CN105769855B - Meroterpenoids compound D1399 is preparing the application in anti-breast cancer medicines - Google Patents
Meroterpenoids compound D1399 is preparing the application in anti-breast cancer medicines Download PDFInfo
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- CN105769855B CN105769855B CN201610144721.9A CN201610144721A CN105769855B CN 105769855 B CN105769855 B CN 105769855B CN 201610144721 A CN201610144721 A CN 201610144721A CN 105769855 B CN105769855 B CN 105769855B
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides meroterpenoids compound D1399 to prepare the application in anti-breast cancer medicines, shown in the structural formula such as formula (I) of the meroterpenoids compound D1399.The present invention is evaluated by external MTT antineoplastic activity and is found, D1399 has significant inhibiting effect to Breast cancer lines MDA-MB-435.Preliminary Study on mechanism shows the endogenous and extrinsic pathway inducing apoptosis of tumour cell that D1399 can be relied on by Caspase simultaneously.Therefore, the D1399 can be applied to prepare anti-breast cancer medicines, and with good development and application prospects,
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, are preparing more particularly, to a kind of meroterpenoids compound D1399
Application in anti-breast cancer medicines.
Background technique
In various diseases, cancer is one of principal disease of causing death.According to WHO report, there are about 600 every year in the whole world
Ten thousand people are devitalized by cancer, estimate that the year two thousand twenty will rise to 10,000,000 people.Breast cancer is the common malignant tumour of women, morbidity
Rate was in slow ascendant trend in past 50 years, and in many western countries, the disease incidence of breast cancer accounts for the head of female cancer
Position.Increase year by year in the health burden of China, cancer, is diagnosed as cancer per year over 1600000 people, 1,200,000 is dead due to cancer.
As other most countries, breast cancer also becomes the most common cancer of Chinese women；Annual Chinese Breast Cancer newly sends out number
Amount and The dead quantity account for global 12.2% and 9.6% respectively.
At present treatment malignant tumour main method include: operative treatment, the chemotherapy of anticancer drug, radiotherapy and
Biological response modifiers and other treatments.Wherein chemotherapy occupies irreplaceable status in treating malignant tumor.For mammary gland
Cancer commonly uses treatment means mainly based on traditional operative treatment, the postoperative radiotherapy being aided with locally or systemically, chemotherapy and interior point
Treatment is secreted, wherein chemotherapy is to treat the important complementary means of breast cancer, and chemotherapy can be substantially reduced the postoperative recurrence of breast cancer
Rate, losing radical cure chance person to advanced breast cancer also has apparent remission rate using chemotherapy.But due to anti-malignant tumor medicine
Poor selectivity, toxic side effect is big, causes malignant tumor patient immunologic hypofunction, and quality of life reduces, this makes chemotherapeutic
The use of object is subject to certain restrictions.Therefore, from different approaches find efficient, low toxicity, special anti-tumor drug is still tumour
The task of top priority of drug therapy.With the development of Cell. Mol, cancer can be defined as to cell cycle abnormality disease.
Some or certain several links that cancer can be regarded as cell cycle regulation or Apoptosis from cellular level get muddled,
Make a kind of cancerization cell unlimitedly blindly state of unordered proliferation.Cell death inducer can pass through the life of regulating cell apoptosis
Object process, the state of control and the unordered proliferation of correction cancerization cell blindness.Therefore, new cell death inducer is possible to develop
The chemotherapeutics of Cheng Xin be used for treating cancer, and detect apoptosis-inducing effect index of biological activity then can be used for screen and
It was found that new anti-cancer active matter.
Mixing source of students terpene (mixed source terpene) be it is a kind of mixed to be coupled by polyisoamylene approach and other biosynthesis pathways produced
Raw mixed source metabolite.Numerous heteroatomic introducings are often had in the biosynthetic process of mixed source metabolite, make score
Different polar centers are formed in minor structure, there is stronger reactivity, thus are easy to combine with large biological molecule.Cause
This, meroterpenoids compound has been the important sources of lead compound.
Summary of the invention
It is an object of the invention to according to deficiency in the prior art, provide a kind of meroterpenoids compound D1399 to exist
Prepare the application in anti-breast cancer medicines.
The present invention reports D1399 in vitro to the inhibiting effect and primary action mechanism of human breast cancer cell growth, is
The antitumor novel drug candidate further developed lays the foundation.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
The present invention provides a kind of meroterpenoids compound D1399 to prepare the application in anti-breast cancer medicines, described mixed
Shown in the structural formula such as formula (I) of source terpenoid D1399:
Meroterpenoids compound D1399 molecular weight of the invention is 503.Its structure uses nuclear magnetic resonance (H-NMR, 13C-
NMR, HSQC, HMBC), the Modern spectroscopies technology such as high resolution mass spectrum (ESI-MS) is measured.The synthetic method of D1399 can join
Examine the prior art, such as US20040127540A.
The present invention proves that D1399 has very strong anti-tumor activity by experiment in vitro, can be used as treatment breast cancer etc. its
The lead compound of his entity tumor can be used for preparing anti-tumor drug.
Further, the present invention has found that the D1399 is to human breast cancer cell in anti-breast cancer test cell line in vitro
The IC of MDA-MB-435 growth inhibition effect50It is 0.89 μM, it is external to inhibit breast cancer cell growth activity significant.
Therefore, the present invention provides one kind and carries out compound joint to cancered any mammal (the especially mankind) is suffered from
The method for the treatment of, this method include giving the compounds of this invention or its Pharmaceutical composition of bacterium.
Further, the drug further includes pharmaceutically acceptable carrier or diluent.
" pharmaceutically acceptable carrier " refers to the non-active ingredient in drug, such as, but not limited to: calcium carbonate, calcium phosphate,
Various sugar (such as lactose, mannitol etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylate copolymer or first
Base acrylate copolymer, gel (gelatin), water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or rilanit special or more
Ethoxy aluminium castor oil, sesame oil, corn oil, peanut oil etc..
" pharmaceutically acceptable diluent " such as starch (such as cornstarch, wheaten starch, potato starch), lactose,
Dextrin, sucrose, pregelatinized starch, microcrystalline cellulose, inorganic salts (such as calcium monohydrogen phosphate, calcium sulfate, residual sour calcium) and mannitol
Deng.
Drug can be any one pharmaceutically acceptable dosage form.Including have suitably form any solid (tablet,
Pill, capsule, granule) etc. or liquid (solution, suspension or emulsion) or oral, local administration or parenteral give
Medicine, they may include the pure compound or combine with any carrier or other pharmacologically active chemical compounds.Work as progress
When parenteral administration, need to carry out sterilization treatment to these compositions.
The administration of the compounds of this invention or composition can be carried out by any method appropriate, and such as venoclysis takes orally
In preparation, peritonaeum and intravenous administration.Our preferred Infusion Times are up to 48 hours.Medicinal group comprising the compounds of this invention
Close object can by a manner of liposome or nanoparticles packing in controlled-release formulation or by other standard transfer modes carry out to
Medicine.
The correct dose of the compound according to specific dosage form, application model and concrete position, patient and will be treated
Tumour and change, also need consider other factors such as age, weight, gender, diet, administration time, discharge rate, patient's disease
Shape, drug combine, reaction sensibility and disease severity, can within the scope of maximum permissible dose (MPD) successive administration or periodically
Administration.
The compound of the present invention and composition can be used together to provide combination therapy with other medicines.Other medicines
Object can form a part of the same composition, or as single formulation same time or different time carry out to
The characteristic of other medicines is not particularly limited in medicine.
Compared with prior art, the invention has the following advantages:
Present invention finds meroterpenoids compound D1399 to prepare the new opplication in anti-breast cancer medicines, resists in vitro
In breast cancer cell growth model, by blue (MTT) colorimetric determination of tetramethyl ribavirin to D1399 to human breast cancer cell
The IC of MDA-MB-435 growth inhibition effect50It is 0.89 μM, it is external to inhibit breast cancer cell growth activity significant.
By the research of the molecular mechanism to D1399 anti-breast cancer, show D1399 by influencing breast cancer cell
The expression quantity of Caspase3, Caspase8, Caspase9, PARP albumen induces cell apoptosis the activity to realize anti-breast cancer,
Further increasing it becomes the possibility of candidate anti-breast cancer medicines, has established theoretical basis for further clinical test.
Detailed description of the invention
When Fig. 1 is that human breast cancer cell MDA-MB-435 is different through the D1399 effect of various concentration in the embodiment of the present invention 1
Between after morphological change result figure.
Fig. 2 is that TUNEL immunofluorescence staining detects D1399 inducing mammary cancer cell MDA-MB- in the embodiment of the present invention 3
The biological activity figure of 435 apoptosis.
Fig. 3 is that TUNEL immunofluorescence staining detects D1399 inducing mammary cancer cell MDA-MB- in the embodiment of the present invention 3
The count results figure of the positive cell of the control group and administration group of 435 apoptosis.
Fig. 4 is that Western Blotting technology detection D1399 processing human breast cancer cell is utilized in the embodiment of the present invention 3
The figure of the expression of apoptosis-related protein after MDA-MB-435.
Specific embodiment
Further illustrate the present invention below in conjunction with specific embodiment, but embodiment the present invention is not done it is any type of
It limits.Unless stated otherwise, the present invention uses reagent, method and apparatus is the art conventional reagents, method and apparatus.
Unless stated otherwise, agents useful for same and material of the present invention are commercially available.
1 D1399 of embodiment is grown to human breast carcinoma MDA-MB-435 cell and the influence of form
It is counted after MDA-MB-435 cell dissociation, by every hole 2.0 × 106A cell is seeded to respectively in P60 culture dish, is set
In 37 DEG C, 5%CO2Culture is incubated in incubator.Be changed to afterwards for 24 hours be followed successively by containing concentration 0,2,4 μM D1399 culture medium, point
After not continuing culture 3,6,9h, the variation of cellular morphology and growth is observed under inverted microscope.
As shown in Figure 1, D1399, which has the growth of human breast carcinoma MDA-MB-435 cell, significantly inhibits effect.2μM
After D1399 handles 3h, MDA-MB-435 cell density is substantially reduced compared with control group, with the increase of drug concentration, cell density
It further significantly reduces, after 6h, cell starts shrinkage occur, obscission, and after 8h, cell is floated, the phenomena of mortality.8μM
After D1399 handles 2h, MDA-MB-435 cell density is substantially reduced compared with control group, with the increase of drug concentration, cell density
It further significantly reduces, mortality occurs in cell after 8h.D1399 has human breast carcinoma MDA-MB-435 cell growth inhibition
Certain concentration dependent and time dependence.There is typical cell in amplification 200 × observable cell under an optical microscope
Apoptosis morphological change, attached cell start volume occur to become smaller, and deform, shrinkage is rounded, falls off.It puts under an optical microscope
There is alveolation phenomenon in the after birth of big 400 × observable cast-off cells.
2 D1399 of embodiment inhibits the dose-effect relationship of human breast cancer cell growth
1, the life using tetramethyl ribavirin indigo plant (MTT) colorimetric determination D1399 to human breast cancer cell MDA-MB-435
Long influence
MTT colorimetric method specific experiment step: will count after human breast cancer cell MDA-MB-435 digestion, by every hole 1.0 ×
104A cell is seeded to respectively in 96 porocyte culture plates, is placed in 37 DEG C, 5%CO2Culture is incubated in incubator.It is changed to afterwards for 24 hours
The culture medium of 0,0.08,0.4,2,10,50 μM of D1399 is followed successively by containing concentration, each concentration is all provided with 3 parallel multiple holes, continues
After cultivating 48h, the variation of microscopically observation cellular morphology and growth.Then every hole is added 20 μ L of 5mg/mL MTT solution, and 37
DEG C effect 4h, abandons supernatant after centrifugation, be added 200 μ L of DMSO, and it is sufficiently dissolving crystallized that oscillator vibrates 10min, sets in microplate reader
Measuring wavelength is the absorbance A value under 490nm, calculates inhibiting rate as follows.Inhibitory rate of cell growth (%)=(control group
Average A-value-experimental group average A-value)/control group average A-value × 100%.The culture hole that control group, that is, D1399 concentration is 0, application
SPSS software carries out data statistic analysis, and calculation of half inhibitory concentration (IC50)。
By MTT colorimetric determination to D1399 to the IC of the growth inhibition effect of human breast cancer cell MDA-MB-43550For
It is 0.89 μM, external to inhibit breast cancer cell growth activity significant.
The research of 3 D1399 anti-breast cancer mechanism of embodiment
1. detecting D1399 body using the Nick End labelling method (TUNEL) that deoxyribonucleotide terminal enzyme (DNA) mediates
The apoptosis of outer inducing mammary cancer cell
It will be counted after MDA-MB-435 cell dissociation, by every hole 1.0 × 105A cell is seeded to respectively has been covered with coverslip
24 porocyte culture plates in, handle cell with 3 μM, 4.5 μM, 6 μM of D1399 afterwards for 24 hours.Culture medium is discarded after 7h, with 4% first
Aldehyde fixes cell 30min, is washed three times with PBS, each 5min.Then 25min, PBS washing are handled with 1%TritonX-100
Three times, each 5min.Cell is covered with 100 μ l equilibration buffers, after 5~10min of equilibrium at room temperature, inhales and abandons equilibration buffer,
After 50 μ l TdT reaction buffers are added on cell, is covered with plastic coverslip to prevent reaction solution from volatilizing on cell, will be trained
Feeding plate, which is placed in wet box, is protected from light 60min in 37 DEG C.It inhales and abandons reaction solution, 2 × SSC room temperature is added and acts on 15min, is washed with PBS
It washs three times, each 5min.Finally the cells from light on coverslip is dried overnight, next day adds the Anti-Fade mounting containing DAPI.
It is observed and is taken pictures under fluorescence microscope and save picture, TUNEL stained positive fluorescence signal is in green, DAPI fluorescence signal
It is blue, and percentage is calculated after taking ten visuals field to carry out the counting of TUNEL staining positive cells, count soft using SPSS 10.0
Part is analyzed, and comparison among groups use one-way analysis of variance, and checkout procedure is indicated with p < 0.05 with statistical significance.
As shown in Fig. 2,3 and 4, detect human breast cancer cell MDA-MB-435 respectively through 1 μM, 2 μM and 4 μ by TUNEL
After the D1399 of M is acted on 6 hours, there is the cell of different degrees of TUNEL stained positive in experimental group, respectively 12.44%,
24.31% and 38.38%；And control group has no that TUNEL stained positive occurs without the cell that D1399 is acted on substantially.
2. the expression of Western blot (Western Blotting) detection apoptosis-related protein
It will be counted after MDA-MB-435 cell dissociation, by every hole 2.0 × 106A cell is seeded to respectively in P60 culture dish,
It is placed in 37 DEG C, 5%CO2Culture is incubated in incubator.Be changed to afterwards for 24 hours be followed successively by containing concentration 0,2,4 μM D1399 culture medium,
Respectively in 0,6,16, collection cell and supernatant, PBS washing 3 times afterwards for 24 hours, the cell pyrolysis liquid processing containing 6%SDS is added.It utilizes
BCA kit measurement protein content.Then protein electrophoresis is carried out, glue 60V, separation gel 80V is concentrated.Electrophoresis is reached to bromophenol blue to be divided
When from glue bottom, albumen is gone into PDVF film, 70V pressure stabilizing electrotransfer 3 hours.After 5% skimmed milk power room temperature is closed 1 hour, 1:
500 are added anti-human 4 DEG C of Caspase9, Caspase8 and PARP antibody overnight incubations.It is washed 3 times, every time 15 minutes with TBST.It is peppery
The secondary antibody of root peroxidase labelling is incubated at room temperature 1 hour.It is washed 3 times, every time 15 minutes with TBST again.It is pressed in darkroom
Film and substrate luminescent solution are incubated at room temperature 1 minute by 0.05mL/cm, tabletting clip sheet 30min, and developing machine exposure is developed a film.
By Western Blotting technology further to apoptosis after D1399 processing human breast cancer cell MDA-MB-435
The precursor and cutting belt of GAP-associated protein GAP Caspase9, Caspase8, Caspase3 and PARP are detected, and discovery is dense with drug
The increase of degree and the extension for handling the time, the precursor of above-mentioned albumen gradually decrease, and cutting belt gradually increases, and illustrate that apoptosis correlation is believed
Number access is activated, and is detailed in Fig. 4.Control of the GAPDH as loading.As a result the MDA-MB-435 cell after illustrating D1399 effect
Apoptosis is occurred by the Caspase endogenous relied on and extrinsic pathway simultaneously.
Claims (4)
1. meroterpenoids compound D1399 is preparing the application in anti-breast cancer medicines, which is characterized in that the meroterpenoids
Shown in the structural formula such as formula (I) for closing object D1399:
(I).
2. application according to claim 1, which is characterized in that the dosage form of the drug be tablet, pill, capsule,
Granula, solution, suspension or emulsion.
3. application according to claim 1, which is characterized in that the drug further includes pharmaceutically acceptable carrier.
4. application according to claim 1, which is characterized in that the drug further includes pharmaceutically acceptable diluent.
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| Title |
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| Pyrrocidine A, a metabolite of endophytic fungi, has a potent apoptosis-inducing activity against HL60 cells through caspase activation via the Michael addition;Shota Uesugi等;《The Journal of Antibiotics》;20151028;第69卷;第133-140页 * |
| Pyrrospirones A and B, apoptosis inducers in HL-60 cells, from an endophytic fungus, Neonectria ramulariae Wollenw KS-246;Yoshihito Shiono等;《Bioorganic & Medicinal Chemistry Letters》;20081011;第18卷;第6050-6053页 * |
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