CN102531964B - Dicarboxylic acid derivatives with anti-tumor effect and preparation method thereof - Google Patents
Dicarboxylic acid derivatives with anti-tumor effect and preparation method thereof Download PDFInfo
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Abstract
The invention relates to dicarboxylic acid derivatives (compounds shown in a formula I) with an anti-tumor effect for a hydroxamic acid histone deacetylase (HDAC) inhibitor, and a preparation method thereof. Hydroxamic acid RCONHOH (II) and dicarboxylic acid monoester HOCOYCOOR1(III) are reacted in an organic solvent or ionic liquid under the action of carbonyldimidazole (CDI) to form the target products (the compounds shown in the formula I). Compared with free hydroxamic acid II, the prodrugs I have higher cell permeability and higher effect of inhibiting tumor cells. The prodrugs can be used for treating tumor patients with tumor cell proliferation.
Description
Technical field
The present invention relates to dicarboxylic acid derivatives and preparation method that a class has antitumor action; specifically, relate to di-carboxylic acid ester derivative and the preparation method of hydroxamic acid histone deacetylases (HDAC) inhibitor with antitumor action.
Background technology
Malignant tumour, claims again cancer, is the mankind's the main lethal cause of disease.It is not only medical problem, more becomes a social problem.Surgical operation, chemotherapy, radiotherapy or three's combination is the current conventional treatment means of cancer therapy clinically.Wherein chemotherapeutic agent, still mainly adopts cell toxicity medicament.This type of drug selectivity is lower, toxicity is larger, tumour cell and normal body tissue is caused and is killed and wounded simultaneously.Therefore find efficient, low toxicity, have the medicine of specific selectivity to become the important directions of current antitumor drug research and development for tumour cell.
NSC 630176 (histone deacetyltransferaseinhibitors; HDACis) the effective activity of inhibition of histone deacetylase (HDAC); promote histone and nonhistones acetylation modification, the biological effect main manifestations of its induction is cell death inducing, cell-cycle arrest, promotion cytodifferentiation and suppresses vasculogenesis.Therefore, suppressing HDACs activity is considered to effectively to suppress tumor growth; Experiment in vivo and vitro demonstration, HDACi can reverse the phenotypic alternation of the tumour cell of nearly all type, makes tumour cell generation cessation of growth cessation and apoptosis; There is good synergistic effect with many antitumor drugs, and can reverse the resistance of some tumour cell.HDACs, as most promising cancer therapy target spot, is extensively approved.
According to its chemical structure, HDACi can be divided into following a few class: hydroximic acid, as Vorinostat (Vorinostat, SAHA, 1); Benzamides, as Tacedinaline, Entinostat; Containing the cyclic tetrapeptide class of Aoe (2-amino-8-oxygen-9,10-epoxy-Kui acyl group) structure, as trapoxin A, trapoxin B; Do not contain the cyclic peptide of Aoe structure, as FK-228; Short chain and aromatic series lipid acid, as Sodium propanecarboxylate, Sodium Valproate and phenylbutyrate sodium.
Vorinostat (Vorinostat, SAHA, 1) and romidepsin (Romidepsin, FK-228,13) successively obtain U.S. FDA approval respectively with trade(brand)name Zolinza and IStodax listing in October, 2006 and in November, 2009, be used for the treatment of cutaneous T cell lymphoma (CTCL).Zolinza clinical development is also carried out for the treatment research of leukemia, mammary cancer, colorectal cancer and diffuse large cell lymphoma (one of non-Hodgkin lymphoma (NHL)); After the report Zolinza combined chemotherapy medicines such as Luong can improve treatment of thyroid carcinoma efficient, Arnold etc. quote Zolinza the in vitro tests of 3 kinds of pancreatic cancer cells are shown, Vorinostat makes it in tenuigenin, express increase by raising P21, pancreatic cancer cell is stoped to the phase in G1, strengthen the antitumous effect of gemcitabine, there are the potentiality for the treatment of carcinoma of the pancreas.
IStodax is used for the treatment of the cutaneous T cell lymphoma patient who previously at least accepted a kind of systematic treatment.It is a kind of novel HDACi, has the advantages such as efficient, low toxicity, effect be special, just can be by apoptosis-induced and significantly kill and wound LNCaP cell in extremely low concentration level.It obtains going back primary structure RedFK-228 by gsh Reduction of Disulfide after entering cell, because the RedFK-228 containing sulfydryl is easily captured in blood, make to be combined with Zn2+ by a water molecules with the upper sulfydryl of Hm7 of longer side chain, its restraining effect is stronger.
The HDACis that is carrying out at present clinical study comprises: the Panobinostat (2 of Novartis company, LBH589, the III phase is clinical), the Belinostat (3 of Topotarget, PXD101, the III phase is clinical), the ITF-2357 (4 of Italfarmaco, the II phase is clinical), the SB-939 (5 of S*BIO, the I phase is clinical), the PCI-24781 (6 of Pharmacyclics, the I phase is clinical), the JNJ-16241199 (7 of J & J, the I phase is clinical), the Entinostat (8 of Syndax, SNDX-275 or MS-275, the II phase is clinical), the Mocetinostat (9 of Methylgene, MGCD-0103, the II phase is clinical), the tacedinaline (10 of Pfizer, Tacedinaline, CI-994, the II phase is clinical), the valproic acid (14 of Topotarget, the III phase is clinical) and CUDC-101 (11, the I phase is clinical) and CHR-3996 (12, the I phase is clinical).Wherein 1-7 and 11 and 12 is hydroximic acid, and 8-10 is benzamides, the 13rd, and cyclic peptide, 14 is low chain fatty acids.
Summary of the invention
The object of the invention is to overcome the deficiency of NSC 630176 (HDACis), the di-carboxylic acid ester derivative of the hydroxamic acid histone deacetylases inhibitor with antitumor action is provided.Compared with the former medicine of hydroxamic acid histone deacetylases inhibitor, this analog derivative cell permeability obviously improves, can be used for suppressing HDAC, for the differentiation of selective induction knurl sexual cell end, cause Growth of Cells stagnate and, apoptosis, thereby reach the object that suppresses this type of cell proliferation, to acute acute myeloid leukemia (AML); For example chronic lymphocytic type leukemia (CLL) of chronic leukemia and chronic granulocytic leukemia (CML), hairy cell, T-cell lymphoma,cutaneous (CTCL), non-skin Peripheral T-cell lymphoma, lymphoma for example adult T-cell leukemia/lymphoma (ATLL), Hodgkin, non Hodgkin lymphoma, large celllymphoma, the dispersivity large B cell lymphoid tumor (DLBCL) relevant to human T-cell lymphotrophic virus (HTLV); Burkitt lymphoma; Basic central nervous system (CNS) lymphoma; Multiple myeloma; Early stage solid tumor for example cerebral tumor, neuroblastoma, retinoblastoma, Wilm ' s tumour, soft tissue sarcoma, oral carcinoma, laryngocarcinoma, esophagus cancer, prostate cancer, bladder cancer, kidney, uterus carcinoma, ovarian cancer, carcinoma of testis, the rectum cancer, colorectal carcinoma, lung cancer, mammary cancer, carcinoma of the pancreas, melanoma and other skin carcinoma, cancer of the stomach, cerebral tumor, liver cancer and thyroid carcinoma have therapeutic action.
The di-carboxylic acid ester derivative of the present invention's hydroxamic acid histone deacetylases inhibitor to be prepared, its structure is suc as formula shown in I:
In formula I, RCONHOH is hydroxamic acid 1-7,11 and 12;
R
1for: hydrogen H, methyl Me, ethyl Et, tertiary butyl t-Bu, phenyl Ph, benzyl Bn, sodium ion, potassium ion, calcium ion, magnesium ion, zine ion, iron ion, aluminum ion etc.;
Y is: (CH
2)
n(n equals 2,3,4,5,6).
The method of compound shown in preparation formula provided by the present invention, its key step is: by hydroxamic acid RCONHOH (its structure is suc as formula shown in II) and di-carboxylic acid monoesters HOCOYCOOR
1(its structure is as shown in formula III) under carbonyl dimidazoles (CDI) effect, in 0-200 ℃ of reaction, makes target compound (compound shown in formula I) in solvent (organic solvent or ionic liquid).
RCONHOH HOCOYCOOR
1
II III
In formula III, the definition of Y is with described identical above.
Embodiment
In preferred technical scheme of the present invention, the di-carboxylic acid ester derivative (I) of hydroxamic acid histone deacetylases inhibitor represents following structure:
Y is: (CH
2)
n(n equals 2,3,4,5,6) or ethylene linkage (CHCH)
n(n=1,2,3) or C3-C8 fat carbocyclic ring, aliphatic heterocycle or aromatic nucleus and aromatic heterocycle Ar or Ar (CHCH) n
1(n
1be 1,2,3); Or (CHCH) n
1ar (CHCH) n
1(n
1be 1,2,3);
Wherein Ar is that Ar is phenyl, naphthyl, 5～6 yuan of aromatic heterocyclics, 5～6 yuan of aromatic heterocyclics of benzo, 6 yuan of fragrant heterocycles 5～6 yuan of aromatic heterocyclics, 6 yuan of fragrant heterocycles of 5～6 yuan of aromatic heterocyclics of the phenyl of replacement, the naphthyl of replacement, replacement, 5～6 yuan of aromatic heterocyclics of benzo of replacement, replacement 5～6 yuan of aromatic heterocyclics;
R
1for: hydrogen H, methyl Me, ethyl Et, tertiary butyl t-Bu, phenyl Ph, benzyl Bn, sodium ion, potassium ion, calcium ion, magnesium ion, zine ion, iron ion, aluminum ion etc.;
R is: above-mentioned hydroxamic acid 1-7,11 and 12 various alkyl.
The method of compound shown in preparation formula provided by the present invention, its key step is: by hydroxamic acid RCONHOH (its structure is suc as formula shown in II) and di-carboxylic acid monoesters HOCOYCOOR
1(its structure is as shown in formula III) under CDI effect, in 0-200 ℃ of reaction, makes target compound (compound shown in formula I) in solvent (organic solvent or ionic liquid).
RCONHOH HOCOYCOOR
1
II III
In formula III, the definition of Y is with described identical above.
In a further preferred technical solution of the present invention, the mol ratio of compound and CDI shown in compound shown in formula II and formula III is 1: 0.5～2.5: 0.5～2.5, and preferred technical scheme is: the mol ratio of compound shown in compound shown in formula II and formula III is 1: 1.1～1.5: 1.1～1.5.
In a further preferred technical solution of the present invention, said reaction medium is organic solvent or ionic liquid, as (but being not limited to): methylene dichloride, trichloromethane, tetracol phenixin, toluene, dimethylbenzene, 1,4-dioxane, N, dinethylformamide (DMF), N,N-dimethylacetamide, methyl-sulphoxide (DMSO), tetramethylene sulfone, 1-butyl-3-methylimidazolium bromide salt ([bmIm] Br), 1-butyl-3-methyl imidazolium tetrafluoroborate ([bmIm] BF
4) or 1-butyl-3-Methylimidazole hexafluorophosphate ([bmIm] PF
6) etc.;
The organic solvent of recommendation of the present invention is: methylene dichloride, trichloromethane and toluene;
The suggestion consumption of described organic solvent is 5mL～20mL/g di-carboxylic acid monoesters HOCOYCOOR
1(its structure is as shown in formula III), that is: every gram of di-carboxylic acid monoesters HOCOYCOOR
1(III) need with the organic solvent described in 5mL～20mL.
In preparation method of the present invention, can adopt thin-layer chromatography (TLC) to judge the terminal of preparation feedback; And the crude product of compound shown in prepared formula I can adopt the purification process of the existing routine such as recrystallization or column chromatography to carry out purifying.
In another specific embodiments of the present invention, the horizontal antitumor activity step of cell in vitro is: cultivator source neuroglial tumor cell U251, Experimental agents is added in cell and acted on, by different drug treating times and activity are set, the pharmaceutically-active time-effect relationship of research experiment and amount-result relation; Adopt mtt assay to calculate growth-inhibiting IC50 value, evaluation experimental medicine is to growth of tumour cell restraining effect, adopt clone forming method, calculate cloning efficiency EC50 value, evaluate the impact that medicine forms tumor cell clone, by safety coefficient TI=EC50/IC50 computationally secure coefficient value, evaluate out active higher compound.
In the di-carboxylic acid ester derivative (I) of hydroxamic acid histone deacetylases inhibitor, YXH-004, YXH-007, YXH-008 and YXH-022 are better than Vorinostat to the inhibition activity of human colon cancer cell strain HCT116.
In another specific embodiments of the present invention, the di-carboxylic acid ester derivative (I) of hydroxamic acid histone deacetylases inhibitor is to acute acute myeloid leukemia (AML); For example chronic lymphocytic type leukemia (CLL) of chronic leukemia and chronic granulocytic leukemia (CML), hairy cell, T-cell lymphoma,cutaneous (CTCL), non-skin Peripheral T-cell lymphoma, lymphoma for example adult T-cell leukemia/lymphoma (ATLL), Hodgkin, non Hodgkin lymphoma, large celllymphoma, the dispersivity large B cell lymphoid tumor (DLBCL) relevant to human T-cell lymphotrophic virus (HTLV); Burkitt lymphoma; Basic central nervous system (CNS) lymphoma; Multiple myeloma; Early stage solid tumor for example cerebral tumor, neuroblastoma, retinoblastoma, Wilm ' s tumour, soft tissue sarcoma, oral carcinoma, laryngocarcinoma, esophagus cancer, prostate cancer, bladder cancer, kidney, uterus carcinoma, ovarian cancer, carcinoma of testis, the rectum cancer, colorectal carcinoma, lung cancer, mammary cancer, carcinoma of the pancreas, melanoma and other skin carcinoma, cancer of the stomach, cerebral tumor, liver cancer and thyroid carcinoma have therapeutic action.
Below by embodiment, the present invention is further set forth, object is only better to understand content of the present invention.Therefore, listed embodiment does not limit the scope of the invention:
4.39g (1.2eq.) the mono succinate tert-butyl ester is added to reaction flask, add 40ml methylene dichloride stirring and dissolving; After 10min, add CDI 3.24g (1.2eq.) in batches, produce a large amount of bubbles, solution by colourless become light yellow; After 10min, TCL detects, and all generates active intermediate, adds 4.39g (1eq.) Vorinostat (SAHA) in batches, TCL detection reaction process, and approximately 2h reacts completely; In reaction flask, add 20ml saturated sodium bicarbonate, extraction, washes twice with 10ml methylene dichloride, wash once with saturated 10mlNaCl, and anhydrous magnesium sulfate drying, suction filtration, filtrate is spin-dried for, and obtains white solid powder, yield 75%; Mp:110.8-112.7 ℃.
1h NMR (400MHz, CDCl
3, see accompanying drawing 1) and δ 8.09 (s, 1H), 7.53 (t, J=8.90,8.90Hz, 2H), 7.33-7.27 (m, 2H), 7.08 (t, J=7.20,7.20Hz, 1H), 2.70 (t, J=6.75,6.75Hz, 2H), 2.58 (t, J=6.72,6.72Hz, 2H), 2.34 (t, J=7.36,7.36Hz, 2H), 2.24 (t, J=6.99,6.99Hz, 2H), (1.74-1.63 m, 4H), 1.45 (s, 4H), 1.43 (s, 9H).
13c NMR (101MHz, CDCl
3, see accompanying drawing 2) and δ 172.35,172.22,171.11,170.88,138.18,128.89,124.17,120.07,81.32,37.11,29.95,28.37,28.21,28.04,27.99,26.91,25.26.
Synthetic (YXH-020) of embodiment 2 YXH-020s
Substitute outside the mono succinate tert-butyl ester (1.2eq.) the other the same as in Example 1, yield: 72% divided by the hexanodioic acid list tert-butyl ester (1.2eq.);
1h NMR (400MHz, d
6-DMSO, is shown in accompanying drawing 3), 10.05 (s, 1H), 7.61 (d, J=7.27Hz, 2H), 7.25 (t, J=7.08,7.08Hz, 2H), 6.99 (t, J=6.42,6.42Hz, 1H), 2.39 (t, 2H), 2.29 (t, 2H), 2.18 (t, 2H), 2.07 (t, 2H), 1.59-1.46 (m, 8H), (1.38 s, 1H), 1.28 (s, 1H);
13c NMR (101MHz, d
6-DMSO, is shown in accompanying drawing 4) 172.49,171.76,171.65,170.26,139.92,128.99,123.25,119.51,79.92,36.80,34.82,32.49,31.32,28.85,28.74,28.20,25.50,25.34,24.38,24.24.
Embodiment 3 YXH-021s (YXH-021)
Substitute outside the mono succinate tert-butyl ester (1.2eq.) the other the same as in Example 1, yield 76% divided by the suberic acid list tert-butyl ester (1.2eq.);
1h NMR (400MHz, d
6-DMSO, is shown in accompanying drawing 5) 10.08 (s, 1H), 7.61 (d, J=7.69Hz, 2H), 7.27 (t, J=7.92,7.92Hz, 2H), 7.00 (t, J=7.35,7.35Hz, 1H), 2.4-2.25 (m, 4H), 2.16 (dd, J=7.27,2.66Hz, 2H), 2.04 (t, J=7.26,7.26Hz, 2H), (1.60-1.41 m, 8H), 1.39 (s, 1H), 1.32-1.21 (m, 8H);
13cNMR (101MHz, d
6-DMSO, is shown in accompanying drawing 6) 172.49,171.76,171.65,170.26,139.92,128.99,123.25,119.51,79.92,36.80,34.82,32.49,31.32,28.85,28.74,28.20,25.50,25.34,24.38,24.24.
Substitute outside the mono succinate tert-butyl ester (1.2eq.) the other the same as in Example 1, yield 70% divided by suberic acid mono-methyl (1.2eq.); Mp:106.9-108.3 ℃.1H NMR (400MHz, d
6-DMSO, is shown in accompanying drawing 7) ppm 9.84 (s, 1H), 7.58 (d, J=7.61Hz, 2H), 7.27 (t, J=7.35,7.35Hz, 2H), 7.00 (t, J=6.97,6.97Hz, 1H), (3.57 s, 1H), 2.41 (t, J=6.64,6.64Hz, 2H), 2.28 (t, J=6.40,6.40Hz, 4H), 2.10 (t, J=6.75,6.75Hz, 2H), 1.46-1.61 (m, 8H), 1.29 (s, 1H);
13c NMR (101MHz, d
6-DMSO, is shown in accompanying drawing 8) 173.78,171.67,170.24,139.81,129.06,123.34,119.48,51.60,36.83,33.61,32.34,31.32,28.84,28.70,28.44,28.31,25.45,25.13,24.66,24.62.
Embodiment 5 YXH-007s (YXH-007)
Substitute outside the mono succinate tert-butyl ester (1.2eq.) the other the same as in Example 1, yield 67% divided by monomethyl succinate (1.2eq.).1H NMR(400MHz，DMSO)δppm 7.59(d，J＝7.94Hz，2H)，7.27(t，J＝7.75，7.75Hz，2H)，7.00(t，J＝7.31，7.31Hz，1H)，3.60(s，1H)，2.70(t，J＝6.28，6.28Hz，2H)，2.61(t，J＝6.25，6.25Hz，2H)，2.29(t，J＝7.39，7.39Hz，2H)，2.10(t，J＝7.22，7.22Hz，2H)，1.61-1.47(m，4H)，1.29(s，4H)；13CNMR(133MHz，DMSO)δppm172.46，171.68，170.99，170.21，139.81，129.06，123.35，119.50，52.01，36.83，32.28，28.83，28.68，28.65，26.78，25.44，25.12；HRMS Calcd.for C
19H
27N
2O
6Na(M+1)，379.1869；Found，379.1870。
Embodiment 6 YXH-008s (YXH-008)
Substitute outside the mono succinate tert-butyl ester (1.2eq.) the other the same as in Example 1, yield 71% divided by mono succinate benzyl ester (1.2eq.).1H NMR(400MHz，DMSO)δppm 11.68(s，1H)，9.85(s，1H)，7.60(d，J＝7.48Hz，2H)，7.25-7.36(m，7H)，7.01(t，J＝6.78，6.78Hz，1H)，5.11(s，1H)，2.72(s，2H)，2.70(s，2H)，2.29(t，J＝6.63，6.63Hz，2H)，2.15(t J＝6.63，6.63Hz，2H)，1.56(m，4H)，1.30(s，4H)；13C NMR(133MHz，DMSO)δppm 171.95，171.68，171.01，170.24，139.83，136.47，129.07，128.87，128.45，128.32，66.18，36.85，32.29，28.84，28.70，26.78，25.46，25.14；HRMS Calcd.for C
25H
30N
2O
6Na(M+Na)，477.2002；Found，477.2002
Embodiment 7 YXH-022s (YXH-022)
Single-ethyl succinate is added in there-necked flask, add 20ml methylene dichloride, stir.After 10min, add CDI in batches, produce a large amount of bubbles in adition process, accumulative total adds 2.32g CDI, adds 2.845g SAHA after 30min in batches.Aftertreatment: reaction solution is spin-dried for, adds dilute sodium bicarbonate solution to stir 10min, suction filtration, dries to obtain white solid powder, yield 75%.。
1h NMR (400MHz, CDCl3, see accompanying drawing 9) ppm 10.37-9.94 (m, 1H), 8.30 (s, 1H), 7.53 (d, J=7.73Hz, 2H), 7.27 (t, J=7.53, 7.53Hz, 2H), 7.06 (t, J=7.09, 7.09Hz, 1H), 4.11 (q, J=7.09, 7.09, 7.09Hz, 2H), 2.71 (t, J=6.45, 6.45Hz, 2H), 2.62 (t, J=6.40, 6.40Hz, 2H), 2.32 (t, J=7.16, 7.16Hz, 2H), 2.22 (t, J=6.74, 6.74Hz, 2H), 1.69-1.69 (m, 4H), 1.34 (s, 4H), 1.23 (t, J=7.11, 7.11Hz, 3H),
13c NMR (101MHz, CDCl
3, see accompanying drawing 10) and ppm:172.36,171.86,171.70,170.66,138.20,128.87,124.16,120.06,61.02,37.14,32.51,28.79,28.49,28.34,26.73,25.32,24.88,24.43,14.10, Calcd.HRMS for C
20h
28n
2o
6na (M+Na) (seeing accompanying drawing 11), 415.1845, Found, 415.1847.
The toxic action of Experimental agents to human colon cancer cell strain HCT116:
Experimental agents is synthetic N-phenyl-N '-end carboxylic acid-substituted acyloxy-suberamide compounds and pharmaceutical salts thereof, and purity is greater than 99%.Be diluted to desired concn with RPMI-1640.Adopt tetrazolium bromide (MTT) toxic action of colorimetric method for determining Experimental agents to the strain of HCT116 human colon cancer cell fast.Logarithmic phase cell (106cell.ml-1) is inoculated in to 96 well culture plates, every hole 0.2ml, add respectively certain density Experimental agents processing, parallel 4 holes of every concentration, control group adds the nutrient solution of equivalent volumes, put 37 ℃, the incubator of 5%CO2 and saturated humidity is cultivated 48h, experiment stops first 4 hours every holes and adds 5mg.ml-1MTT 10 μ l, cultivation finishes rear every hole and adds 0.04N dimethyl sulfoxide (DMSO) (DMSO), every hole 150 μ l, vibration 10min, treat that MTT reduzate dissolves completely, by BioRad 550 type microplate reader, take 550nm as experiment wavelength, 655nm is for to measure its optical density with reference to wavelength, calculate inhibiting rate and the inhibiting rate of medicine to cell of tumour cell, and with the different concns of medicine and the mapping of the inhibiting rate of cell, determine the half-inhibition concentration (IC50) of cell.Experimental result is as shown in table 1 below, and Experimental agents YXH1-6 compound is shown in accompanying drawing 12 to the growth-inhibiting effect of HCT116, and Experimental agents YXH7-11 compound and positive drug SAHA are shown in accompanying drawing 13 to the growth-inhibiting effect of HCT116.
Table one: the cytotoxicity of Experimental agents to human colon cancer cell strain HCT116
The growth-inhibiting effect of embodiment 9 Experimental agents to people source neuroglial tumor cell U251
Experimental agents is synthetic hydroxamic acid di-carboxylic acid monoester derivates (I), and purity is greater than 99%.Be diluted to desired concn with RPMI-1640.Body adopts mtt assay to calculate growth-inhibiting IC50 value, and evaluation experimental medicine is to cytotoxicity effect, and method is as described in embodiment mono-.
Adopt clone forming method to calculate half clone and form concentration EC50., method is as follows, and the single-layer culturing cell in the vegetative period of taking the logarithm is with 0.25% tryptic digestion and blow and beat into individual cells, for subsequent use in the RPMI of 10% new-born calf serum RPMI-1640 cell suspension.According to the multiplication capacity of cell, its suspension is diluted to 200-300 cell/mL, is inoculated in 24 orifice plates with 1mL/ hole, cell is uniformly dispersed.Put in the incubator of 37 ℃ of 5%CO2 and saturated humidity and leave standstill and cultivate 24h.To after testing drug gradient dilution, add in 24 orifice plates, parallel 3 holes of every concentration, control group adds the nutrient solution of equivalent volumes, put in the incubator of 37 ℃ of 5%CO2 and saturated humidity and cultivate 7 days, often observe, in the time that major part clone contains more than 20 cell, stop cultivating.In the lower observation of microscope (40 times), counting is greater than 20 clone's numbers more than cell.The impact that final evaluation medicine forms tumor cell clone, by safety coefficient TI=EC50/IC50 computationally secure coefficient value TI, evaluates out active higher compound.
The toxic action of embodiment 10 Experimental agents to kinds of tumor cells
Experimental agents is synthetic hydroxamic acid di-carboxylic acid monoester derivates, and purity is greater than 99%.Be diluted to desired concn with RPMI-1640.In this specific embodiments of the present invention, hydroxamic acid di-carboxylic acid monoester derivates (I) is to acute acute myeloid leukemia (AML); For example chronic lymphocytic type leukemia (CLL) of chronic leukemia and chronic granulocytic leukemia (CML), hairy cell, T-cell lymphoma,cutaneous (CTCL), non-skin Peripheral T-cell lymphoma, lymphoma for example adult T-cell leukemia/lymphoma (ATLL), Hodgkin, non Hodgkin lymphoma, large celllymphoma, the dispersivity large B cell lymphoid tumor (DLBCL) relevant to human T-cell lymphotrophic virus (HTLV); Burkitt lymphoma; Basic central nervous system (CNS) lymphoma; Multiple myeloma; Early stage solid tumor for example cerebral tumor, neuroblastoma, retinoblastoma, Wilm ' s tumour, soft tissue sarcoma, oral carcinoma, laryngocarcinoma, esophagus cancer, prostate cancer, bladder cancer, kidney, uterus carcinoma, ovarian cancer, carcinoma of testis, the rectum cancer, colorectal carcinoma, lung cancer, mammary cancer, carcinoma of the pancreas, melanoma and other skin carcinoma, cancer of the stomach, cerebral tumor, liver cancer and thyroid carcinoma have therapeutic action.
Accompanying drawing explanation
Fig. 1 is the hydrogen spectrogram of YXH-019 (YXH-019);
Fig. 2 is the carbon spectrogram of YXH-019 (YXH-019);
Fig. 3 is the hydrogen spectrogram of synthetic (YXH-020) of YXH-020;
Fig. 4 is the carbon spectrogram of synthetic (YXH-020) of YXH-020;
Fig. 5 is the hydrogen spectrogram of YXH-021 (YXH-021);
Fig. 6 is the carbon spectrogram of YXH-021 (YXH-021);
Fig. 7 is the hydrogen spectrogram of YXH-004 (YXH-004);
Fig. 8 is the carbon spectrogram of YXH-004 (YXH-004);
Fig. 9 is the hydrogen spectrogram of YXH-022 (YXH-022);
Figure 10 is the carbon spectrogram of YXH-022 (YXH-022);
Figure 11 is the high resolution mass spectrum figure of YXH-022 (YXH-022);
Figure 12 is the figure of the growth-inhibiting effect of Experimental agents YXH1-6 compound to HCT116;
Figure 13 is Experimental agents YXH7-11 compound and positive drug SAHA press down effect figure to the growth of HCT116.
Claims (4)
1. a class is suc as formula the prodrug of the NSC 630176 of the structure representative of I--the di-carboxylic acid ester derivative of hydroxamic acid, it is characterized in that, and shown in its structural formula as I, its inhibition activity to tumour is better than hydroxamic acid:
Wherein, Y represents following structure: (CH
2)
n, wherein:
N equals at 2 o'clock, R
1for: methyl Me or benzyl Bn; N equals at 6 o'clock, R
1for: methyl Me;
R is:
2. the preparation method of prodrug claimed in claim 1, is characterized in that, it is by hydroxamic acid RCONHOH and di-carboxylic acid monoesters HOCOYCOOR
1in solvent, under carbonyl dimidazoles effect, make target compound in 0-200 ℃ of reaction, hydroxamic acid RCONHOH and di-carboxylic acid monoesters HOCOYCOOR
1and the mol ratio of carbonyl dimidazoles is 1: 1.1～1.5: 1.1～1.5.
3. preparation method claimed in claim 2, it is characterized in that, described solvent is organic solvent or ionic liquid, comprise: methylene dichloride, trichloromethane, tetracol phenixin, toluene, dimethylbenzene, 1,4-dioxane, N, dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide, tetramethylene sulfone, 1-butyl-3-methylimidazolium bromide salt, 1-butyl-3-methyl imidazolium tetrafluoroborate or 1-butyl-3-Methylimidazole hexafluorophosphate.
4. preparation method claimed in claim 3, is characterized in that, the consumption of described organic solvent is 5mL～20mL/g di-carboxylic acid monoesters HOCOYCOOR
1, that is: every gram of di-carboxylic acid monoesters HOCOYCOOR
1need with the organic solvent described in 5mL～20mL.
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| US4801721A (en) * | 1984-08-16 | 1989-01-31 | Ryan James W | Stereospecific synthesis of carboxyalkyl peptides |
| WO2005110399A2 (en) * | 2004-04-29 | 2005-11-24 | The Regents Of The University Of California | Zinc-binding groups for metalloprotein inhibitors |
| WO2006028523A2 (en) * | 2004-04-29 | 2006-03-16 | THE REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN DIEGO USDC Technology Transfer Office | Hydroxypyridinone, hydroxypyridinethione, pyrone, and thiopyrone metalloprotein inhibitors |
| CN101010298A (en) * | 2004-04-05 | 2007-08-01 | 默克Hdac研究有限责任公司 | Histone deacetylase inhibitor prodrugs |
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|---|---|---|---|---|
| US4801721A (en) * | 1984-08-16 | 1989-01-31 | Ryan James W | Stereospecific synthesis of carboxyalkyl peptides |
| CN101010298A (en) * | 2004-04-05 | 2007-08-01 | 默克Hdac研究有限责任公司 | Histone deacetylase inhibitor prodrugs |
| WO2005110399A2 (en) * | 2004-04-29 | 2005-11-24 | The Regents Of The University Of California | Zinc-binding groups for metalloprotein inhibitors |
| WO2006028523A2 (en) * | 2004-04-29 | 2006-03-16 | THE REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN DIEGO USDC Technology Transfer Office | Hydroxypyridinone, hydroxypyridinethione, pyrone, and thiopyrone metalloprotein inhibitors |
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