WO2015016441A1 - Nouvel acide hydroxamique à base d'isatine, et composition anticancéreuse le contenant en tant que principe actif - Google Patents

Nouvel acide hydroxamique à base d'isatine, et composition anticancéreuse le contenant en tant que principe actif Download PDF

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WO2015016441A1
WO2015016441A1 PCT/KR2013/012035 KR2013012035W WO2015016441A1 WO 2015016441 A1 WO2015016441 A1 WO 2015016441A1 KR 2013012035 W KR2013012035 W KR 2013012035W WO 2015016441 A1 WO2015016441 A1 WO 2015016441A1
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cancer
formula
oxoindolin
compound
hydroxyheptanamide
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PCT/KR2013/012035
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English (en)
Korean (ko)
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한상배
김영수
홍진태
남응우옌하이
마이덩두티
푸옹덩판티
킴오안다오티
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한국보건산업진흥원
충북대학교 산학협력단
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Publication of WO2015016441A1 publication Critical patent/WO2015016441A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring

Definitions

  • Novel isatin-based hydroxytoxane and an active ingredient comprising the same as an active ingredient
  • the present invention relates to a novel isatin-based hydroxamic acid and an anticancer composition comprising the same as an active ingredient. [Background technology]
  • Histone acetylases HATs
  • histone deacetylases HDACs
  • HDACs histone deacetylases
  • Class II HDACs known as sirtuin, include Sirtl-7, a NAD + -dependent enzyme.
  • Class IV contains only one enzyme HDAC11, which characterizes both class I and class II HDACs [2].
  • HDACs In some cancer cell lines and in vivo preclinical models, it is known that inhibition of HDACs induces cell differentiation, aptosis and cell cycle arrest. Therefore, HMC inhibitors are currently attracting attention as anticancer agents [3-6].
  • HDAC inhibitors such as trichostatin A, SAHA (Vorinostat), MS-27-275 (Entinostat), LBH-589 (Panobinostat), PXD-101, And oxamf latin et al. [7-12] (see FIG. 1).
  • SAHA was licensed in 2006 as a treatment for several types of lymphomas. 5
  • HDAC histone deacetylase
  • an object of the present invention is to provide a novel isatin-based hydroxamic acid compound.
  • Another object of the present invention to provide an anticancer pharmaceutical composition comprising the novel isatin-based hydroxamic acid compound as an active ingredient.
  • Still another object of the present invention is to provide a method for treating cancer, comprising administering the novel isatin-based hydroxamic acid compound to a patient in need thereof.
  • Still another object of the present invention is to provide a use of the isatin-based hydroxytoxane compound for the manufacture of a medicament for the treatment of cancer.
  • Still another object of the present invention is to provide a method for preparing the novel isatin-based hydroxamic acid compound.
  • the present invention provides a isatin-based hydroxamic acid compound represented by the following Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof.
  • R is hydrogen, halogen, C ⁇ C 5 alkyl, or nitro.
  • R is hydrogen, halogen, d-Cs alkyl, or nitro. According to a preferred embodiment of the present invention, the formula 1 or formula
  • the substituent R in 2 is at the 5 or 7 carbon position of the isatin ring.
  • halogen as said R substituent is fluorine (F), chlorine (C1), or bromine (Br).
  • pharmaceutically acceptable salt in the present invention is meant to include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. If the compounds of the present invention have basic properties, the base forms can be converted to pharmaceutically acceptable acid addition salts by treating with a suitable acid.
  • Suitable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; Or acetic acid, trifluoroacetic acid, propanoic acid, hydroxyacetic acid, lactic acid, fibric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methane sulfonic acid, ethanesulfonic acid, banzen Organic acids such as sulfonic acid, P-toluenesulfonic acid, cyclic acid, salicylic acid, P-aminosalicylic acid and pamoic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; Or acetic acid, trifluoroacetic acid, propanoic acid, hydroxyacetic acid, lactic acid, fibric acid, oxalic acid, mal
  • the acid forms can be converted to their pharmaceutically acceptable base addition salts by treatment with a suitable organic or inorganic base.
  • suitable base salt forms are, for example, ammonium salts, alkali and alkaline earth metal salts (eg lithium, sodium, potassium, magnesium, calcium salts, etc.), salts with organic bases (eg benzatin, N- Methyl-glucamine, hydravamin salts and salts with amino acids (eg arginine, lysine and the like).
  • the isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 is any one of the following compounds: N-hydroxy-7- (3- (hydroxythoxyimino) ⁇ 2-oxoindolin -1 ⁇ Yl) heptanamide; the (5-fluoro-3- (hydroxyimino) ⁇ 2-oxoindolin-1-yl;) -N-hydroxyheptanamide; the (5-chloro-3- (hydroxyi) Mino) -2-oxoindolin-1-yl) -N-hydroxyheptanamide; 7- (5-bromo-3- (hydroxyimino) -2-oxoindolin-1-yl) -N- Hydroxyheptanamide; N-hydroxy-g (3- (hydroxyimino) -5-nitro—2-oxoindolin-1-yl) heptanamide; N-hydroxy-7- (3 ′ Mino) -5-methyl-2-oxoindolin-1-
  • the present invention provides a pharmaceutical composition for anticancer comprising the compound of Formula 1 or Formula 2 described above as an active ingredient.
  • the compound of the present invention has the effect of promoting the acetylation of histones through the inhibitory activity of histone deacetylase. That is, the isatin-based hydroxamic acid compound of the present invention induces intracellular histones into a high acetylation state by inhibiting the activity of histone deacetylase.
  • the compounds of the present invention exhibit anti-cancer efficacy by exhibiting cytotoxic effects on various cancer cell lines, as demonstrated in the specific examples below.
  • Cancer the disease to be treated by the pharmaceutical composition of the present invention, is characterized by aggressive characteristics in which cells divide and grow, ignoring normal growth limits, invasive characteristics infiltrating surrounding tissues, and It is a generic term for diseases caused by cells having metastatic properties that spread to other parts of the body.
  • the cancer to be treated is breast cancer, lung cancer, stomach cancer, liver cancer, hematologic cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye sarcoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer , Colorectal cancer, fallopian tube cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer. More preferably colon cancer, breast cancer, prostate cancer, pancreatic cancer, or lung cancer.
  • the pharmaceutical composition for anticancer of the present invention comprises (i) a pharmaceutically effective amount of the hydroxamic acid compound of Formula 1 or Formula 2 described above; And ( ⁇ ) pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in the formulation, lactose, dextrose sucrose, sorbbi, mantle, starch, acacia rubber, calcium phosphate, alginate, gelatin, 'siliceous kalseum microcrystalline selrol Ross, polyvinyl an pyrrolidone, selreul Ross, water syrup, methyl selreul Ross, methylhydroxy benzoate, propylhydroxy-ethoxy-benzoate, talc, magnesium stearate, and mineral oils such as Including but not limited to.
  • the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
  • a lubricant e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • Appropriate dosages of the pharmaceutical compositions of the present invention may be prescribed in a variety of ways depending on factors such as formulation method, mode of administration, age, body weight, morbidity, food, time of administration, route of administration, rate of excretion, and reaction response. Can be. 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 may be administered orally or parenterally, and when administered parenterally, may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like.
  • the concentration of the active ingredient included in the composition of the present invention is determined in consideration of the purpose of treatment, the duration of the patient's condition, the severity of the disease and the like, and is not limited to a specific range of concentration.
  • the pharmaceutical composition of the present invention can be easily carried out by those skilled in the art to which the present invention pertains.
  • the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or may be in the form of axes, powders, granules, tablets or capsules, and may further include a dispersant or stabilizer.
  • the present invention provides a method for administering a pharmaceutically effective amount of a isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof to a patient in need of treatment of cancer. It provides a method of treating cancer comprising.
  • R is hydrogen, halogen, d-Cs alkyl, or nitro.
  • R is hydrogen, halogen, d-Cs alkyl, or nitro.
  • halogen in Formula 1 or Formula 2 is fluorine (F), chlorine (C1) or bromine (Br).
  • the isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 is any one of the following compounds: N-hydroxy- (3 ′ (hydroxyimino) -2 -Oxoindolin-1-yl) heptanamide; 7- (5-fluoro-3— (hydroxyimino) -2-oxoindolin-1 ⁇ yl) -N-hydroxyheptanamide; (5-chloro ⁇ 3 ′ (hydroxyimino) -2-oxo Indolin-1-yl)- N-hydroxyheptanamide; 7- (5-Bromo-3 ′ (hydroxythoxymino) -2-oxoindolin-1-yl;)-N-hydroxyheptanamide; N-hydroxy-7- (3- (hydroxyoxyimino) -5-nitro-2-oxoindolin-1 ylyl) heptanamide, N-hydroxy-7- (3- (hydroxyimino) -5-methyl-2-oxoindolin
  • the cancer is breast cancer, lung cancer, stomach cancer, liver cancer, hematologic cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, Colorectal cancer, fallopian tube cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer.
  • the compound has an activity of promoting acetylation of histones through the inhibition of histone deacetylase.
  • the present invention provides the use of an isatin-based hydroxamic acid compound represented by Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer. -[Formula 1]
  • R is hydrogen, halogen, dC 5 alkyl, or nitro o
  • R is hydrogen, halogen, dC 5 alkyl, or nitro. According to a preferred embodiment of the present invention, the formula 1 above . Or halogen in Formula 2 is fluorine (F), chlorine (C1) or bromine (Br).
  • the isatin-based hydroxytoxane compound represented by Formula 1 or Formula 2 is any one of the following compounds: N-hydroxy- (3- (hydroxyimino) —2- Oxoindolin-1-yl) heptanamide; 7- (5-fluoro-3- (hydroxyimino) -2-oxoindolin-1 boilyl) -N-hydroxyheptanamide; 7- (5-chloro-3- (hydroxyimino) ⁇ 2-oxoindolin-1-yl) -N-hydroxyheptanamide; 7- (5-bromo-3- (hydroxyimino) -2 -oxo the turned-yl;) -N- hydroxy-heptanoic acid amide; N- hydroxy-7- (3- (hydroxyimino) -5-nitro-2-oxo -1 is turned euil) heptane amide; N-hydroxy-he (3- (hydroxyimino) -5-methyl-2-oxoind
  • the cancer is breast cancer, lung cancer, stomach cancer, liver cancer, hematological cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye sarcoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colon cancer , Fallopian tube cancer, endometrial cancer, Cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer.
  • the compound has an activity of promoting acetylation of histones through the inhibition of histone deacetylase.
  • the present invention provides a method for preparing the isatin-based hydroxamic acid compound of Formula 1, comprising the following steps:
  • the invention comprises the following steps It provides a method for preparing the isatin-based hydroxamic acid compound of Formula 2:
  • the present invention relates to a 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 of histone deacetylase (HDAC) and exhibits cytotoxicity in various cancer cells, thereby exhibiting anticancer efficacy, and thus can be developed as an active ingredient of a powerful anticancer agent.
  • HDAC histone deacetylase
  • FIG 1 shows the chemical structures of histone deacetylase (HDAC) inhibitors known to date.
  • HDAC histone deacetylase
  • Figure 2 shows the results confirming the effect of the synthetic compounds of the present invention on histone acetylation in SW620 cells.
  • the cells were treated for 24 hours at a concentration of compound ⁇ ⁇ .
  • the levels of acetylated histones - ⁇ 3 and - ⁇ 4 in total cell lysates were determined by Western blot analysis.
  • SAHA is represented by a stick model by marking carbon, nitrogen and oxygen atoms in yellow, blue and red, respectively.
  • Compounds 3a and 6a represent carbon atoms in cyan and magenta, and nitrogen and oxygen atoms in blue and red, respectively, in a stick model.
  • Important parts of the enzyme interactions are represented by stick models representing carbon, nitrogen and oxygen in green, blue and red, respectively.
  • Zn 2+ ions are shown as dark gray spheres.
  • N- (4-aminophenyl-3-yl) benzamide is a carbon, nitrogen and oxygen atom yellow, Indicated by the stick model by marking in blue and red, respectively.
  • Compounds 3a and 6a represent carbon atoms in grey-blue and white, and nitrogen and oxygen atoms in blue and red, respectively, in a stick model.
  • Important parts of the enzyme interactions are represented by stick models representing carbon, nitrogen and oxygen in green, blue and red, respectively.
  • Zn 2+ ions are represented by gray spheres.
  • Electron ionization (EI), electrospray ionizat ion (ESI) and high resolution mass spectra were measured using PE Biosystems API 2000 and Mar iner ⁇ E mass spectrometers, respectively.
  • Reagents and solvents are available from Aldrich or Fluka Chemical Corp. (Mi lwaukee, WI, USA) or purchased from Merk. The solvent was used by distillation and drying.
  • N-hydroxy'7- (5 / 7-substituted-3-hydroxyimino-2-oxoindolein '1 ⁇ yl) heptanamide (3a-g) was synthesized according to the following formula (1).
  • Banungsik 1 shows the synthesis process of isatin-3-oxime hydroxamic acid of the present invention.
  • the reagents and conditions of the reaction in the synthesis are as follows: a) ethyl gbromoheptanoate, K 2 CO 3 , KI, DMF; b) hydroxylamine hydrochloride, NaOH, MeOH, THF.
  • Banungsik 2 is a synthetic process of the 3 ' -methoxime isatin hydroxamic acid Shows.
  • the reagents and conditions in the synthesis are as follows: (a) methoxylamine hydrochloride, pyridine, ethanol, 8 (rc, 3 hours; (b) ethyl 7-bromoheptanoate, C0 3 , I, DMF, rt, 24 h; (c) hydroxylamine hydrochloride, NaOH, MeOH, THF, 0 ° C. 30 min.Compounds of compound 6a-6g start each 5- / substituted isatin-3-metaspecific.
  • 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 ° C. NaOH (10 mol equiv) solution was slowly dropped into the reaction mixture which was kept constant at _5 ° C. After 30 minutes, the reaction contents were poured into cooling water and the crude product was precipitated by adjusting the pH to 7 using HC1 15% solution. The crude product was recrystallized from ethane to give 3a-3g of compound in medium to high yield (5% to 90%).
  • Compound 6a-6g was synthesized through the procedure of Banung Formula 2. Isatin-3'-meroxime hydroxamic acid (Compound 6a-6g) was synthesized by converting isatin to 3-meroxime derivative 4 using mexylamine hydrochloride under reflux under conditions (Ref. 2) Reference). The structures of the obtained compounds and intermediates were clearly identified directly through spectral studies including IR, MS, 1H NMR, 13C NMR, and elemental analysis.
  • HDAC Histone Deacetylase
  • the inhibitory activity of histone- ⁇ 3 and histone- ⁇ 4 deacetylation at ⁇ concentration was evaluated by Western blot analysis for the synthesized hydroxamic acid compound (Compound 3a 3g and Compound 6a-6g).
  • Western blot was performed by the following method. First, the cells were lysed in RIPA complete solution (50 mM Tris HC1 [pH 8.0], 5 mM EDTA, 150 mM NaCl, 1% NP-40, 0.1% SDS, and 1 mM phenylraethylsul fonyl f luoride). Protein extract was obtained.
  • Protein concentration in lysates was measured using the Bio-Rad Protein Assay Kit (Bio-Rad Laboratories Inc., Hercules, CA, USA) according to the manufacturer's instructions. Samples were separated on SDS-PAGE and the nitrocells were transferred to the rose membrane. Membranes were incubated with blocking complete fluid (TBS with 0.2% Tween-20 and 3% skim milk) and then searched using primary antibodies against acetyl histone ⁇ H3, -H4, and GAPDH. After washing, the membranes were searched using a red pepper peroxidase conjugated secondary antibody. Detection was done using an enhanced chemi luminescent protein (ECL) detection system (Amersham Biosciences, Litt le Chal font, UK). (2) Activity measurement result of compound
  • compounds 3a-3d and 3f —3g markedly increased the acetylation of histone- ⁇ 3 and histone- ⁇ 4 through inhibition of HDAC enzymes at ⁇ ⁇ concentration.
  • SAHA a well-known HDAC inhibitor, increased histone acetylation in a similar manner.
  • SRB Sulprohodamine B cell proliferation assays were used to assess the antiproliferative activity of the synthesized compounds.
  • these compounds were screened to inhibit the growth of these cancer cells against SW620 (human colorectal cancer) cell line at a concentration of 30 ⁇ .
  • SW620 human colorectal cancer
  • both Compounds 3a-3f and 6a-6f completely inhibit the growth of SW620 cells at a concentration of 30 ⁇ . Therefore, all of these compounds were converted into SW620 and four additional human cancer cell lines, MCF-7 (breast cancer), PC-3 (prostate cancer) at five different concentrations (30, 10, 3, 1, 0.3 ⁇ ).
  • cytotoxic activity against cancer cells was generally correlated with HDAC inhibitory activity. As shown in FIG. 2, Compounds 6d-6f that did not inhibit HDAC enzyme activity showed the lowest cytotoxic activity against cancer cells. On the other hand, compounds 6a-6c, and 6g, which showed a strong inhibitory activity of HDAC enzymes, as confirmed by the significant increase in acetylation levels of histones—H3 and -H4, all of the five cancer cell lines tested. It also showed strong cytotoxicity against.
  • Compound 6e alone showed an indeterminate biological activity profile, which compound Although it did not inhibit HDAC activity at the analyzed concentration (1 ⁇ M), it showed strong cytotoxicity against four cancer cell lines (SW620, MCF-7, PC-3, AsPC-l) that measured activity. It showed weak anticancer activity only against NCI-H460 cell line. Except for compound 3e and compound 6d-6f, all other compounds showed stronger activity than positive control compound SAHA in terms of cytotoxic activity against cancer cell lines. In particular, compound 3d showed 45-fold stronger cytotoxicity than SAHA against the ' AsPC-l cell line (pancreatic cancer cell line). Compound 3b also showed about 30-fold stronger cytotoxicity against SW620 cell line (colon cancer cell line).
  • 1 represents the concentration of a compound that reduces cell growth by 50% and the number represents the average result of three replicates with a deviation of less than 10%.
  • 2 is cell line: SW620, colon cancer; MCF-7, breast cancer; PC3, prostate cancer; AsPC-l, pancreatic cancer; NCI-H460, lung cancer; 3 SAHA (suberoyl ni 1 ide hydroxamic acid), positive control.
  • HDAC2 complex with N- (2—aminophenyl) benzamide was selected (27, PDB ID: 3MAX). Because histone-H3 and histone-H4 deacetylation are regulated by HDAC1 and HDAC2, docking experiments of Compound 3a and Compound 6a against HDAC2 were performed. As a result of the docking experiment, it was confirmed that both compounds 3a and 6a are well located at the active site of HDAC2, and that the hydroxamic acid part is well located at the zinc-binding site (FIG. 4).

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Abstract

La présente invention concerne un nouvel acide hydroxamique à base d'isatine et une composition anticancéreuse le contenant en tant que principe actif. Un composé d'acide hydroxamique selon la présente invention présente des effets anticancéreux car il a une activité d'inhibition de l'histone désacétylase (HDAC) et une cytotoxicité is-à-vis de différentes cellules cancéreuses, et peut donc être développé en un principe actif puissant pour un agent anticancéreux.
PCT/KR2013/012035 2013-07-30 2013-12-23 Nouvel acide hydroxamique à base d'isatine, et composition anticancéreuse le contenant en tant que principe actif WO2015016441A1 (fr)

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