen as the R substituent is fluorine (F), chlorine (Cl), or bromine (Br).

According to another preferred embodiment of the present invention, the isostene-based hydroxamic acid compound represented by Formula 1 or Formula 2 is any one of the following compounds:

N-hydroxy-7- (3- (hydroxyimino) -2-oxoindolin-1-yl) heptanamide;

7- (5-fluoro-3- (hydroxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide;

7- (5-chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide;

7- (5-bromo-3- (hydroxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide;

N-hydroxy-7- (3- (hydroxyimino) -5-nitro-2-oxoindolin-1-yl) heptanamide;

N-hydroxy-7- (3- (hydroxyimino) -5-methyl-2-oxoindolin-1-yl) heptanamide;

7- (7-chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide;

N-hydroxy-7- (3- (methoxyimino) -2-oxoindolin-1-yl) heptanamide;

7- (5-fluoro-3- (methoxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide;

7- (5-chloro-3- (methoxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide;

7- (5-bromo-3- (methoxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide;

N-Hydroxy-7- (3- (methoxyimino) -5-nitro-2-oxoindolin-1-yl) heptanamide;

N-hydroxy-7- (3- (methoxyimino) -5-methyl-2-oxoindolin-1-yl) heptanamide; And

7- (7-Chloro-3- (methoxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide.

According to another aspect of the present invention, there is provided an anticancer pharmaceutical composition comprising the compound of formula (I) or (II) described above as an active ingredient.

According to a preferred embodiment of the present invention, the compound of the present invention has an effect of promoting histone acetylation through the inhibitory activity of histone deacetylase. That is, the isostane-based hydroxamic acid compound of the present invention induces intracellular histone to a high acetylation state by inhibiting the activity of the histone deacetylase.

The compounds of the present invention exhibit cytotoxic effects against various cancer cell lines and demonstrate anticancer efficacy, as demonstrated in the following specific example.

&Quot; Cancer " which is a disease to be treated by the pharmaceutical composition of the present invention is characterized by aggressive characteristics of cells that divide and grow by ignoring normal growth limits, invasive characteristics that penetrate surrounding tissues, It is a generic term for diseases caused by cells with metastatic characteristics that spread to other parts of the body.

According to a preferred embodiment of the present invention, the cancer to be treated is selected from breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or ocular melanoma, uterine sarcoma, ovarian cancer, Endometrial cancer, small bowel cancer, endocrine cancer, thyroid cancer, pituitary cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone cancer. More preferably a colon cancer, a breast cancer, a prostate cancer, a pancreatic cancer, or a lung cancer.

The anticancer pharmaceutical composition of the present invention comprises (i) a pharmaceutically effective amount of the hydroxamic acid compound of the above-described formula (1) or (2); And (ii) a pharmaceutically acceptable carrier.

The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The appropriate dosage of the pharmaceutical composition of the present invention may be determined by various methods depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate and responsiveness of the patient It can be prescribed. On the other hand, the dosage of the pharmaceutical composition of the present invention is preferably 0.001-1000 mg / kg (body weight) per day.

The pharmaceutical composition of the present invention can be administered orally or parenterally, and when administered parenterally, it can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration, or the like.

The concentration of the active ingredient contained in the composition of the present invention is determined in consideration of the purpose of the treatment, the condition of the patient, the period of time required, the severity of the disease, and the like. The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

The present invention relates to novel isatin-based hydroxamic acid and an anticancer composition comprising the same as an active ingredient. The hydroxamic acid compound of the present invention has an inhibitory activity against histone deacetylase (HDAC), exhibits cytotoxicity in various cancer cells and exhibits anticancer efficacy, and thus can be developed as an active ingredient of a potent anticancer drug.

Figure 1 shows the chemical structure of hysteretic deacetylase (HDAC) inhibitors so far known.
Figure 2 shows the effect of the synthetic compounds of the present invention on histone acetylation in SW620 cells. Cells were treated for 24 hours at a concentration of 1 [mu] M. Levels of acetylated histone-H3 and -H4 in total cell lysates were determined by western blot analysis.
Figure 3 shows the actual binding of SAHA to HDAC8 and the simulated docking appearance of compounds 3a and 6a. SAHA labeled the carbon, nitrogen, and oxygen atoms in yellow, blue, and red, respectively, as a stick model. The compounds 3a and 6a are represented by a stick model in which carbon atoms are indicated by cyan and magenta, and nitrogen and oxygen atoms are indicated by blue and red, respectively. Significant parts of the enzyme's interaction are represented by stick models that represent carbon, nitrogen, and oxygen, respectively, in green, blue, and red, respectively. Zn ²⁺ ions are denoted by dark gray sphere.
Figure 4 shows the actual binding figure of N- (4-aminophenyl-3-yl) benzamide for HDAC2 and the simulated docking appearance of compounds 3a and 6a. N- (4-aminophenyl-3-yl) benzamide was labeled with a stick model in which carbon, nitrogen and oxygen atoms were respectively labeled yellow, blue and red. In the compounds 3a and 6a, carbon atoms are represented by gray-blue and white, and nitrogen and oxygen atoms are represented by blue and red, respectively, in a stick model. Significant parts of the enzyme's interaction are represented by stick models that represent carbon, nitrogen, and oxygen, respectively, in green, blue, and red, respectively. Zn ²⁺ ions are denoted by dark gray sphere.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

I. Synthesis of compounds

1. Materials and Methods

All compounds were homogeneously obtained and thin-layer chromatographed on Whatman® 250 Jm Silica Gel GF Uniplates and visualized under UV light at λ 254 and 365 nm wavelengths. The boiling point was measured using an Electrothermal Melting Point apparatus. Purification using chromatography was performed by open flash silica gel column chromatography using Merck silica gel 60 (240 to 400 mesh). The nuclear magnetic resonance spectrum (1 H NMR) was determined on a Bruker DPX 500 MHz FT NMR spectrometer using tetramethylsilane as the internal standard and DMSO-d ₆ as the solvent unless otherwise specified. Chemical shifts were recorded in parts per million (ppm) downfield from the internal standard tetramethylsilane. Electron ionization (EI), electrospray ionization (ESI) and high resolution mass spectra were measured using PE Biosystems API 2000 and Mariner ㄾ mass spectrometers, respectively. The reagents and solvents are commercially available from Aldrich or Fluka Chemical Corp. (Milwaukee, WI, USA) or Merk. The solvent was distilled and dried.

2. Synthetic Example

Synthesis Example 1 Synthesis of N-hydroxy-7- (5/7-substituted-3-hydroxyimino-2-oxoindolin-1-yl) heptanamide (Compound 3a-3g)

(5/7-substituted-3-hydroxyimino-2-oxoindolin-1-yl) heptanamide (3a-g) was synthesized according to the following reaction scheme 1.

[Reaction Scheme 1]

Scheme 1 shows a process for synthesizing isatin-3-oxime-based hydroxamic acid of the present invention. Reagents and conditions of the reaction in the synthesis process are as follows: a) ethyl 7-bromoheptanoate, K ₂ CO ₃ , KI, DMF; b) Hydroxylamine hydrochloride, NaOH, MeOH, THF.

(1) Compound 3a: Synthesis of N-hydroxy-7- (3-hydroxyimino-2-oxoindolin-1-yl) heptanamide

A compound 1a solution (147 mg, 1 mmol) in DMF was cooled to -5 ℃ and added to _{K 2 CO 3 (165.5 mg,} 1.2 mmol). The mixture was then stirred at -5 ℃ at room temperature stirred for 45 minutes, and added to CH ₃ OH (0.5 ml) and KI (8.3 mg, 0.05 mmol) . After stirring for 15 min, a solution of ethyl 7-bromoheptanoate in DMF (1 ml) was added and the resulting reaction mixture was stirred for 24 h at 60 C. After the reaction was complete the reaction mixture was cooled and 10 Compound 2a was finally obtained in the form of a brown-yellow oil. Yield: 80%; Rf = 0.8 (from DCM). ≪ Desc / / MeOH, 30/1).

A solution of compound 2a (289 mg, 1 mmol) in a methanol / tetrahydrofuran mixture (1/1, 3 mL) was cooled to -5 [deg.] C followed by the addition of hydroxylammonium chloride (195 mg, 10 mmol). NaOH (0.4 g, 10 mmol) was dissolved in 2 ml of water, cooled to -5 [deg.] C and added to the mixture. The mixture was stirred at -5 < 0 > C until compound 2a was completely reacted. The reaction mixture was acidified to pH 7 by addition of 15% HCl solution to induce precipitation. The precipitate was filtered, washed with water, dried at 60 < 0 > C and recrystallized from ethanol to give a yellow solid compound.

Yield: 65%. mp: 192-194 [deg.] C. Rf = 0.65 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3420, 3251 (OH), 3050 (NH), 2927, 2865 (CH, CH2), 1650, 1629 (C.dbd.O), 1558 (C.dbd.C). ESI-MS (m / z): 305.4 [MH] <">. (1H, s, NH), 8.68 (1H, brs, OH), 7.97 (1H, d, J = 7.5 Hz), 7.42 (1H, t, J = 7.5 Hz), 7.06-7.10 (2H, m), 3.67 (2H, t, Hz, CH 2), 1.55-1.57 (2H, m, CH 2), 1.44-1.47 (2H, m, CH 2), 1.25-1.26 (4H, m, CH 2). 13 C NMR (125 MHz, DMSO-d 6, ppm): δ 169.20, 163.00, 143.00, 143.00, 132.12, 126.12, 126.98, 122.56, 115.24, 109.18, 32.21, 30.70, 28.21, 26.90, 25.96, 25.01. Anal. Calcd. For C15H20N3O4 (306.34): C, 58.81; H, 6.58; N, 13.72. Found: 58.64; H, 6.61; N, 13.55.

Other compounds 3b-3g were synthesized starting from the respective 5- / 7-substituted isostin via methods analogous to those used for the synthesis of compound 3a above.

(2) Compound 3b: 7- (5-Fluoro-3- (hydroxyimino) -2-oxoindolin- N - Synthesis of hydroxyheptanamide

Yield: 67.5%. mp: 188-190 [deg.] C. Rf = 0.67 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3417,3220 (OH), 3057 (NH), 2936,2859 (CH, CH2), 1714, 1662 (C = O), 1618, 1598 (C = C). ESI-MS (m / z): 323.1 [MH] -, 346.0 [M + Na] < + >. (1H, br s, OH), 7.75 (1H, d, d, J = 8Hz). 1H NMR (500 MHz, DMSO- J = 8.0, 2.5 Hz), 7.30 (1H, td, J = 9.0, 2.5 Hz, H6), 7.14 (1H, dd, J = 8.5, 4.0 Hz, H7), 3.68 (2H, m, CH2), 1.92 (2H, t, J = 7.5 Hz, CH2), 1.54-1.57 . 13 C NMR (125 MHz, DMSO-d 6, ppm): δ 169.58, 163.32, 159.31, 143.71, 139.89, 118.74, 118.55, 116.24, 116.17, 114.51, 114.30, 110.67, 110.61, 32.65, 28.67, 27.27, 26.39, Anal. Calcd. For C15H18FN3O4 (323.32): C, 55.72; H, 5.61; N, 13.00. Found: C, 55.75; H, 5.57; N, 13.21.

(3) Compound 3c: 7- (5-Chloro-3- (hydroxyimino) -2-oxoindolin- N - Synthesis of hydroxyheptanamide

Yield: 60.0%. mp: 197.0-199 [deg.] C. Rf = 0.60 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3424, 3216 (OH), 3050 (NH), 2933, 2859 (CH, CH2), 1714, 1659 (C = O), 1608 (C-C). ESI-MS (m / z): 338.5 [MH] <">. (1H, brs, OH), 7.95 (1H, d, J = 2.5 Hz, H4), 7.49 (1H, (d, J = 8.5, 2.5 Hz, H6), 7.16 (1H, d, J = 8.5 Hz, H7), 3.68 Hz, CH2), 1.54-1.56 (2H, m, CH2), 1.44-1.47 (2H, m, CH2), 1.25-1.26 (4H, m, CH2). 13 C NMR (125 MHz, DMSO-d 6, ppm): δ 169.00, 162.61, 142.73, 141.79, 131.38, 126.23, 126.13, 116.32, 110.71, 32.12, 28.14, 26.75, 25.84, 24.91. Anal. Calcd. For C15H18ClN3O4 (339.77): C, 53.02; H, 5.34; N, 12.37. Found: C, 53.13; H, 5.29; N, 12.42.

(4) Compound 3d: 7- (5-Bromo-3- (hydroxyimino) -2-oxoindolin- N - Synthesis of hydroxyheptanamide

Yield: 62.0%. mp: 192-195 [deg.] C. Rf = 0.61 (DCM / MeOH = 9/1). IR (KBr, cm -1): 3455 (OH), 2926, 2856 (CH, CH 2), 1665 (C = O), 1602 (C = C). ESI-MS (m / z): 384.9 [MH, 81Br] -, 382.9 [MH, 79Br] (1H, dd, J = 8.0, 2.0 Hz, H6), 6.88 (1H, d, J = 2.0 Hz, 1H) (2H, m, CH 2), 1.44 (2H, t, J = 8.0 Hz, H7), 3.68 1.47 (2H, m, CH 2), 1.26 (4H, m, CH 2). 13 C NMR (125 MHz, DMSO-d6 + CDOD3, ppm): δ 169.07, 165.95, 143.86, 136.80, 127.46, 122.44, 117.93, 112.88, 108.88, 38.45, 32.15, 28.23, 27.41, 25.99, Anal. Calcd. For C15H18BrN3O4 (384.23): C, 46.89; H, 4.72; N, 10.94. Found: C, 46.90; H, 4.74; N, 10.97.

(5) Compound 3e: N Synthesis of hydroxy-7- (3- (hydroxyimino) -5-nitro-2-oxoindolin-1-yl) heptanamide

Yield: 61.0%. mp: 201-203 [deg.] C. Rf = 0.67 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3307 (OH), 2936, 2858 (CH, CH2), 1747, 1729 (C = O), 1630, 1611 (C = C). ESI-MS (m / z): 348.5 [MH] <">. (1H, s, NH), 8.67 (2H, s, H4-OH overlap), 8.34 (1H, (d, J = 8.0 Hz, H6), 7.35 (1H, d, J = 9.0 Hz, H7), 3.75 2H, m, CH 2), 1.46-1.47 (2H, m, CH 2), 1.27 (4H, m, CH 2). 13 C NMR (125 MHz, DMSO-d 6, ppm): δ 169.01, 163.26, 148.27, 142.32, 142.10, 128.30, 121.47, 115.02, 109.42, 32.12, 28.15, 26.84, 25.83, 24.91. Anal. Calcd. For C15H18N4O6 (350.33): C, 51.43; H, 5.18; N, 15.99. Found: C, 51.45; H, 5.21; N, 15.85.

(6) Compound 3f: N Synthesis of hydroxy-7- (3- (hydroxyimino) -5-methyl-2-oxoindolin-1-yl) heptanamide

Yield: 70.0%. mp: 181-183 [deg.] C. Rf = 0.67 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3304 (OH), 3039 (NH), 2929, 2862 (CH, CH2), 1699 (C.dbd.O), 1650, 1618 (C.dbd.C). ESI-MS (m / z): 318.1 [MH] -, 288.2 [M-NOH] -, 342.0 [M + Na] -. (1H, s, NH), 7.82 (1H, s, OH, oxime), 8.65 (1H, brs, OH), 10.32 (1H, d, J = 7.5 Hz, H7), 7.23 (1H, d, J = 7.5 Hz, H6), 6.98 (2H, t, J = 7.0Hz, CH2), 1.55 (2H, m, CH2), 1.45 (2H, m, CH2), 1.25 (4H, m, CH2). 13 C NMR (125 MHz, DMSO-d 6, ppm): δ 169.01, 162.95, 143.65, 140.84, 132.21, 131.45, 127.47, 115.25, 108.86, 32.15, 28.16, 26.85, 25.90, 24.95, 20.48.

(7) Compound 3g: 7- (7-Chloro-3- (hydroxyimino) -2-oxoindolin- N - Synthesis of hydroxyheptanamide

Yield: 65.0%. mp: 190-192 [deg.] C. Rf = 0.62 (DCM / MeOH = 9/1). IR (KBr, cm -1): 3353, 3297 (OH), 3109 (NH), 3021 (CH, aren), 2930, 2862 C). ESI-MS (m / z): 338.1 [MH] <">. (1H, s, NH), 8.03 (1H, dd, J = 7.5, 1.0 Hz, H6) , 7.42 (1H, dd, J = 8.5, 1.0 Hz, H4), 7.08 (1H, t, J = 8.0Hz, H5), 3.97 (2H, m, CH 2), J = 7.5 Hz, CH 2), 1.59-1.61 (2H, m, CH 2), 1.46-1.49 (2H, m, CH 2), 1.27-1.28 13C NMR (125 MHz, DMSO-d6 + CDOD3, ppm): δ 169.01, 163.41, 142.15, 138.59, 133.85, 125.87, 123.99, 118.18, 114.29, 40.73, 32.12, 29.15, 28.15, 25.73, 24.96.

Synthesis Example 2 Synthesis of N-Hydroxyl-7- (5/7-substituted-3-methoxyimino-2-oxoindolin-1-yl) heptanamide (Compound 6a-6g)

[Reaction Scheme 2]

Scheme 2 shows the synthesis process of 3'-methoxime satin hydroxamic acid. Reagents and conditions in the synthesis process are as follows: (a) methoxylamine hydrochloride, pyridine, ethanol, 80 C, 3 hours; (b) ethyl 7-bromoheptanoate, K ₂ CO ₃ , KI, DMF, rt, 24 h; (c) Hydroxylamine hydrochloride, NaOH, MeOH, THF, 0 < 0 > C. 30 minutes. Compounds 6a-6g were synthesized by methods analogous to those used for compound 3a using the respective 5- / 7-substituted isatin-3-methoxy as starting material. The 5- / 7-substituted isatin-3-methoxse was synthesized in good yields (75-96%) from the 5/7-substituted isostene [17,18].

(1) Compound 6a: N- Synthesis of hydroxy-7- (3- (methoxyimino) -2-oxoindolin-1-yl) heptanamide

Yield: 75.0%. mp: 191-193 [deg.] C. Rf = 0.71 (DCM / MeOH = 9/1). IR (KBr, cm -1): 3399 (OH), 3249 (NH), 3038 (CH, aren), 2933, 2862 (CH, CH 2), 1704, 1647 C). ESI-MS (m / z): 318.2 [MH] -, 287.0 [M-NHOH] -. (1H, brs, OH), 7.87 (1H, d, J = 7.5 Hz), 7.46 (1H, t, J = 7.5 Hz), 7.20 (1H, d, J = 8.0 Hz), 7.07 (1H, t, J = 7.5 Hz), 4.20 M, CH2), 1.92 (2H, t, J = 7.0Hz, CH2), 1.56 (2H, m, CH2), 1.45-1.47 (2H, m, CH2), 1.26 (4H, m, CH2). 13C NMR (125 MHz, DMSO-d6, ppm):? 169.06, 162.15, 143.68, 143.28, 132.96, 127.34, 122.61, 114.87, 109.40, 64.40, 32.14, 28.14, 26.77, 25.87, 24.95. Anal. Calcd. For C16H21N3O4 (319.36): C, 60.17; H, 6.63; N, 13.16. Found: C, 60.21; H, 6.59; N, 13.22.

(2) Compound 6b: 7- (5-Fluoro-3- (methoxyimino) -2-oxoindolin- N - Synthesis of hydroxyheptanamide

Yield: 72.0%. mp: 200-202 [deg.] C. Rf = 0.70 (DCM / MeOH = 9/1). IR (KBr, cm -1): 3331 (OH), 3234 (NH), 3045 (CH, aren), 2931, 2861 (CH, CH 2), 1702, 1655 C). ESI-MS (m / z): 334.7 [M-2H] -, 697.4 [2M + Na] -. (1H, brs, OH), 7.65 (1H, dd, J = 8.0, 2.5 Hz, H4), 7.33 (1H, td, J = 9.25, 2.5 Hz, H6), 7.14 (1H, dd, J = 8.5, 4.0 Hz, H7), 4.21 (3H, s, OCH3) (2H, m, CH 2), 1.91 (2H, t, J = 7.0 Hz, CH 2), 1.53-1.56 . 163.10, 162.03, 158.83, 156.93, 142.96, 140.02, 119.23, 119.04, 115.41, 115.33, 114.50, 114.29, 110.52, 110.46, 64.67, 32.15, 28.16, 26.71, 25.86, 24.95.

(3) Compound 6c: 7- (5-Chloro-3- (methoxyimino) -2-oxoindolin- N - Synthesis of hydroxyheptanamide

Yield: 78.0%. mp: 198-199 [deg.] C. Rf = 0.70 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3431 (OH), 3259 (NH), 2935, 2859 (CH, CH2), 1714, 1645 (C = O), 1609 (C = C). ESI-MS (m / z): 352.2 [MH] <">. (1H, s, H4), 8.70 (1H, brs, OH), 7.50 (1H, d, J = 8.0 Hz, H6), 7.16 (1H, d, J = 8.0 Hz, H7), 4.22 (3H, s, OCH3), 3.65 = 7.0 Hz, CH 2), 1.53 (2H, m, CH 2), 1.44 (2H, m, CH 2), 1.25 (4H, m, CH 2). 13 C NMR (125 MHz, DMSO-d 6, ppm): δ 169.04, 161.77, 142.44, 142.41, 132.30, 126.54, 126.38, 115.97, 111.00, 64.71, 33.92, 33.57, 32.09, 28.11, 26.67, 25.80,

(4) Compound 6d: 7- (5-Bromo-3- (methoxyimino) -2-oxoindolin- N - Synthesis of hydroxyheptanamide

Yield: 70.0%. mp: 205-207 [deg.] C. Rf = 0.76 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3400 (OH), 3222 (NH), 2935, 2856 (CH, CH2), 1722, 1647 (C = O), 1604 (C = C). ESI-MS (m / z): 398.0 [M-], 382.9 [M-CH3] -. (1H, d, J = 8.0 Hz, 1H). 1H NMR (500 MHz, DMSO-d6 + CDOD3, ppm):? 7.94 , 2H), 4.22 (3H, s, OCH3), 1.53 (2H, m, CH2), 3.65 (2H, t, 1.44 (2H, m, CH 2), 1.25 (4H, m, CH 2). 13C NMR (125 MHz, DMSO-d6 + CDOD3, ppm): δ 168.69, 161.66, 142.80, 142.32, 135.13, 129.22, 116.41, 114.00, 111.47, 64.72, 32.21, 28.15, 26.68, 26.18, 25.84, 25.03.

(5) Compound 6e: N Synthesis of hydroxy-7- (3- (methoxyimino) -5-nitro-2-oxoindolin-1-yl) heptanamide

Yield: 70.0%. mp: 203-205 [deg.] C. Rf = 0.67 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3210 (OH), 2934, 2856 (CH, CH2), 1729 (C = O), 1611 (C = C). ESI-MS (m / z): 363.0 [MH] -, 348.0 [M-CH3] -. (1H, s, OH), 8.35 (1H, d, J = 9.0, 2.5 Hz, H6), 8.49 (1H, d, J = 2.0 Hz, H4), 7.35 (1H, d, J = 9.0 Hz, H7), 4.29 (3H, s, OCH3) 1.92 (2H, t, J = 7.0Hz, CH2), 1.54-1.58 (2H, m, CH2), 1.43-1.49 (2H, m, CH2), 1.26-1.27 (4H, m, CH2). 13C NMR (125 MHz, DMSO-d6, ppm):? 169.05, 162.43, 148.87, 142.34, 141.79, 129.06, 121.84, 114.74, 109.72, 65.20, 32.11, 28.13, 26.76, 25.80, 24.91.

(6) Compound 6f: N Synthesis of hydroxy-7- (3- (methoxyimino) -5-methyl-2-oxoindolin-1-yl) heptanamide

Yield: 78.0%. mp: 193-195 [deg.] C. Rf = 0.75 (DCM / MeOH = 9/1). IR (KBr, cm -1): 3400 (OH), 3217 (NH), 3047 (CH, arylene), 2926, 2856 (CH, CH 2), 1706, 1638 C). ESI-MS (m / z): 332.0 [MH] <">. 7.00 (1H, s, H4), 7.26 (1H, d, J = 8.0 Hz, H6), 7.00 (1H, s). 1H NMR (500 MHz, DMSO- (d, J = 8.0 Hz, H7), 4.19 (3H, s, OCH3), 3.64 (2H, t, J = 7.0Hz, CH2), 2.27 = 7.5 Hz, CH 2), 1.53-1.55 (2H, m, CH 2), 1.43-1.46 (2H, m, CH 2), 1.24-1.25 (4H, m, CH 2). 13 C NMR (125 MHz, DMSO-d 6, ppm): δ 169.02, 162.11, 143.38, 141.44, 133.13, 131.65, 127.81, 114.90, 109.15, 64.34, 32.12, 28.13, 26.76, 25.85, 24.93,

(7) Compound 6g: 7- (7-Chloro-3- (methoxyimino) -2-oxoindolin- N - Synthesis of hydroxyheptanamide

Yield: 75.0%. mp: 189-191 [deg.] C. Rf = 0.72 (DCM / MeOH = 9/1). IR (KBr, cm-1): 3232 (NH), 3059 (CH, aren) 2937, 2858 (CH, CH2), 1728 (C = O), 1605 (C = C). ESI-MS (m / z): 352.0 [MH] -, 338.1 [M-CH3] -. (1H, brs, OH), 7.90 (1H, d, J = 7.5 Hz, H6), 7.47 (1H, (d, J = 8.0Hz, H4), 7.09 (1H, t, J = 8.0 Hz, H5), 4.22 (3H, s, OCH3), 3.95 2H, t, J = 7.5Hz, CH2), 1.56-1.60 (2H, m, CH2), 1.44-1.50 (2H, m, CH2), 1.27 (4H, m, CH2). 13 C NMR (125 MHz, DMSO-d 6, ppm): δ 169.00, 162.57, 141.92, 139.21, 134.76, 126.36, 124.10, 117.84, 114.49, 64.79, 40.87, 32.10, 29.06, 28.13, 25.69, 24.95.

3. Summary of Compound Synthesis Results

The synthesis of the hydroxamic acid compound 3a-3g is shown in Scheme 1 above. In the first step, isatin and its 5-or 7-substituted derivatives and 1 molar equivalent of K ₂ CO ₃ are dissolved in DMF (dimethylformamide) and then 1 molar equivalent of ethyl 7-bromoheptano Was added dropwise at room temperature. The reaction mixture was heated to 60 < 0 > C with stirring for 24 hours and cooled again to ambient temperature. Each corresponding reaction mixture was poured into a 10% solution of cooled HCl to precipitate the ester compound 2a-2g. Recrystallization from n-hexane / acetone gave the intermediate compound 2a-2g in good yield (65-90%). The ester compounds were dissolved in a mixture of methanol-tetrahydrofuran (1/1). Hydroxylamine hydrochloride (10 mol equiv.) Was added and the resulting suspension was cooled to -5 [deg.] C. A solution of NaOH (10 mol equiv) was slowly dropped into the reaction mixture held constant at -5 < 0 > C. After 30 minutes, the reaction contents were poured into cooling water and the pH was adjusted to 7 using a 15% solution of HCl to precipitate the crude product. The crude product was recrystallized from ethanol to give 3a-3g of intermediate to high yield (50-90%).

Compound 6a-6g was synthesized through the process of Reaction Scheme 2 above. (6a-6g) was synthesized by converting isatin to the 3-methoxime derivative 4 using methoxylamine hydrochloride under reflux in ethanol conditions (see Scheme 2) . The structures of the obtained compounds and intermediates were directly and clearly confirmed through spectral studies including IR, MS, 1 H NMR, 13 C NMR and elemental analysis and the like. In contrast to the 3-oxime compounds 3a to 3g, in the isatin-3-methoxycinnamic acid (compounds 6a to 6g), the -OH protons were substituted with methyl groups, There is no hydrogen bond. The isatin-3-methoxy (compounds 6a to 6g) was obtained as pure E-isomers as confirmed by spectroscopic data and correlation. NOE analysis on selected compound 3b showed a clear correlation between the methyl protons of the H-4 'and 3' methoxymethyl groups. In addition, in the ¹ H NMR spectrum of the compounds 6a to 6g, the peak corresponding to H-4 'shifted more consistently 0.2-0.3 ppm upward compared with that of the compounds 3a to 3g. This was due to the protective effect of the E-methoxy group. The preferential formation of the E-isomer for the isatin-3'-alkyl oxime is mentioned and discussed in literature [23-25].

Ⅱ. Evaluation of biological activity of compounds

1. Measurement of inhibitory activity of histone deacetylase (HDAC)

(1) Western blot

The inhibitory activity of histone-H3 and histone-H4 deacetylation at 1 mu M concentration was evaluated by Western blot analysis on the synthesized hydroxamic acid compounds (compounds 3a to 3g and compounds 6a to 6g). Western blotting was performed by the following method. First, the total protein extract was obtained by dissolving the cells in RIPA buffer (50 mM Tris-HCl [pH 8.0], 5 mM EDTA, 150 mM NaCl, 1% NP-40, 0.1% SDS, and 1 mM phenylmethylsulfonyl fluoride) . Protein concentrations in the lysates were determined using a Bio-Rad protein assay kit (Bio-Rad Laboratories Inc., Hercules, Calif., USA) according to the manufacturer's instructions. Samples were separated on SDS-PAGE and transferred to a nitrocellulose membrane. Membranes were incubated with blocking buffer (TBS containing 0.2% Tween-20 and 3% skim milk) and then screened using primary antibodies against acetyl histone-H3, -H4, and GAPDH. After washing, the membranes were screened using horseradish peroxidase-conjugated secondary antibodies. Detection was performed using an enhanced chemiluminescent protein (ECL) detection system (Amersham Biosciences, Little Chalfont, UK).

(2) Results of activity measurement of the compound

As shown in the results of FIG. 2, compounds 3a-3d and 3f-3g significantly increased the acetylation of histone-H3 and histone-H4 through inhibition of HDAC enzyme at a concentration of 1 μM. SAHA, a well-known HDAC inhibitor, also increased histone acetylation in a similar manner. Only 3e, a compound having a 5-nitro group on the isatin moiety, did not inhibit the HDAC enzyme and histone-H3 and histone-H4 were completely deacetylated.

For compounds 6a-6g, the four compounds of compounds 6a-6c and 6g significantly increased the acetylation of histone-H3 and histone-H4, similar to SAHA, compounds 3a-3d and 3f-3g. However, Compound 6d (5-Br substituent), Compound 6e (5-nitro substituent) and Compound 6f (compound containing 5-CH ₃ group) did not show significant inhibitory activity of HDAC enzyme at the analyzed concentrations. From the obtained results, (i) the presence of a nitro group at position 5 of the isatin moiety is not favorable for HDAC inhibition; (Ii) methylation of the 3'-oxime group and the simultaneous presence of bulky substituents such as -Br or -CH ₃ at the 5-position on the adamantine ring (compounds 6d and 6f) And it was found.

2. Evaluation of anticancer activity by measuring cytotoxicity against cancer cells

(1) Evaluation method

(American Type Culture Collection (ATCC, Manassas, Va., USA) was used as an anti-cancer agent for human cancer cell lines NCI-H460 (lung cancer), PC3 (prostate cancer), SW620 (colorectal cancer), MCF- USA). Cells are played in 96 well plates at a density of 9 x 10 ³ cells / well plated and treated with samples for 48 hours and incubated overnight. The compound was dissolved in dimethyl sulfoxide (DMSO) and used. Cytotoxicity was assessed by the method of Skehan P, Storeng R, Scudiero D, Monk A, MacMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR. New colorimetric cytotoxicity assay for anticancer drug screening. J. Natl Cancer Inst 1990; 82: 1107-1112] by a slightly modified method [12]. IC ₅₀ values were calculated according to the Probits method. The values measured for each compound are the average values of three independent measurements.

(2) Antiproliferative Activity Evaluation Results on Cancer Cell Lines

The antiproliferative activity of compounds synthesized using SRB (sulforhodamine B) cell proliferation assay was evaluated. First, these compounds were screened against SW620 (human colon cancer) cell line at a concentration of 30 [mu] M to inhibit growth of this cancer cell. As a result of screening, it was confirmed that both of the compounds 3a-3f and 6a-6f completely inhibited the growth of SW620 cells at a concentration of 30 μM. Thus, all of these compounds were tested for SW620 and four additional types of human cancer cell lines, MCF-7 (breast cancer), PC-3 (prostate cancer), and the like, at five different concentrations (30, 10, AsPC-1 (pancreatic cancer), and NCI-H460 (lung cancer) cell lines. The IC ₅₀ (concentration at which 50% cell proliferation inhibition is attained) of each compound was measured and summarized in Table 1 below. SAHA was used as a positive control. According to the experimental data shown in the following Table 1, the cytotoxicity of the compound 3a-3f to the cancer cell line showed a good agreement with the HDAC inhibitory activity. That is, compounds 3a-3d and 3f-3g, which completely inhibited HDAC enzyme activity at a concentration of 1 μM, had IC ₅₀ values in the micromolar or very low micromolar range for all five cancer cell lines tested And showed excellent cytotoxic effects on cancer cell lines. On the other hand, compound 3e, which did not exhibit the HDAC enzyme inhibitory activity at a concentration of 1 μM, had the lowest IC ₅₀ activity against cancer cells while having an IC ₅₀ value of 19.69 μM (FIG. 2).

For compounds 6a-6f, cytotoxic activity against cancer cells generally correlated with HDAC inhibitory activity. As shown in Fig. 2, Compound 6d-6f, which did not inhibit HDAC enzyme activity, showed the lowest cytotoxic activity against cancer cells. On the other hand, compounds 6a-6c, and 6g, which exhibited activity to strongly inhibit HDAC enzymes, as evidenced by a significant increase in the acetylation levels of histone-H3 and -H4, were tested in all five cancer cell lines tested But also showed strong cytotoxicity. Only compound 6e showed an undefined biological activity profile, which did not inhibit the activity of HDAC at the concentration (1 μM) analyzed, but the four cancer cell lines (SW620, MCF-7, PC-3 , AsPC-1) showed strong cytotoxicity and showed antitumor activity. NCI-H460 cell line showed weak anti-cancer activity. Except Compound 3e and Compound 6d-6f, all other compounds showed stronger activity than the positive control compound SAHA in terms of cytotoxic activity against cancer cells. Particularly, Compound 3d showed 45 times stronger cytotoxicity than SAHA in AsPC-1 cell line (pancreatic cancer cell line). Compound 3b also showed about 30 times stronger cytotoxicity against the SW620 cell line (colon cancer cell line). Substituents with different sizes and electron affinities in the 3-oxime series compounds (3a-3g) do not appear to have a significant effect on cytotoxicity. On the other hand, large substitutions at position 5 on the Isatin ring had a negative effect on the cytotoxicity of the 3 'methoxyl compounds (6d and 6f). Actin 1a-1g, their corresponding 3-oxime and 3-methoxy derivatives did not specifically show cytotoxicity against the 5 different types of cancer cells tested (data not shown). Thus, as evidenced by the strongly elevated levels of histone-H3 and histone-H4 acetylation induced by compounds 3a-3g and 6a-6g, the introduction of the hydroxamic acid moiety results in compounds 3a-3g and 6a-6g Is believed to be an important mechanism for the anticancer cytotoxicity of these compounds to play a crucial role in cytotoxic effects on cancer cells and inhibition on HDAC.

compound R Molecular Weight Cytotoxicity (IC ₅₀ , ¹ μM) / cell line ² SW620 MCF-7 PC3 AsPC-1 NCI-H460 Compound 3a -H 305.33 0.64 0.79 0.98 1.10 0.89 Compound 3b 5-F 323.32 0.11 1.55 2.73 1.72 1.50 Compound 3c 5-Cl 339.77 0.65 0.68 0.85 1.86 0.85 Compound 3d 5-Br 384.23 0.29 1.77 2.21 0.08 0.97 Compound 3e 5-NO ₂ 350.33 3.39 1.34 19.69 4.68 7.71 Compound 3f 5-CH ₃ 319.36 0.99 1.19 0.62 2.44 2.09 Compound 3g 7-Cl 339.77 1.05 1.74 1.57 1.82 1.35 Compound 6a -H 319.36 0.73 1.71 1.67 1.22 0.75 Compound 6b 5-F 337.35 1.11 2.42 1.15 0.97 0.97 Compound 6c 5-Cl 353.80 0.49 1.56 2.33 0.49 0.76 Compound 6d 5-Br 398.25 2.32 7.79 8.91 1.68 2.90 Compound 6e 5-NO ₂ 364.35 1.35 0.94 1.69 0.84 14.27 Compound 6f 5-CH ₃ 333.38 1.07 16.67 0.35 5.48 1.19 Compound 6g 7-Cl 353.80 0.26 0.34 0.29 0.63 0.35 SAHA 264.32 3.70 6.42 4.31 3.66 2.77

In Table 1, ¹ is the concentration of the compound that reduces cell growth by 50%, and the number is a deviation of less than 10%, which represents the average result of three repeated experiments. ² is the cell line: SW620, colon cancer; MCF-7, breast cancer; PC3, prostate cancer; AsPC-1, pancreatic cancer; NCI-H460, lung cancer; ³ SAHA (suberoylanilide hydroxamic acid), positive control.

3. Simulation of bond structure with HDAC enzyme

To understand the interaction between the HDAC enzyme and its inhibitory compounds, a docking simulation was performed using the active site of HDAC. A docking study was performed using the AutoDock Vina program [14]. The initial structure of the HDAC8 enzyme (complex with SAHA, 25) and the initial structure of the HDAC2 enzyme, [27] with Protein Data Bank (PDB) ID: 3MAX), and the coordinates for the compounds were generated using GlycoBioChem PRODRG2 Server (http://davapc1.bioch.dundee.ac.uk/prodrg/) [30]. The grid map for the docking study was centered on the SAHA binding site and after removal of SAHA (for HDAC8) or N- (2-aminophenyl) benzamide (for HDAC2) from the complex structure, A space of 26 x 26 x 22 points was included [13-15]. The AutoDock Vina program is run with four-way multithreading, and the other parameters in the AutoDock Vina program are placed in the default settings.

After SAHA was removed from the composite structure, a control docking experiment was performed with SAHA on the crystal structure of HDAC8 using the AutoDock Vina program [28] [14,15].

To obtain information on the interconnection between the compounds and HDAC, a docking simulation was performed using the active site of the HDAC. As the docking template, the structure of HDAC8 complexed with SAHA was chosen because it is easy to obtain this crystal structure (25, Protein Data Bank ID: 1T69). After SAHA was removed from the composite structure, docking experiments were performed using SAHA as a control for the crystal structure of HDAC8 using the AutoDock Vina program [26]. As a result of the docking experiment, it was confirmed that the compounds 3a and 6a located at the active sites had more stable energy than SAHA (FIG. 3). The stabilization energies of the expected binding modes for compounds 3a and 6a were -5.3 and -5.6 kcal / mol, while SAHA was -4.4 kcal / mol. Therefore, according to the results of the docking experiments, it was confirmed that the compounds 3a and 6a had greater affinity for HDAC8 than SAHA.

In addition to docking studies for HDAC8, HDAC2 complexes with N- (2-aminophenyl) benzamide were selected (27, PDB ID: 3MAX). Since histone-H3 and histone-H4 deacetylation is regulated by HDAC1 and HDAC2, docking experiments of Compound 3a and Compound 6a against HDAC2 were additionally performed. As a result of the docking experiment, it was confirmed that both of the compounds 3a and 6a were well located in the active site of HDAC2, and that the hydroxamic acid moiety was well located in the zinc-binding site (FIG. 4). The expected stabilization energies for the coupled modes were -6.7 kcal / mol for both compounds 3a and 6a, and -7.5 kcal / mol for N- (2-aminophenyl) benzamide. Thus, both compounds showed strong binding affinity for HDAC2.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (6)

A isatin-based hydroxamic acid compound represented by the following formula (1) or (2).
[Chemical Formula 1]

Wherein R is halogen, C ₁ -C ₅ alkyl, or nitro.
(2)

In Formula 2, R is hydrogen, halogen, C ₁ -C ₅ alkyl, or nitro.
2. A compound according to claim 1, wherein the halogen is fluorine (F), chlorine (Cl) or bromine (Br).
2. The compound according to claim 1, wherein the isostene-based hydroxamic acid compound represented by Formula 1 or Formula 2 is any one of the following compounds:
7- (5-fluoro-3- (hydroxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide;
7- (5-chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide;
7- (5-bromo-3- (hydroxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide;
N-hydroxy-7- (3- (hydroxyimino) -5-nitro-2-oxoindolin-1-yl) heptanamide;
N-hydroxy-7- (3- (hydroxyimino) -5-methyl-2-oxoindolin-1-yl) heptanamide;
7- (7-chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide;
N-hydroxy-7- (3- (methoxyimino) -2-oxoindolin-1-yl) heptanamide;
7- (5-fluoro-3- (methoxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide;
7- (5-chloro-3- (methoxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide;
7- (5-bromo-3- (methoxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide;
N-Hydroxy-7- (3- (methoxyimino) -5-nitro-2-oxoindolin-1-yl) heptanamide;
N-hydroxy-7- (3- (methoxyimino) -5-methyl-2-oxoindolin-1-yl) heptanamide; And
7- (7-Chloro-3- (methoxyimino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide.
An anticancer pharmaceutical composition comprising the compound of any one of claims 1 to 3 as an active ingredient.
The method of claim 4, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or ocular melanoma, uterine sarcoma, ovarian cancer, rectal cancer, Wherein the cancer is cancer, endometrial cancer, cervical cancer, small bowel cancer, endocrine cancer, thyroid cancer, pituitary cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer or bone cancer.
5. The anticancer pharmaceutical composition according to claim 4, wherein the compound has an activity of promoting histone acetylation through inhibition of histone deacetylase.

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