CN102633668B - Use of compound in therapeutic drug for diseases related to disorder of transcription factor - Google Patents
Use of compound in therapeutic drug for diseases related to disorder of transcription factor Download PDFInfo
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Abstract
The invention discloses the use of a compound and the drug composite of the compound in the preparation of a therapeutic drug or an ancillary therapeutic drug for diseases related to the disorder of transcription factor or ancillary factor of the transcription factor. The compound is the compound shown in the formula (I), the Z-A-Z' or the pharmacologically acceptable salt or prodrug. The use of the compound has the beneficial effects that the micromolecule compound provided by the invention is derived from pair transcription factors, such as the analysis of foxp P3 and/or myocyte enhancement factor 2 molecular structure and the interaction locus of the binding protein of the foxp P3 and/or the myocyte enhancement factor 2 molecular structure. Therefore, the micromolecule compounds can be used for adjusting the function of the related transcription factor, wherein the function comprises the interaction influencing the relevant transcription factor and the binding protein comprising various transcription factors. Due to the function adjustment of the foxp P3 and/or the myocyte enhancement factor 2, the micromolecule compounds have obvious drug and treatment uses to the malignant tumor, in particular to the treatment of the malignant tumor such as the carcinoma of uterine cervix, the breast cancer and the like, so that the animal experiment shows that the compound is extremely good in inhibition effect.
Description
Technical field
The present invention relates to compound pharmacy field, be specifically related to compound and pharmaceutical composition thereof and producing and the application in the medicine of the cofactor dysfunction of transcription factor or transcription factor or adjuvant therapy medicaments.
Background technology
Most malignant tumours come from the disorder of the regulatory mechanism relevant with Growth of Cells, wherein usually relate to the imbalance of one or more cell growth control link.Oncogenic generation is led in out of control cell continued propagation and division.Tumour cell as organized arround capable intrusion, and likely invades other organs by all means by original site or arrives other positions of health, is namely considered to malignant tumour, is commonly called as cancer.According to source, malignant tumour can be divided into again and originate from various epithelial " cancer " and originate from reticular tissue or " sarcoma " from mesoblastic cell.2008, the whole world had 1,270 ten thousand people to suffer from malignant tumour, and death toll is up to 7,600,000 people.In China, malignant tumour has become first Disease causation, year morbidity 2,600,000 people, year death toll 1,800,000 people.
It is disturb and block proliferation process that current oncotherapy mainstream medicine major part acts on: as directly destroyed DNA, inserting DNA profiling, affect nucleic acid synthesis, disturb DNA to synthesize, suppressing microtubule assembling and affect protein synthesis, the chemotherapeutics that namely this kind of medicine is commonly called as.Because this kind of medicine is nonspecific for the impact of cell, namely all there is lethal effect for tumour cell and normal cell, its toxic side effect highly significant.DNA cumulative interference class medicine also may be induced new sudden change thus be increased the probability of the following suffers from cancer of patient simultaneously.
The then specificity of medicine and the targeting type more of the research of new type antineoplastic medicine in recent years; as the kinases medicine that is representative with lattice row stomach, with his be representative Histone deacetylase inhibitor class medicine, cell death inducing class medicine and antibody class medicine of promise of throwing oneself on the ground.These medicines and modern biomedical research are more tight, and more focusing on blocking stimulates the signal transducting system of tumor growth and the responding system in downstream.
Cervical cancer (Cervical Cancer) is one of most common cancer of women, China and other developing country's sickness rate higher.Cervical cancer has become the highest female cancer of China's mortality ratio in recent years.
The infection of the morbidity of cervical cancer and human papillomavirus (Human papilllomavirus, HPV) has direct correlation, and the infection of prevention HPV will become the most effective means of cervical cancer inhibiting sickness rate.But up to now, the HPV vaccine that China does not also go on the market, prevailing vaccine is respectively from Mo Ke company (Merck) and Glan element-SmithKline company (GSK) in the world, and effective immunization rate reaches 80% and 70% respectively.Even if but above-mentioned vaccine enters China market, its high immunization fee also can make the women's scope protected have the limitation of certain degree with (needing three doses of immunity, market value $ 390, Yue He $2,500).
Make regular check on and contribute to finding cervical cancer as early as possible, but because cervical cancer is in early days often without any symptom, easily ignored by patient.In China, the patient of about 70% misses the best period of operative treatment for late period when being diagnosed as cervical cancer.
The treatment of cervical cancer there is no specific medicament, what relatively commonly use clinically now is that the Cocktail treatment of taking as the leading factor with cis-platinum is aided with radiotherapy, it is efficient can only reach 30-50%, and these nonspecific cytotoxic chemicals for the holistic health of patient and life quality negative effect clearly.
The compound that the present invention relates to is transcription factor conditioning agent, especially the conditioning agent of jaw box protein P3 and/or myocyte enhancer factor 2, can directly affect above-mentioned functional transcription factor, and the interaction of above-mentioned transcription factor between its transcriptional co-factor (people such as Guo, Proc Natl Acad Sci U S A., 2007,104 (11): 4297-302; The people such as Han, JMol Biol., 2005,345 (1): 91-102; The people such as Han, Nature, 2003,422 (6933): 730-4).Thus Tumor suppression grows required genetic expression, inducing apoptosis of tumour cell, thus reach antineoplastic effect.
Summary of the invention
Object of the present invention is exactly for above-mentioned defect of the prior art, provides a kind of micromolecular compound that can be used as the cofactor of conditioning agent selective binding transcription factor or transcription factor.
To achieve these goals, technical scheme provided by the invention is:
Formula (I) compound is acceptable salt or precursor medicine on Z-A-Z ' or its pharmacology, wherein
Each Z and Z ' is independently five yuan or hexa-atomic aromatic ring or fragrant heterocycle, or the ring system of being closed by 2-3 aromatic ring or fragrant heterocycle a pair of horses going side by side;
Heteroatoms on each fragrant heterocycle is O, N or S;
Ring system is substituted ring or unsubstituted ring;
Substituting group on ring is :-R
1, halogen ,-NO
2,-CN ,-SCN ,-OH ,-NH
2,-SH ,-OR
1,-NR
1r
1' ,-SR
1,-SOR
1,-SO
2r
1,-CONR
1r
1' ,-SO
2nR
1r
1' ,-COOR
1or-O-COR
1; Wherein
R
1with R
1' be independently H or the alkyl comprising 1-10 carbon atom;
A is the one in following two kinds of structures:
A () has-(A ')
nthe structure fragment of-form, wherein
n＝1-20；
Each A ' is independently-CR
2r
2'-,-NR
2-,-O-,-S-,-SO-,-SO
2-or-CO-, wherein R
2with R
2' be independently H, halogen or the alkyl comprising 1-6 carbon atom;
Connected by singly-bound, double bond or three key between every two adjacent A ';
B () comprises the structure fragment of 1-20 carbon atom, be cycloaliphatic ring, aromatic nucleus or the ring system by the conjunction of 2-3 ring a pair of horses going side by side;
Wherein containing hydrogen, halogen, oxygen, nitrogen or sulphur atom.
Further, in above-claimed cpd, A is A
1-A
2-A
3;
A
1and A
3independently-CR
3r
3'-,-CONR
3-,-NR
3cO-,-CO-,-SO
2-,-O-,-S-,-NR
3-,-COO-,-OCO-,-SO
2nR
3-,-NR
3sO
2-; R
3with R
3' be independently hydrogen, halogen or the alkyl comprising 1-6 carbon atom;
A
2for the structure fragment that backbone length is 1-12 carbon atom, wherein
Carbon atom on main chain is also replaceable is oxygen, nitrogen or sulphur;
Main chain includes singly-bound, double bond or three key;
Main chain includes-CR
4r
4'-,-O-,-NR
4-,-CO-,-CONR
4-,-COO-,-S-,-SO-,-SO
2-,-SO
2nR
4-, wherein R
4with R
4' be independently hydrogen, halogen or the alkyl comprising 1-6 carbon atom.
Further, above-claimed cpd is any one in following micromolecular compound:
Another object of the present invention there is provided a kind of pharmaceutical composition, comprises the above-claimed cpd of pharmaceutically acceptable carrier and the treatment significant quantity as activeconstituents.
3rd object of the present invention there is provided the application in the medicine producing relevant disease of lacking of proper care to the cofactor of transcription factor or transcription factor or adjuvant therapy medicaments of above-claimed cpd and pharmaceutical composition thereof.
Further, above-claimed cpd is optionally in conjunction with the cofactor of transcription factor or transcription factor as conditioning agent.
Further, described transcription factor is jaw box protein P3 and/or myocyte enhancer factor 2.
Further, the cofactor of above-mentioned transcription factor is any one in calcineurin Binding Protein 1, histon deacetylase (HDAC), E1A associated proteins P300, CREB associated proteins, extracellular signal-regulated kinase 5, myogenic differentiation albumen, Smad albumen, nuclear factor of activated T cells, cardiac muscle element or positive transcriptional elongation factor b.
Further, above-mentioned to transcription factor or the cofactor of transcription factor relevant disease of lacking of proper care be malignant tumour.
Further, above-mentioned malignant tumour is come from epithelial cancer or come from reticular tissue or the sarcoma from mesoblastic cell; Include leukemia, myelodysplastic syndrome, malignant lymphoma, multiple myeloma, cancer of the stomach, colon/rectum cancer, lung cancer, mammary cancer, germinocarcinoma, liver cancer, skin carcinoma, bladder cancer, prostate cancer, uterus carcinoma, cervical cancer and/or ovarian cancer.
Be preferably cervical cancer.
Further, the effective dose of above-claimed cpd is that every kilogram of raw object weighs 10
-6g-5g.
Further, the route of administration of above-claimed cpd is pharmaceutically acceptable route of administration, including, but not limited to intravenous drip, intravenous injection, subcutaneous injection, subcutaneous embedding, oral administration, gastric infusion, external application administration and/or vagina administration.
Beneficial effect of the present invention is: micromolecular compound provided by the invention derives from transcription factor, as the analysis in jaw box protein P3 and/or myocyte enhancer factor 2 molecular structure and binding protein interactions site thereof.This type of micromolecular compound therefore, it is possible to regulate the function of associated transcription factor, comprising the interaction affected between associated transcription factor and its associated proteins comprising many transcription factors.By the adjustment for jaw box protein P3 and/or myocyte enhancer factor 2 function, this type of micromolecular compound has obvious medicine and therepic use for malignant tumour, especially for the treatment of the malignant tumour such as cervical cancer, mammary cancer, experimentation on animals shows, and inhibition is splendid.
Accompanying drawing explanation
Fig. 1 is that transcription factor conditioning agent suppresses human cervical carcinoma cell propagation.
Cervical cancer cell in cultivation adds different concns transcription factor conditioning agent YT30, and control group then adds non-activity compound YT19, with detecting viable count and calculating cell inhibitory rate after 48 hours.
Fig. 2 is that transcription factor conditioning agent can induce human cervical carcinoma cell apoptosis.
A the cervical cancer cell in () cultivation adds different concns transcription factor conditioning agent YT30, control group then adds non-activity compound YT19, active with detecting caspase 3/7 after 48 hours.
B () 20 μMs of YT30 process Caski cells, after 48 hours, add Hoechst33258 dyeing and observations.
Fig. 3 is the mensuration of the inhibiting rate of transcription factor conditioning agent in different cell.
Transcription factor conditioning agent YT30 and YT54 is added in cervical cancer cell Caski, HeLa cell in cultivation and human fibroblasts Fibroblast, l cell L929, control group then adds non-activity compound YT19, with detecting viable count and calculating cell inhibitory rate and IC50 after 48 hours, as shown in table 1.
Fig. 4 is the apoptosis of transcription factor conditioning agent induction different carcinoma cell strain.
Human cervical carcinoma cell strain HeLa (Fig. 4 .1) in cultivation, Caski (Fig. 4 .2), C33A (Fig. 4 .3) and human oophoroma cell line SKOV3 (Fig. 4 .4) are after transcription factor conditioning agent YT30 and YT54 acts on 48 hours, adopt AnnexinV/PI dyeing confocal laser scanning microscope, and flow cytomery is early stage and late apoptic rate, calculate apoptotic index (AI) (table 2.1-2.4) according to AnnexinV/PI and flow cytomery result.
Fig. 5 is the growth curve of nude mice cervical cancer transplanted tumor.
Nude mice right dorsal sc inoculation Caski cell, treatment group abdominal injection transcription factor conditioning agent YT30 after a week, continues 5 weeks;
Control group abdominal injection solvent.Use vernier caliper measurement Tumor diameter, draw growth curve with gross tumor volume.
Fig. 6 is the growth curve of SCID mouse cervical cancer transplanted tumor.
The right dorsal sc inoculation of SCID mouse, treatment group abdominal injection transcription factor conditioning agent YT30 after a week, continues 26 days; Control group abdominal injection solvent.Use vernier caliper measurement Tumor diameter, draw growth curve with gross tumor volume.
Embodiment
Embodiment 1:
Transcription factor conditioning agent suppression human cervical carcinoma cell propagation is also apoptosis-induced:
Take the logarithm human cervical carcinoma cell strain in vegetative period Caski, SiHa, HeLa and C4I (Caski and SiHa is the strain of HPV16 positive cell, HeLa and C4I is the strain of HPV18 positive cell) is inoculated in 96 orifice plates, and at 37 DEG C, volume fraction is 5%CO
2saturated humidity incubator in overnight incubation, add the transcription factor conditioning agent YT30 of different concns respectively, control group then adds and YT30 structural similitude, the active compound YT19 but unrestraint transcription factor and HDACs interact, continues cell proliferation and apoptosis are carried out in cultivation detection after 48 hours.Utilize the CellTiter-Glo cytoactive fluorometric assay box of Promega company (Madison, WI) to detect the activity of cell, concrete steps are with reference to shop instruction.Be calculated as follows cell inhibitory rate: inhibiting rate (%)=(1-test group fluorescent value/control group fluorescent value) × 100%.Caspase 3 is the crucial effector molecules in apoptosis pathway, and utilize Caspase-Glo 3/7 test kit of Promega company (Madison, WI) to detect Caspase3/7 active, concrete steps are with reference to shop instruction.Be calculated as follows relative Caspase3/7 active: Caspase3/7 activity (%)=test group fluorescent value/control group fluorescent value × 100%.Hoechest33258 fluorescent dye is utilized to detect the apoptosis of Caski cell.The YT30 process Caski cell of 20 μMs is after 48 hours, and add Fluorochrome Hoechst 33258 to final concentration 30 μ g/mL, 37 DEG C of lucifuges dye 1 hour, observations under excitation wavelength is 350nm fluorescent microscope.Control group adds DMSO.Normal cell core rounded or oval, Distribution of chromatin is even, and the nucleus of apoptotic cell owing to concentrating in sapphirine or core be leaflet, shred, limit collection.Count the apoptotic cell number in 500 cells, draw apoptosis percentage.
YT30 adopts the assessment of CellTiter-Glo method to the impact that human cervical carcinoma cell is bred, found that YT30 all has restraining effect to the propagation of 4 cervical tumor cells in 5 μMs ~ 20 μMs concentration ranges, drug level is higher, restraining effect is stronger, present obvious dose-dependent effect relation, as shown in Figure 1.YT30 adopts Caspase3/7 Activity determination and the assessment of Hoechest 33258 fluorescent staining method to apoptotic impact.Found that after the YT30 elicitor Hela Cell Apoptosis of different concns, compare with DMSO solvent control group, the Caspase-3 activity of 4 cervical tumor cells all has and increases, and in dose-dependently, in people's SCC cell strain CaSki and SiHa of the HPV16 positive, Caspase-3 activity increases significantly, as shown in Figure 2 a.Hoechest33258 fluorescent dye count results showed the YT30 process of 20 μMs after 48 hours, and the apoptosis ratio of Caski cell is apparently higher than DMSO control group (57.6% ± 4.8%vs 1.5% ± 1.2%; P < 0.01), as shown in Figure 2 b.
Embodiment 2:
The IC50 measuring and calculating of transcription factor conditioning agent antithetical phrase cervical cancer cell lines and normal fibroblast:
According to method in embodiment 1, human cervical carcinoma cell strain Caski, HeLa in vegetative period of taking the logarithm and human fibroblasts Fibroblast and l cell L929.Calculate respectively and to add after the YT30 of different concns and similar compound YT54 48 hours, the cell inhibitory rate after 72 hours and IC50, as shown in Figure 3.The inhibition concentration of transcription factor conditioning agent antithetical phrase cervical cancer cell lines is starkly lower than normal fibroblast, in table 1.
Table 1
Wherein, l cell and human fibroblast are negative control, and to compound responsive degree all far below cancer cells, in accompanying drawing, L929 48 hours figure are representative.
Embodiment 3:
After YT30 and YT54 effect human cervical carcinoma cell HeLa, Caski, C33A and human oophoroma cell line SKOV348 hour, adopt AnnexinV/PI dyeing confocal laser scanning microscope, and flow cytomery is early stage and late apoptic rate, calculates apoptotic index (AI) (apoptotic index is the per-cent that in microscope/cell instrument, apoptotic cell accounts for total cell count) according to AnnexinV/PI and flow cytomery result.
YT30 and YT54 effect HeLa (as shown in Fig. 4 .1), Caski (as shown in Fig. 4 .2), C33A (as shown in Fig. 4 .3) and SKOV3 (as shown in Fig. 4 .4) cell AnnexinV/PI flow cytomery after 48 hours, presents typical early stage and late apoptic image.
Calculating apoptotic index (AI) according to flow cytomery result shows after transcription factor regulatory factor YT30 and YT54 act on 48 hours, HeLa (see table 2.1), Caski (see table 2.2), C33A (see table 2.3) and SKOV3 (see table 2.4) all have obvious apoptosis, and apoptosis rate has the dependency of time and dosage.
Table 2.1
Table 2.2
Table 2.3
Table 2.4
Embodiment 4:
The growth of the obvious cervical cancer inhibiting transplanted tumor in nude mice of transcription factor conditioning agent:
Animal: BALB/c nu/nu nude mice, purchased from Simenson Laboratories, 4 ~ 5 week age, female, weight average (18.06 ± 0.72) g.At no-special pathogen (Specific pathogen Free, SP) raise the animal experimental center in University of Southern California under condition, and follow university's management of laboratory animal and the use council, California and the United States Federal's human experimentation animal instruction manual regulation.Mouse can arbitrarily obtain food and water.
10 nude mices are divided into YT30 treatment group and solvent control group at random, often organize 5, are in the Caski cell of logarithmic phase, every nude inoculation 5 × 10 in nude mice right dorsal sc inoculation 0.2ML
6individual cell.Observe generalized case and the growth of xenografted situation of nude mice, when after one week, transplanted tumor grows to diameter about 0.3 ~ 0.5cm, treatment group abdominal injection myocyte enhancer factor 2 conditioning agent YT3050mg/kg, volume injected 200ul, once a day, successive administration 5 days weekly, continues 5 weeks; Control group abdominal injection solvent (20%w/v (2-Hydroxypropyl)-β-cyclodextrin of 20%DMSO, 80%PBS preparation).Measure body weight at least 2 times weekly, according to body weight adjustment administration total amount.At least 2 times with vernier caliper measurement knurl body major diameter (a) and minor axis (b) weekly, calculates gross tumor volume as follows: volume (V)=4 π/3 × (b/2)
2× (a/2), draws growth curve with gross tumor volume, observes diet and the mental status change of nude mice simultaneously.Tumour inhibiting rate is calculated: tumour inhibiting rate (%)=(control group gross tumor volume-experimental group gross tumor volume)/control group gross tumor volume × 100% with gross tumor volume.If nude mice body weight decrease beyond 20% in experimentation, or Tumor diameter is more than 1.5cm, then put to death this nude mice.After last injection next day complete taking-up subcutaneous tumors tubercle weighing.By each important organ of knurl tubercle sample and nude mice as packing such as liver,kidney,spleens, insert liquid nitrogen cryopreservation respectively or 10% formalin fixes paraffin embedding, in order to the use of immunohistochemical methods and other experiment.Conventional row Hematoxylin-eosin (HE) dyeing of paraffin section, the pathological change of transplanted tumor, nude mice liver, nephridial tissue after the medication of light Microscopic observation.
Inoculation Caski cell is after one week, and transplanted tumor in nude mice all grows to diameter and is about 0.3-0.5cm, transplanting succeed rate 100%.After YT30 treats 5 weeks, control group gross tumor volume is 639.37 ± 329.28mm
3, treatment group tumors volume is 88.14 ± 96.57mm
3, compared with control group, the inhibitory rate 85% for the treatment of group, tumor weight is also significantly less than control group, difference tool statistical significance (see Fig. 4 and table 3).
Table 3
In addition control group has 1 nude mice to occur metastasis.These changes illustrate that YT30 significantly can suppress the growth of Caski transplanted tumor.The generalized case for the treatment of group nude mice as the mental status, body weight etc. at treatments period without considerable change, hepatic and renal tissue form and weave construction normal.Liver cell is without inflammatory cell infiltration, and without sex change, hemorrhage, downright bad, central vein is without changes such as expansions; Glomerular epithelium without the change such as hyperplasia, hemorrhagic necrosis, uriniferous tubules without inflammatory cell infiltration, without sex change, hemorrhage, downright bad.This illustrates that 50mg/kg/d abdominal injection YT30 has good tolerance nude mice.The transplanted tumor growth in nodositas substantially, movable, control group oncocyte arrangement disorder under opticmicroscope, cellular form height atypia, differ in size, form is irregular, multinuclear, engrain, mitosis figures is common, and treatment group oncocyte volume-diminished, mitosis figures is relatively less.
Embodiment 5:
Transcription factor conditioning agent suppresses the growth of human cervical carcinoma SCID mouse transplanted tumor:
CB1 Reconstruction in Sever Combined Immunodeciency (SCID) female mice is adopted to repeat the experiment of YT30 cervical cancer inhibiting transplanted tumor in nude mice.Because control group occurs that transplanted tumor Tumor diameter is more than 1.5cm after YT30 abdominal injection treats 26 days, put to death all SCID mouse, other experimental procedure is identical with test example 2.Inoculation Caski cell is after one week, and SCID mouse transplanted tumor all grows to diameter about 0.5 ~ 0.7cm, transplanting succeed rate 100%.After YT30 treats 26 days, control group gross tumor volume is 799.63 ± 167.56mm
3, treatment group tumors volume is 415.37 ± 146.03mm
3, compared with control group, the inhibitory rate about 50% for the treatment of group, tumor weight is also significantly less than control group, difference tool statistical significance (see Fig. 5 and table 4).
Table 4
In addition control group has 1 SCID mouse to occur metastasis.These changes illustrate that YT30 significantly can suppress the growth of SCID mouse cervical cancer transplanted tumor.The generalized case for the treatment of group SCID mouse as the mental status, body weight etc. at treatments period without considerable change.
Last it is noted that the foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although with reference to previous embodiment to invention has been detailed description, for a person skilled in the art, it still can be modified to the technical scheme described in foregoing embodiments, or carries out equivalent replacement to wherein portion of techniques feature.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (6)
1. the compound application of lacking of proper care in the medicine of relevant cervical cancer or adjuvant therapy medicaments in preparation and the cofactor of transcription factor or transcription factor, it is characterized in that, the structure of described compound is shown below:
2. apply as claimed in claim 1, it is characterized in that: described compound as conditioning agent optionally in conjunction with the cofactor of transcription factor or transcription factor.
3. apply as claimed in claim 2, it is characterized in that: described transcription factor is jaw box protein P3 and/or myocyte enhancer factor 2.
4. apply as claimed in claim 2 or claim 3, it is characterized in that: the cofactor of described transcription factor is any one in calcineurin Binding Protein 1, histon deacetylase (HDAC), E1A associated proteins P300, CREB associated proteins, extracellular signal-regulated kinase 5, myogenic differentiation albumen, Smad albumen, nuclear factor of activated T cells, cardiac muscle element or positive transcriptional elongation factor b.
5. apply as claimed in claim 4, it is characterized in that: the effective dose of described compound is that every kilogram of raw object weighs 10
-6g-5g.
6. apply as claimed in claim 5, it is characterized in that: the route of administration of described compound is intravenous drip, intravenous injection, subcutaneous injection, subcutaneous embedding, oral administration, gastric infusion, external application administration and/or vagina administration.
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