CN1199946C - Specific indole compound and its preparation and use in treating and preventing cancers - Google Patents
Specific indole compound and its preparation and use in treating and preventing cancers Download PDFInfo
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Abstract
The present invention relates to a series organic heterocyclic compound, a JN-2518 series compound, a preparation method thereof and applications in treating and preventing cancer and other diseases. The series compound is obtained by the organic synthesis reaction and is applied to the medicine field. The series compound can specifically inhibit the cell cycle kinase activity, block cell proliferation and induce apoptosis. Thereby, the growth of various tumor cells of colon cancer, prostatic cancer, breast cancer, neuroblastoma, etc. of the human body can be efficiently inhibited. The series compound has low toxic and side effects and can be used for treating various diseases of human and animals, such as malignant tumors, senile dementia, psoriasis, cardiovascular disease, glomerular nephritis, AIDS, etc.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to a class and draw diindyl heterogeneous ring compound JN-2518 series, and preparation method thereof with the medicine and pharmacology purposes.This series compound can specificity suppress cell-cycle kinases activity, the multiple diseases such as malignant tumour that can be used for treating and preventing humans and animals.
Background technology
Because EPDML progress, the further improvement of early diagnosis and therapy method has obtained significant achievement in treatment for cancer and prevention more than ten years in the past.According to U.S. tumour association statistics, from beginning in 1999, the tumor incidence of the U.S. was slightly downtrending.However, in the U.S., tumour remains one of principal disease that threatens people's life.In China, because some bad living habit of environmental pollution and people, the sickness rate of malignant tumour still continues to rise.Tumour constantly increases people's threat.Though surgical operation and radiocurable continuous maturation, the continuous appearance of new methods of treatment such as gene therapy etc., still none method can replace chemotherapy up to now.On the other hand, because existing cancer therapy drug, though have certain curative effect, they are cell toxicity medicament mostly, have serious toxic side effect.So, the PTS of excavating new and effective low toxicity, not only challenging, and be the task of top priority that can't avoid.
Tumour cell, the infinite multiplication owing to the regulatory function of having lost the cell cycle running.A typical cell cycle can be divided into G1, S, G2 and M phase (see figure 1).The G1 phase is the pre-synthesis phase of also claiming gap phase (GAP) or DNA.For mammalian cell, the G1 phase is very important.This phase provides various albumen for dna replication dna.Wherein restriction point (Restriction point, or R point) is the important step of control cell progress, directly determines the cell whereabouts, i.e. cell: or leave the cell cycle (G that enters stationary phase
o), under the effect of chemotherapeutics, enter stationary phase and the effect of hiding medicine as normal reproducible histoorgan and cancer cells; Or enter apoptosis, when can't repairing, its DNA damaged then under the effect of cancer suppressor gene P53, enters apoptosis as cell; Or differentiation and maturation irreversibly leaves the cell cycle, this be the normal cell tissue growth sophisticated mainly by way of; Or cross restriction point R, and constantly enter S again and again, G2 and M phase and infinite multiplication (such as cancer cells).
In the cell cycle process, the albumen composition that most critical is controlled whole cell engine is the cell-cycle kinases (hereinafter referred cell-cycle kinases or Cdks) that cyclin relies on, cyclin (Cyclins) and corresponding endogenous arrestin (cdkI).Up to now, 15 kinds of cyclins have been found at least, the endogenous arrestin of 9 kinds of Cdks and two families.They are active in different cell cycle phases respectively.
Typical cell-cycle kinases has the enzyme active center district that it is made up of 300 amino acids, and with cyclin and endogenous arrestin bonded site.Cell-cycle kinases must combine with corresponding cyclin, form cyclin/cell-cycle kinases (Cyclin/Cdks) mixture and just have kinase activity, and this mixture is if combine with endogenous arrestin cdkI again, and then kinase activity disappears.The Cyclin/Cdks mixture formed in the special stage of cell cycle, and its activity is that constantly operation of cell cycle institute is requisite.
Studies show that it is unusual that nearly all tumour cell all has various cell-cycle kinases, or the expression of cyclin height, or the activation of cell-cycle kinases height, or endogenous arrestin disappearance.For example, unusual up to 85% mammary cancer patient CyclinD/Cdk4/6.So, suppress cell-cycle kinases, then can stop cell proliferation (but not being to kill cell) effectively.And then, perhaps promote the cytodifferentiation maturation, perhaps promote apoptosis, reach the effect of treatment kinds of tumors.Can think that cell cycle kinase inhibitors is the novel broad-spectrum anti-cancer drug of a class.Simultaneously, because they are to suppress cell proliferation (cytostatic), rather than kill cell (cytotoxic), this class medicine should have lower toxic side effect.Based on this, seek the New Policy that cell cycle kinase inhibitors has become the cancer therapy drug research and development.This class medicine, or directly act on the catalytic active center of cell-cycle kinases, or act on the cell-cycle kinases truck indirectly.The Flavopiridol of national cancer institute (NCI) research and development for example is at present just in clinic trial.Though this compound is because outside chemical stability of self and problem such as selectivity need improve, clinical prospect was still exciting.
Summary of the invention
The objective of the invention is to seek a specific specificity Benzazole compounds.This compound is a cell cycle kinase inhibitors, the special inhibition cell-cycle kinases of energy, blocking-up cell proliferation, bring out apoptosis, thereby can be used for the treatment of the multiple disease of humans and animals such as malignant tumour etc. and the JN-2518 series compound of prevention, and the preparation method of this series compound and medicine and pharmacology purposes;
Another object of the present invention is to seek the preparation method of a specific specificity Benzazole compounds;
The present invention also aims to provide a specific specificity Benzazole compounds in diseases such as treatment and preventing cancer the pharmaceutics formulation that may use.Can be used for malignant tumour and other treatment of diseases and prevention.
Its main technical schemes is that the basic structure formula of this compound is:
Wherein:
1.R
1＝CH
3，(CH
2)
nCH
3，C
2H
4OH，n＝1-5；
2.R
2＝CH
3，(CH
2)
nCH
3，C
2H
4OH，n＝1-5；
3.R
3＝Cl，Br.F.
Another structural formula of this compound is:
Wherein:
1.R
1＝CH
3，(CH
2)
nCH
3，C
2H
4OH，n＝1-5；
2.R
2＝CH
3，(CH
2)
nCH
3，C
2H
4OH，n＝1-5；
3.R
3＝Cl，Br.F.
The 3rd kind of structural formula of this compound is:
Wherein:
1.R
1＝CH
3，(CH
2)
nCH
3，C
2H
4OH，n＝1-5；
2.R
2＝CH
3，(CH
2)
nCH
3，C
2H
4OH，n＝1-5；
3.R
3＝Cl，Br.F.
The exemplary configuration formula of this compound is:
The another kind of exemplary configuration formula of this compound is:
The preparation method of described compound; it is characterized in that with 2-ketone indoles purine (3; Oxindole) and isatin (4; Isatin) be basic raw material; the compound 5 of process nitrogen acetylization reaction and the chlorination intermediate 6 of isatin carry out condensation and obtain compound 7 in toluene; the ethylating product 8 of nitrogen acidic conditions go down protecting group (ethanoyl) compound 9, its chemical equation is:
After obtaining compound 9, obtain product 1 with azanol reaction again, its chemical equation is:
The purposes of one specific specificity Benzazole compounds is characterized in that this compound can special inhibition cell-cycle kinases activity, brings out apoptosis, is used for the treatment of and prevents disease such as malignant tumour.
The tumour of indication comprises various leukemia and various solid tumor.
In use, can be single therapy, can also be combination therapy.Combination therapy can be and other chemotherapy coupling, can also with the herbal medicine coupling, or with operation, radiotherapy, immunotherapy, hormonotherapy, couplings such as gene therapy.Combination therapy can be to treat simultaneously, can also be different precedence treatments.
Described other disease mainly includes, but not limited to senile dementia, psoriasis, cardiovascular disorder, glomerulonephritis and AIDS etc.
The JN-2518 series compound can adopt any medicine-feeding way as medicinal, any administering mode.Promptly can be oral, injection sucks, and Transdermal absorption is implanted, the limit, chamber, mucous membrane, and intravenous drip etc.
The JN-2518 series compound can be made tablet as medicinal, pill, and capsule, paste, creme, patch, pulvis, injection, sprays, implant is fastened agent, multiple formulation such as drops.
The present invention is by MTT and srb assay, and to studies show that of human cancer cell, JN-2518 is to mammary cancer, colorectal carcinoma, and hormone-dependent type and hormone independent form prostate cancer and neuroblastoma all have the good restraining effect.Particularly importantly JN-2518 also has good restraining effect to the hormone independent form prostate cancer of feeling simply helpless clinically.
The present invention is by mtt assay, studies show that of the cancer cells that advanced prostate cancer patient ascites is shifted, and JN-2518 is at the outstanding anticarcinogen taxol of a line, daunorubicin, different vincristins etc. produce under the drug-fast situation, and good curative effect is still arranged.
The present invention by to the comparison of rat w256 mammary cancer tumour inhibiting rate studies show that JN-2518 has significant anti-cancer activity to W256, and this antitumour activity directly is directly proportional with dosage.
The present invention is by to HUVEC with the LNCAP cell-cycle kinases is active discovers that JN-2518 can optionally suppress the cell-cycle kinases activity.
The present invention has confirmed that by the research to PARP albumen depression of order and the formation of dna ladder type band JN-2518 can cancer cell specific induction of apoptosis.
JN-2518 is a brand-new chemical structure compound, owing to be special cell cycle kinase inhibitors, this patent directly is used for the treatment of JN-2518 and prevents animal tumor.Animal described here mainly refers to the people, but is not limited only to the people, as also being applicable to poultry etc.Simultaneously, studies show that recently that many other diseases are also relevant unusually with cell-cycle kinases, so JN-2518 also can be used for treating senile dementia, psoriasis, cardiovascular system diseases and glomerulonephritis etc.Hereinafter for example, only be in order to prove this practical applicability, rather than attempt to limit the range of application of this invention.
Be noted that JN-2518 in tumour or other disease treatment process, can be a single therapy, can also be and 2 kinds, 3 kinds or more multiple medicines thing combination therapy, administration simultaneously, or different precedence administration.Here said combination therapy can be and other Western medicine that herbal medicine merges use, or and hormonotherapy, radiotherapy, immunotherapy, chemotherapy, cold therapy and gene combined treatment.
Medicament production treatment tumour and other disease that this invention provides, these products contain the JN-2518 of effective dose and all suitable additives that other pharmaceutical industry is adopted, and various suitable medicine-feeding way.
Consummate drug manufacture technology comprises that the prodrug that uses nontoxic pharmaceutical industry to accept is raw material, adopts the synthetic JN-2518 of several different methods.Consummate drug manufacture technology also comprises uses solvent that pharmaceutical industry the accepts solvent as JN-2518, water for example, and mineral oil, edible oil, dimethyl sulfoxide (DMSO), etc.
JN-2518 can be made into oral administration, local application, inhalation, formulations such as anum administration.Use material that nontoxic pharmaceutical industry accepts as carrier, additives, excipient.Be pointed out that once more administering mode can be a drug combination.Can obey form of administration comprises: tablet, capsule, tincture, lozenge, oral syrup or other all suitable formulations.
JN-2518 can be made into the formulation that is administered systemically, and comprising: subcutaneous injection, intradermal injection, intramuscular injection, intravenous injection, intraspinal injection, intrathecal injection, or other any drug administration by injection and instillation.In addition, the JN-2518 preparation still contains other pharmaceutically all available non-toxic substances except that the JN-2518 that contains effective dose.Comprise one or more carriers, thinner, additives, and if necessary, other medicinal component.
JN-2518 can be made into any type of oral dosage form, comprising: tablet, and lozenge, the soft or hard capsule can be obeyed aqua, tincture, oral administration mixed suspension, pulvis, emulsifying agent etc.Oral dosage form can contain one or more sweeting agents, correctives, and color agent and sanitas are to guarantee that color is perfect and to be convenient to take.
The excipient that is used for the JN-2518 tablet can be the thinner of falling property, as lime carbonate, and yellow soda ash, calcium lactate, calcium phosphate, sodium phosphate; System granule: W-Gum, alginic acid; Tackiness agent: starch, gelatin or gum arabic; Slipping agent: stearic acid, Magnesium Stearate or talcum powder.Adopt all known technologies, make dressing or the tablet of having no clothes.Coated dosage form comprises enteric coating and slow release formulation.The material that is used for slow release formulation can be glycerine monoester or dialycerides salt.
The JN-2518 capsule can be a hard capsule, can also be soft capsule.The material that is used for hard capsule can be lime carbonate, calcium phosphate or kaolin.Be used for the material such as the water of soft capsule, oils comprises peanut oil, sweet oil or liquid paraffin.
The oral water type of JN-2518 suspension can be formulated with the JN-2518 and the suitable diluent of effective dose.Its dilution suspensoid can be sodium cellulose glycolate or methylcellulose gum, Vltra tears, alginic acid sodium salt, polyvinylpyrrolidone, tragcanth, gum arabic.Dispersion agent or wetting agent comprise: natural phospholipid, as Yelkin TTS, or the condenses of alkene oxide and lipid acid, as 17 alkyl oxidation of ethylene alkanols, or ethene and fatty acid part esterification condensation thing, or hexitol such as the single oleate of polyoxyethylene sorbitol, or ethylene oxide and fatty acid part fat condensation product, and alcohol anhydride, as polyethylene sorbyl alcohol methyl esters hydrochlorate.The oral water type of JN-2518 suspension also may contain one or more sanitass, as ethyl to or o-hydroxy st-yrax salt; Contain one or more sweeting agents, as sucrose or asccharin.
JN-2518 oil type suspension can be suspended in the JN-2518 of effective dose in the vegetables oil, as soybean oil, and peanut oil, sweet oil, sesame oil, theobroma oil.Or Dormant oils, as liquid paraffin.Said preparation also can contain thinner, as beeswax, and wax, or cetyl alcohol, sweeting agent mentioned above, and correctives and stablizer are as antioxidant vitamin C (xitix).
Adopt aforesaid dispersion agent, wetting agent, suspensoid, sanitas, correctives, sweeting agent, and color agent, JN-2518 also can be made into oil-in-water preparation.
JN-2518 makes oil-in-water emulsifiers.Its oil phase can be aforesaid vegetables oil, as soybean oil, and sweet oil, peanut wet goods.Can also be liquid paraffin, Dormant oils, or the mixture of two classes.Emulsifying agent can be natural emulsifying agent, as kordofan gum, or tragcanth, natural phospholipid such as soybean phospholipid, Yelkin TTS, lipid acid, the fat of hexitol or acid anhydride or half resin are as the sorbose monoester.Also artificial chemical materials, ethylene oxide half fat condenses is as polyethylene sorbyl alcohol monoester salt.The oil-in-water type emulsion preparation of JN-2518 also can contain sweeting agent and correctives etc.
The syrup of JN-2518 and tincture can adopt sweeting agent, as propyl alcohol, and propylene glycol, sorbyl alcohol or sucrose.Said preparation also can contain wetting agent, sanitas, correctives, color additives.
The injection of JN-2518 can adopt aseptic parenteral solution or oily suspension.It can use all dispersion agent, wetting agent or suspensoids that are suitable on the pharmaceutics.Said preparation can be aseptic transparent liquid, uses all thinners that are suitable on the pharmaceutics, as 1, and 3-butanediol, water, Ringer ' s solution, or physiological saline.In addition, aseptic lipid also can be used as solvent or suspensoid.It can be synthetic glycerine monoester or two fat, and lipid acid is as oleic acid etc.
JN-2518 also can be made into suppository, as supp anal etc.Suppository can be combined by a certain amount of JN-2518 and corresponding non-stimulated excipient.Excipient is solid at normal temperatures, but liquefies and the release medicine under anus body temperature.The excipient that is suitable for comprises theobroma oil and macrogol class.
The formulation that is administered systemically of JN-2518 according to used carrier concentration, can be a suspension type, also lysotype.For easy-to-use or alleviate patient's misery, can add sanitas, buffer reagent and local anesthetic.
JN-2518 also can be used as animal doctor's medication.Take for ease of animal, the preparation that contains JN-2518 can add in the animal speech material or in the drinking-water.Also can be made into easily formulation as food or the drink of animal.
For going into, when the above-mentioned disease of treatment, the dosage range of JN-2518 tentatively is decided to be per kilogram of body weight 0.01mg to 15mg, or by 60 kilograms of body weight per capita about every day of 0.6mg to 900mg.According to administering mode, JN-2518 can be made into single dose formulation or multiple agent type.Dose unit tentatively is decided to be and contains effective ingredient 1mg to 500mg.
Every day, administration number of times was decided according to sick the kind.In most cases, no more than four times of every day.Be to be noted that dosage may depend on multiple factor, as the age, body weight, healthy state, sex, diet, and administration time, approach, the state of an illness and medicine unite use etc.So final dosage regimen should be determined as the case may be by the doctor.
The priority compounds that this patent is mentioned has the ideal pharmacological property, and it comprises but is not limited only to following aspect: superior oral administration biaavailability, hypotoxicity, low plasma protein binding ratio and ideal inside and outside transformation period.Though this compounds can pass through hemato encephalic barrier, this is its advantage to the treatment central nervous system disease, and at the treatment peripheral diseases, lower brain Plasma Concentration is even more ideal.
Compare the beneficial effect that is had with background technology:
Experiment shows: JN-2518 can combine with the ATP-binding site of cell-cycle kinases.Because two functional groups of this compound can form more hydrogen bond with the ATP-binding site of enzyme, so bigger avidity is arranged, and then can more effectively strive unexpectedly, thereby suppress the activity of this enzyme with ATP than ATP.This compound can suppress cytokine A, and the cell-cycle kinases activity that B and D mediated suppresses cell proliferation, cell death inducing.Multiple human body tumour cell is had stronger restraining effect, and half effective inhibition concentration is between 1-9 μ M.Inhibiting rate to rat experiment tumour W256 reaches 70%.The Flavopiridol that develops with the state-run DKFZ of the U.S. compares, and JN-2518 has following characteristics:
1, Flavopiridol is a flavonoid compound, and physico-chemical property is unstable.Must intravenously administrable.This is extremely inconvenient for the patient who needs long term administration.And the JN-2518 physico-chemical property is stable, and is not only oral effective, and can be made into multiple formulation.
2, because physico-chemical property is unstable, Flavopiridol is in vivo easily by metabolic inactivation.So its external activity can not act in the antimer.JN-2518 is quite different.
3, Flavopiridol not only suppresses cell-cycle kinases, and arrestin kinase c (PKC), the protein kinase A multiple requisite protein kinases of normal cell function of keeping such as (PKA), so its poor selectivity, side effect is many.And experiment shows that JN-2518 then is special cell cycle kinase inhibitors.
4, Flavopiridol has the toxic side effect of flavonoid compound, and excellent its is that GI irritation is serious.And the JN-2518 parent nucleus compound does not have this toxic action, and other side effect is slight.
The new compound JN-2518 of brand new is a very promising broad spectrum anticancer new drug.
Description of drawings
Fig. 1: cell cycle distribution, Regulation Mechanism, crucial modulin and effect thereof;
Fig. 2: JN-2518 to hormone-dependent prostate cancer cell LNCAP effect-concentration rely on curve and with the comparison of other medicines;
Fig. 3: JN-2518 and other chemotherapeutics are to the effect and the comparison thereof of former B1011 prostate cancer ascites metastasis cancer cell of being commissioned to train foster;
Fig. 4: JN-2518 cell cycle kinase inhibitory activity;
Fig. 5: JN-2518 induces the PARP proteolytic degradation;
Fig. 6: JN-2518 induces the formation of LNCAP cell (A) and N2A cell (B) dna ladder shape band.
Embodiment
The chemosynthesis of experimental example 1:JN-2518 and structural identification
(1) materials and methods
1. reagent: 2-ketone indoles purine (Oxindole), isatin (Isatin), iodoethane, phosphorus pentachloride, oxammonium hydrochloride, reagent such as diacetyl oxide and toluene are purchased the Sigma-Aldrich chemical reagents corporation in the U.S..
2. method: 2-ketone indoles purine (3, Oxindole) in diacetyl oxide, reflux and obtain nitrogen acetylate 5.Isatin (4; Isatin) and phosphorus pentachloride in benzole soln, react the chlorination intermediate 6 that obtains and refluxed 2 hours in dry toluene with compound 5 immediately; wash quiet successively with toluene and ethanol behind the solid filtering that obtains; recrystallization obtains compound 7 in dimethylformamide; again under alkaline condition with iodoethane react nitrogen alkylation reaction product 8; the ethylating product 8 of nitrogen acidic conditions go down protecting group (ethanoyl) compound 9, react in 20% ethanol with oxammonium hydrochloride more at last and obtain product 1.
(2) result:
With mass spectrum, nucleus magnetic resonance, the infrared instrument that waits confirms that structure obtains product 1.
Experimental example 2:JN-2518 is to the restraining effect of human cancer cell
What hereinafter exemplify is JN-2518 and other top-priority compound some examples to oncotherapy.We reiterate at this, though we are example with the treatment tumour only, this does not also mean that these compounds only are used for the treatment of tumour.
(1) materials and methods
Reagent: JN-2518 and series compound, synthetic by our laboratory, with mass spectrum, nuclear-magnetism, infrared affirmation structure is with high pressure liquid chromatography (HPLC) purifying.Purity is＞98.0%.JN-2518 is the garnet crystalline powder, and molecular weight is 305.During experiment, with the DMSO wiring solution-forming, in-20 ℃ of preservations.Vitamin A acid, daunorubicin, taxol are purchased the Sigma chemical reagents corporation in the U.S..NS389, a new epoxy thing enzyme II inhibitor is purchased in U.S. biomolecules research laboratory (Biomol.Research Lab).Other chemical reagent of experiment except that specifying, is all purchased the Sigma chemical reagents corporation in the U.S..
Cell cultures: human carcinoma cell line, mammary cancer; MCF-7, SKBR-3; Colorectal carcinoma; LDVO, DLD-1, prostate cancer: male sex hormone dependent form LNCAP and male sex hormone independent form PC-3, DU 145; Neuroblastoma: the N2A cell is purchased the Collection in American Type Culture.Cell places 37 ℃, 5% CO
2In the incubator, to contain the RPMI1640 substratum of 10% foetal calf serum and penicillin-Streptomycin sulphate.
MTT and SRB:MTT and SRB experimental technique are summarized as follows as [1] as described in the document: the cancer cells in the vegetative period of taking the logarithm, be inoculated in the 96-orifice plate, and cell density is every hole 5000 cells/200 μ l.Adding waits the medicine of serial dilution after 24 hours.Cell continues to cultivate 72 hours under drug effect.After the nutrient solution of 100 μ l is taken out in every hole, add 50 μ lMTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] solution continues to cultivate 4 hours.Dissolve the latent throw out of atropurpureus first with 200 μ l hydrochloric acid-aqueous isopropanols, measure absorbance value in 540nm wavelength place.If adopt srb assay, then after 72 hours, remove all nutrient solutions, after cell is fixed 1 hour with 10% Tricholroacetic Acid, put in the air seasoning 24 hours, add 50 μ lSRB (sulforhodamine B) dyeing 20-30 minute, with 1% Glacial acetic acid washing 5 times, put in the air after the seasoning, add 10mM Tris-HCl (pH10.0) solution dissolving red-purple albumen-SRB mixture of 200 μ l, measure absorbance value in 600nm wavelength place.Try to achieve the mean value of respectively organizing testing data, with experimental group control group is calculated cell and generate inhibiting rate.With Sigma Plot mapping software paint cell growth rate---drug level semilog plot, and try to achieve the medium effective concentration (IC50) of medicine.
(2) result:
Adopt MTT and two kinds of analytical procedures of SRB, we study the antitumour activity of JN-2518.What table 1-3 listed is JN-2518 and other chemotherapeutics half effective inhibition concentration to various cancer cells.Fig. 2 is the JN-2518 that enumerates and other medicine drug effect-drug level curve to hormone-dependent prostate cancer cell LNCAP effect.By showing 1-3 and Fig. 2 as can be seen, no matter be mammary cancer (MCF-7, SKBR-3, table 1), colorectal carcinoma (LOVO, DLD-1, table 2), hormone-dependent type (LNCAP) and hormone independent form prostate cancer (PC-3, DU-145, table 3), still nerve metrocyte carcinoma (N2A, IC50 1.2 μ M) is all comparatively responsive to JN-2518, its half effective inhibition concentration IC50 is between 1-9 μ M (seeing Table 1-3), and is similar to clinical common chemotherapeutics.The result shows that JN-2518 has stronger antitumour activity.
Table 1:JN-2518 is to breast cancer cell half effective inhibition concentration (IC50, μ M)
Reach comparison (mtt assay) with other chemotherapeutics.
| Medicine | Clone | |
| MCF-7 | SKBR-3 | |
| JN-2518 | 4.72±0.54 | 3.29±0.47 |
| Daunorubicin | 0.054±0.011 | 0.061±0.005 |
| Vitamin A acid | 21.45+3.78 | ＞50 |
| NS389 | ＞200 | ＞200 |
Table 2:JN-2518 suppresses effective concentration (IC50, μ M) to the half of colon cancer cell
Reach comparison (mtt assay) with other chemotherapeutics.
| Medicine | Clone | |
| LOVO | DLD-1 | |
| JN-2518 | 6.41±0.83 | 3.19±0.17 |
| Daunorubicin | 0.035±0.04 | 0.094±0.013 |
| Vitamin A acid | 75.34±12.49 | 49.70±5.72 |
| Taxol | 0.0037±0.0005 | 0.0032±0.0004 |
| NS389 | ＞200 | ＞200 |
Table 3:JN-2518 suppresses effective concentration (IC50, μ M) to the half of prostate cancer cell
Reach comparison (mtt assay) with other chemotherapeutics.
| Medicine | Clone | ||
| LNCAP | PC-3 | DU145 | |
| JN-2518 | 2.59±0.41 | 3.19±0.57 | 8.12±0.74 |
| Daunorubicin | N/A | 0.24±0.02 | 0.11±0.01 |
| Vitamin A acid | 15.95±3.19 | ＞50 | ＞50 |
| NS389 | 65.54±9.46 | ＞200 | ＞200 |
| Proscar | 40.60±7.12 | 133.68±12.94 | N/A |
| Casodex | 57.40±7.21 | 120.11±17.31 | N/A |
| Taxol | 0.00035±0.0001 | 0.00296±0.001 | 0.00577±0.001 |
(3) discuss
By MTT and SRB experiment, be not difficult to find out that JN-2518 has stronger antitumour activity, it is more much better than than cell induction differentiation agent vitamin A acid (Retinoid acid, IC50:21.5-＞50 μ M) and new epoxy thing enzyme II inhibitor NS389 (IC50＞200 μ M) to the cancer cells restraining effect.JN-2518 also is better than clinical Casodex that uses always (IC50:57.4 μ M) and Proscar (IC50:40.6 μ M) greatly to the restraining effect of hormone-dependent prostate cancer cell LNCAP.What is more important, (PC-3, DU-145), JN-2518 also has the good restraining effect for the hormone independent form prostate cancer cell of feeling simply helpless clinically.By contrast, PC-3 and DU-145 cell have then descended nearly 10 times to taxol susceptibility.
Neuroblastoma N2A cell is more responsive to JN-2518, and its IC50 is 1.2 μ M.Because this compound is fat-soluble structure, might be easy to by hemato encephalic barrier, and then help the treatment of brain tumor.
Though compare with daunorubicin or taxol, the JN-2518 antitumous effect is weak, and the former is promptly producing stronger toxic side effect under effective drug level, produces serious bone marrow depression when the plasma drug level 0.05 μ M as taxol.And JN-2518 toxicity is very low, and the mouse LD50 of its precursor compound is 3.9g/kg.
It is worthy of note, be not difficult to find out that though the LNCAP cell is very much responsive to taxol, experiment is difficult to record its IC90, because no matter concentration is much, always there is the cell about 15-20% insensitive by Fig. 2.Its reason may be these cells under the taxol effect, enter the G0 phase and the further effect of hiding medicine.In contrast, JN-2518 has better curative effect-concentration curve.This result shows that also JN-2518 is if different sequencing administrations with taxol then may produce significant synergy.
In addition, JN-2518 does not have significant difference to the IC50 of examination tumour cell, and these are different with other chemotherapeutics, as colorectal carcinoma and breast cancer cell to daunorubicin than the prostate cancer cell sensitivity, this explanation JN-2518 acts on the public target spot that cell generates.
Experimental example 3:JN-2518 is to the effect of prostate cancer ascites metastasis cancer cell:
(1) materials and methods
Reagent: JN-2518 sees experimental example 1.Daunorubicin, taxol, white arsenic (As
2O
3), Triochstatin A (TSA) purchases the Sigma chemical reagents corporation in the U.S..Other chemical reagent of experiment except that specifying, is all purchased the Sigma chemical reagents corporation in the U.S..
Cell cultures: the human cancer cell B1011 that former prostate cancer ascites of being commissioned to train foster shifts is by patient's ascites, by centrifugal collection cancer cells, and in 37 ℃, 5%CO
2In the incubator, to contain the RPMI1640 culture medium culturing of 10% foetal calf serum and penicillin-Streptomycin sulphate.After cultivating a week, the cell growth is stablized fast.The B1011 cancer cells of taking the logarithm vegetative period is with the antitumour activity of mtt assay research JN-2518.
The MTT:MTT experimental technique is as indicated above.
(2) result and discussion
The B1011 cancer cells come from one late period prostatitis carninomatosis people ascites.This patient is to hormone and other multiple chemotherapy resistance, and for helping the responsive chemotherapeutics of patient selection, we are inoculated in the 96-orifice plate with the former foster cancer cells (B1011) of being commissioned to train, and carry out aforesaid MTT experiment with different chemotherapeutics.The result as shown in Figure 3.Experiment shows that the B1011 cancer cells is comparatively responsive to JN-2518, and its sensitivity is than white arsenic (As
2O
3) slightly strong (2.8 μ M are to 4.2 μ M).But white arsenic toxicity is big, and under clinical permission dosage, its effective blood drug concentration does not reach 4.2 μ M.
To other anticarcinogen commonly used such as taxol of try, daunorubicin, different vincristin etc., B1011 cell be resistance all.Is 0.35nM as the LNCAP prostate cancer cell to purple triol IC50, but the B1011 cell increases to 5nM to the IC50 of this medicine.That is, the B1011 cell has descended nearly 15 times to taxol susceptibility! The B1011 cell is suitable to the resistance and the taxol of daunorubicin and different vincristin.On the contrary, LNCAP and B1011 cell are to the susceptibility of JN2518 quite (LNCAP IC50 2.59 μ M, to B1011,2.8 μ M), and JN2518 be described, and not only the prostate cancer to early stage hormone-dependent type is effective, and effective equally to the prostate cancer of transfer in late period.
Experimental example 4:JN-2518 is to the antitumous effect of rat w256 mammary cancer:
(1) materials and methods
Material: JN-2518 sees experimental example 1-2.The Wistar rat is provided by the U.S. state-run cancer research institute Experimental Animal Center.
Method:
The preparation of drug suspension: get a certain amount of JN-2518 in mortar, add several tweens-100 and grind with medicine, the water that adds capacity again grinds standby behind abundant suspendible.
Rat w256 breast cancer model and dosage regimen: studies show that for many years rat w256 mammary cancer and human tumor have dependency preferably, and then have a wide range of applications [2,3].So this patent adopts this model, studied the JN-2518 antitumous effect.Get 40 of the Wistar rats of 60-80 gram, be divided into 4 groups at random by body weight, ten every group, inoculation 1-2 * 10, oxter
6The W256 oncocyte.Inoculate back 24 hours, difference orally give 0,50, the JN-2518 of 100mg/kg, once a day, totally ten days.With endoxan as positive control (giving 60mg/kg) in first day and the 5th day abdominal cavity.After last administration 24 hours, put to death animal, take out whole knurl pieces and weigh.Average knurl with the average knurl anharmonic ratio control group of test group is heavy, tries to achieve tumour inhibiting rate by (1-T/C).Measure its significant difference with the T check.
(2) result and discussion
As shown in table 4, JN-2518 has significant anti-cancer activity to W256, and its antitumour activity directly is directly proportional with dosage.Under 100mg/kg dosage, JN-2518 reaches more than 70% the inhibiting rate of W256.Under same test conditions, the endoxan positive controls also demonstrates stronger antitumour activity, but from the survival of animal and body weight change as can be seen, JN-2518 is under 100mg/kg dosage, no animal dead, and the weight of animals increases to some extent, do not have any toxicity sign.And the endoxan group, not only the mean body weight of animal descends to some extent, and rat death in the 8th day after administration is arranged, and demonstrates overt toxicity.
Table 4, JN-2518 is to the restraining effect of rat w256 mammary cancer
| Group | Dosage | Number of animals (beginning/end) | Tumor weight (g) | Body weight change (g) | Inhibiting rate % (1-T/C) % | The |
| Contrast | ||||||
| 0 | 10/10 | 8.94±1.20 | +22.7 | 0 | ||
| JN-251 8 | 50mg/kg× 10* | 10/10 | 4.60±0.74 | +9.4 | 48.54 | ＜0.05 |
| JN-251 8 | 100mg/kg × 10* | 10/10 | 2.57±0.47 | +7.6 | 71.29 | ＜0.01 |
| Endoxan | 60mg/kg× 2** | 10/9 | 1.35±0.21 | -4.9 | 84.9 | ＜0.01 |
*: oral administration (P.O.); *: intraperitoneal administration (I.P.).
The kinase whose restraining effect of experimental example 5:JN-2518 cell cycle:
(1) materials and methods:
Material: the poly-propionic acid amide gel reagents of protein electrophoresis, SDS, electrophoretic buffer, albumen electrotransfer damping fluid is purchased the Bio-Rad life science company in the U.S..Other chemical reagent of experiment except that specifying, is all purchased the Sigma chemical reagents corporation in the U.S..Cell-cycle kinases antibody is used in test, cdk2, and cdk4, antibody such as Cyclin D1 are purchased in the Protein Sepharose A+G of Santa Cruz biotech company and are purchased in oncogene Inc.[
32P]-ATP purchases in PerkinElmer life science company.
Cell cultures: see experimental example 2.
The restraining effect of cell-cycle kinases: we are experimental model with HUVEC and LNCaP cell, have studied JN-2518 cell cycle kinases and other associated kinase effect.HUVEC and LNCaP cell be EMB (endothelial cell basal medium) and RPMI 1640 culture medium culturing to contain 10% foetal calf serum respectively.JN-2518 with given concentration handled 24 hours with the cell of logarithmic phase.Collecting cell, washing, and with the described method of document [4] extraction total protein.With 100 μ g albumen in the presence of the multiple protein enzyme inhibitors, under 4 ℃ with cdk2, cdk4, Cyclin D1, specific antibodies such as ERK2 carry out immunoprecipitation and spend the night.After washing four times with damping fluid, washs once to measure the active damping fluid of cell-cycle kinases again this immunoprecipitation complex.With the cell-cycle kinases of immune purifying with its damping fluid suspendible, [
32P]-ATP (0.5 μ Ci/100 μ M) exists down and histone h1 reacted 10 minutes.The histone of phosphorylation, it represents corresponding cell-cycle kinases activity respectively, and is with X-diffraction picture record, quantitative with the density scanner after separation and purification.And compare with control group, try to achieve inhibiting rate with (1-T/C) %.Positive controls, cell is handled with the PD98058 (ERK1/2, the special inhibitor of podocyte division kinases) of different concns, to measure enzymic activity with method.
(2) result and discussion
Fig. 4 is the representative instance of JN-2518 cell cycle kinases and other associated kinase effect.Experiment shows adopts above-mentioned cell system, JN-2518 cell cycle kinases cdk2, and cdk4/6 has significant inhibitory effect, and its IC50 is between 1.5-6.2 μ M.We infer that if adopt pure enzyme system, this restraining effect may be more obvious.But under the same conditions, this compound is to protein kinase C (PKC), and the short discrete kinases of cell (MAP kinase) etc. are influence not, illustrates that JN-2518 cell cycle kinase inhibitory activity has selectivity preferably.Though, according to medium effective concentration, the Flavopiridol that JN-2518 reports not as document, its to the medium effective concentration of the cell-cycle kinases 1,2 of pure enzyme system and 4 10
-9To 10
-8In the molconcentration scope [5].Be to be noted that though good active is arranged, wherein some compound was said nothing of whole animal effective because of not passing through cytolemma abiology activity when some compound adopted pure enzyme.
The effect of experimental example 6:JN-2518 pair cell apoptosis induced:
Because PARP[Poly (ADP-ribose)-Polymerase] proteic degraded and the formation of dna ladder shape band, it is apoptotic key character and be widely used in apoptotic research [6,7], we study the effect of JN-2518 cell death inducing.
(1) materials and methods
Material: the DNA sepharose, albumen gathers propionic acid amide electrophoresis agents useful for same, purchases the Bio-Rad life science company in the U.S..Other chemical reagent of experiment except that specifying, is all purchased the Sigma chemical reagents corporation in the U.S..The PARP monoclonal antibody is purchased the Pharmingen in the U.S., A Becton Dickinson company.Western blot detection reagent and other articles for use are purchased the Amershan life science company in the U.S..
Cell cultures: see experimental example 2.
Apoptosis is analyzed:
1) Western blotting detects the proteic depression of order of PARP:
The human neuroblastoma cell N2A of logarithmic phase was handled 48 hours with the JN-2518 or the 20nM taxol (positive control) of different concns.Collecting cell, washing is extracted albumen with literature method [8], quantitatively.Get 100 μ g albumen and carry out the poly-propionic acid amide gel electrophoresis of SDS-.Behind the electrophoresis, the albumen electricity is forwarded on the nitrocellulose membrane, detects with special PARP antibody, and with β-Actin antibody as interior mark.Gained X-diffraction picture is quantitative with the density scanner.
2) JN-2518 inducing DNA trapezoid belt forms: the Human Prostate Cancer Cells LNCAP and the human neuroblastoma cell N2A of logarithmic phase were handled 48 hours with the JN-2518 or the taxol (positive control) of different concns.Collecting cell, washing is extracted DNA with literature method [8], with 2% agar Tang Ling gel electrophoresis DNA isolation fragment, photographic recording.
(2) result and discussion
As previously mentioned, suppress cell-cycle kinases cdk4/6 and other cell-cycle kinases such as cdk2, then cause the cell cycle operation to be obstructed, and then promote cytodifferentiation, or cell death inducing.For confirming this inference, we observe the JN-2518 cell death inducing.
As shown in Figure 5, under the JN-2518 effect, the PARP protein band of 110Kda obviously reduces, and under the same experimental conditions, as the β-Actin albumen of interior originality contrast no change then.The result shows that JN-2518 has activated apoptosis truck, cell death inducing.Form experiment by dna ladder shape band, this conclusion is fully confirmed.
By Fig. 6 A and B as can be seen, no matter be the LNCAP prostate cancer cell, still neuroblast N2A, JN-2518 all can obviously cause the formation of dna ladder shape band.Its action intensity and MTT experiment matches, and the N2A cell forms than LNCAP cell sensitivity dna ladder shape band,, can significantly induce to produce dna ladder shape band during less than 5.0 μ M at drug level.
Conclusion: we show that the listed compound of JN-2518 and this patent thereof is the very attractive anticancer compound of a class in preliminary experiment.They are the special cell cycle kinase inhibitors of a class, the normal operation of blocking-up tumour cell cycle, cell death inducing.Tumour cell to various human all has stronger antitumous effect, and its IC50 is between 1 to 9 μ M.The experimental animal models tumour also there is stronger restraining effect.So JN-2518 has represented the novel cancer therapy drug of a class.
Claims (6)
1, a specific specificity Benzazole compounds is characterized in that the structure of this compound is:
Wherein:
R
1＝H，CH
3，(CH
2)
nCH
3，C
2H
4OH，n＝1-5；
R
2＝CH
3，(CH
2)
nCH
3，C
2H
4OH，n＝1-5；
R
3＝H，Cl，Br，F；
R
4＝H。
2, specificity Benzazole compounds according to claim 1 is characterized in that, the structural formula of this specificity Benzazole compounds is:
3, a kind of method for preparing the described specificity Benzazole compounds of claim 2; it is characterized in that: with 2-ketone indoles purine and isatin is basic raw material; the compound 5 of process nitrogen acetylization reaction and the chlorination intermediate 6 of isatin carry out condensation and obtain compound 7 in toluene; the ethylating product 8 of nitrogen gets compound 9 at the acidic conditions protecting group ethanoyl that goes down, and its chemical equation is:
After obtaining compound 9, obtain product 1 with azanol reaction again,
4, a kind of medicinal compositions is characterized in that, described medicinal compositions contains the described specificity Benzazole compounds of claim 1 of safe and effective therapeutic dose, and pharmaceutically acceptable carrier.
5, medicinal compositions according to claim 4 is characterized in that, the formulation of described medicinal compositions is tablet or pill or capsule or paste or creme or patch or pulvis or injection or sprays or implant or suppository or drops or oil-in-water emulsion.
6, the purposes of the described specificity Benzazole compounds of claim 1 is characterized in that, is used to prepare the solid tumor for the treatment of the human or animal or the medicinal compositions of leukemia or senile dementia or psoriasis or cardiovascular disorder or glomerulonephritis or acquired immune deficiency syndrome (AIDS).
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021385181A CN1199946C (en) | 2002-10-29 | 2002-10-29 | Specific indole compound and its preparation and use in treating and preventing cancers |
| PCT/CN2003/000901 WO2004039797A1 (en) | 2002-10-29 | 2003-10-27 | A special kind of indole compounds, their preparation, and their use in treatment and prevention of those disease such as cancer |
| AU2003280544A AU2003280544A1 (en) | 2002-10-29 | 2003-10-27 | A special kind of indole compounds, their preparation, and their use in treatment and prevention of those disease such as cancer |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021385181A CN1199946C (en) | 2002-10-29 | 2002-10-29 | Specific indole compound and its preparation and use in treating and preventing cancers |
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| Publication Number | Publication Date |
|---|---|
| CN1424312A CN1424312A (en) | 2003-06-18 |
| CN1199946C true CN1199946C (en) | 2005-05-04 |
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|---|---|---|---|
| CNB021385181A Expired - Fee Related CN1199946C (en) | 2002-10-29 | 2002-10-29 | Specific indole compound and its preparation and use in treating and preventing cancers |
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| Country | Link |
|---|---|
| CN (1) | CN1199946C (en) |
| AU (1) | AU2003280544A1 (en) |
| WO (1) | WO2004039797A1 (en) |
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| CN101074229B (en) * | 2007-06-08 | 2010-09-01 | 无锡杰西医药科技有限公司 | 7-azaindirubin and 7-azaisoindigo derivative production and pharmaceutical use |
| CN103333161B (en) * | 2013-05-28 | 2015-09-30 | 滁州市洛达生物科技有限公司 | The preparation of 1 '-oxo Indirubin and purposes |
| CA3048357A1 (en) | 2016-12-29 | 2018-07-05 | Minoryx Therapeutics S.L. | Heteroaryl compounds and their use |
| CN111808078B (en) * | 2020-06-22 | 2022-10-11 | 济南爱思医药科技有限公司 | Lenalidomide derivative for inhibiting IDO1 activity and preparation method and application thereof |
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| JPS609023B2 (en) * | 1981-06-19 | 1985-03-07 | イスクラ産業株式会社 | Indirubin derivatives and antitumor agents containing them |
| JPS617254A (en) * | 1984-06-20 | 1986-01-13 | Isukura Sangyo Kk | Bisindolinone and carcinostatic agent consisting essentially of same |
| WO1999062503A2 (en) * | 1998-05-29 | 1999-12-09 | Cnrs (Centre National De Recherche Scientifique) France Innovation Scientifique Et Transfert | Use of indigoid bisindole derivatives for the manufacture of a medicament to inhibit cyclin dependent kinases |
| HUP0200724A3 (en) * | 1999-04-12 | 2002-10-28 | Eisenbrand Gerhard | Indigoid bisindole derivatives and pharmaceurical compositions containing them |
| FR2801216A1 (en) * | 1999-11-23 | 2001-05-25 | Centre Nat Rech Scient | Use of indirubine derivatives to inhibit 3 beta-glycogen synthase kinase, for the treatment of diabetes, neurodegenerative disorders, manic-depressive disorders, cancers, or parasites |
| DE10061162A1 (en) * | 2000-11-30 | 2002-07-11 | Schering Ag | Aryl-substituted indirubin derivatives, their preparation and use |
-
2002
- 2002-10-29 CN CNB021385181A patent/CN1199946C/en not_active Expired - Fee Related
-
2003
- 2003-10-27 WO PCT/CN2003/000901 patent/WO2004039797A1/en not_active Application Discontinuation
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| WO2004039797A1 (en) | 2004-05-13 |
| AU2003280544A1 (en) | 2004-05-25 |
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