CN109646679A - The purposes of iron chelator and its officinal salt - Google Patents
The purposes of iron chelator and its officinal salt Download PDFInfo
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Abstract
The present invention relates to field of medicaments, and in particular to the purposes of a kind of iron chelator and its officinal salt.Present invention discover that the expression of kinds of tumor cells surface PD-L1 can be effectively reduced in iron chelator and its officinal salt, release the mediation of PD-1/PD-L1 access includes melanoma, bladder cancer, non-small cell lung cancer, application in the immunosupress of kinds of tumors such as bladder cancer head and neck cancer, Hodgkin lymphoma, clear-cell carcinoma, Merkel cell cancer is different from the new application for treating certain diseases or symptom because caused by excessively being built up internal iron ion.
Description
Technical field
The present invention relates to field of medicaments, and in particular to the purposes of a kind of iron chelator and its officinal salt.Such as
La Luosi (Deferasirox), deferoxamine mesylate (Desferrioxamine), Deferiprone, L1NA11, Deferitrin or
Its officinal salt.
Background technique
Iron chelator includes any with medicinal usage, the controlling as chelated iron in the patient for needing iron to chelate
Agent is treated, including 3,5- diphenyl-1,2,4-triazoles derivative or its salt with formula (I),
Wherein R1And R5Simultaneously or it is independent of each other be hydrogen, halogen, hydroxyl, low alkyl group, Halo-lower alkyl, lower alkyl
Oxygroup, halogen-lower alkoxy, carboxyl, carboxyl, carbamoyl, N- elementary alkyl amido methanoyl, N, bis--lower alkyl of N-
Base carbamoyl or nitrile；R2And R4Simultaneously or it is independent of each other be hydrogen, unsubstituted or substituted low-grade alkane acidyl or aroyl or
The group that person can remove in physiological conditions；R3It is hydrogen, low alkyl group, hydroxy lower alkyl, Halo-lower alkyl, carboxylic
Base-low alkyl group, elementary alkoxy carbonyl-low alkyl group, R6R7N-C (O)-low alkyl group, unsubstituted or substituted aryl or virtue
Base-low alkyl group or unsubstituted or substituted heteroaryl or heteroarylalkyl；R6And R7Simultaneously or it is independent of each other be hydrogen, it is rudimentary
Alkyl, hydroxy lower alkyl, alkoxy-lower alkyl groups, hydroxy alkoxy base-low alkyl group, Amino-lower alkyl, N- lower alkyl
Base Amino-lower alkyl, N, N- bis--lower alkylamino-lower alkyl, N- (hydroxy lower alkyl) Amino-lower alkyl,
(hydroxy lower alkyl) Amino-lower alkyl of N, N- bis- or the nitrogen-atoms being bonded with them are formed together azepine alicyclic ring.
Deferasirox (4- [3,5- bis- (2- hydroxy phenyl) -1,2,4- triazol-1-yl] benzoic acid) is with salicylic acid for original
Material through multi-step chemical reaction synthesis, U.S. FDA approval first can conventional use of oral drive chalybeate, with trivalent iron
(Fe3+) there is high selectivity, the aglucon with 3 protrusions is mainly used for the ratio of 2:1 in conjunction with iron high-affinity
Reduce the chronic iron overload for receiving the patient of long-term transfusion because of the diseases such as β-thalassemia and other chronic anaemias.It is clinical
It proves that it, with good safety and tolerance, and can significantly reduce heart, liver iron load, is easy to be accepted by patients.Together
When, also there is antimycotic (mucor such as grown in rich ferrous environment), suppressing cell reproduction, anti-malarial, anti-oxidation stress
Damage, anti-cell poison such as induce cell apoptosis at the pharmacological profiles；It can be used for the diseases such as secondary hemochromatosis, porphyria cutanea tarda
The treatment of disease.
Deferoxamine mesylate is N- [5- [3- [(5- Aminopentyl) Hydroxycarboamoyl] propionamido] amyl] -3-
[[5- (N- hydroxyacetamido) amyl] carbamoyl] propionyl hydroxamic acid list methanesulfonates (salt) is crinosity streptomycete
The metabolite of (Stryptomyces pilosis), some of iron-containing amine substances are chemically treated, except after de-iron
It is made, belongs to hydroximic acid complexing agent, hydroxamic acid group is with the ratio of 1:1 and trivalent iron (Fe3+) high-affinity combination, it is mainly used for urgency
Property iron poisoning and chronic iron accumulate caused by disease.Its molecular weight is 656.79, structural formula are as follows:
Deferiprone is 3- hydroxyl -1,2- lutidines -4 (1H) -one, is mainly used for treatment tolerance or is unwilling to receive existing
The excessive patients with thalassemia of the iron load for thering is chelating agent to treat.
Deferitrin with following formula 4,5- dihydro -2- (2,4- dihydroxy phenyl) -4- methylthiazol -4 (S)-formic acid
Or GT56-252, L1NA11 are two generation Deferiprone (L1) classes with following formula 1- allyl -2- methyl -3- pyridone -4- ketone
Like object, they are also for treating the excessive Anemic patients of iron load.
In recent years, immunotherapy created several advanced cancer " clinical cure " miracles in succession, became " strong in anticancer struggle
Heart agent ".Wherein most noticeable, most commonly used clinical application is exactly the immune treatment of immunologic test point inhibitor PD-1/PD-L1
Method.In many advanced cancers, PD-1 receptor is the high expression in T cell, PD-L1 receptor late high table on tumour cell
It reaches, and PD-1 once docks success, PD-1/PD-L1 Pathway Activation with PD-L1, immunocyte can not play identification tumour cell
Effect, just will not offensive attack, tumour cell perfection escape, tumour immunity inhibit occur.PD-1/PD-L1 immunotherapy is just
It is that tumour control is realized by drugs block PD-1/PD-L1 access, the immune system attack tumour cell of human activin itself
With the purpose of healing.Researcher has confirmed that most of late tumor can all express PD-L1 receptor, this is that is, theoretical
Upper PD-1/PD-L1 immunotherapy can help to the treatment of multiple tumours.FDA approval PD-1/PD-L1 immune drug has had four
A is Nivolumab (Opdivo) respectively, Pembrolizumab (Keytruda), Atezolizumab (Tecentriq) and
Avelumab (Bavencio), the first two are anti-PD-1 antibody, latter two is anti-PD-L1 antibody, the granted treatment of these drugs
Kinds cancer.Although PD-1/PD-L1 immunotherapy shows curative effect in kinds cancer treatment, the above drug is antibody medicine,
It is compared to small-molecule drug, preparation, storage, transport and technical costs are higher, these lead to patient medication cost
It is excessively high；In addition the therapy only has 20%-40% for the effective percentage of most of cancer, can also be again after some patientss remission
The problem of recurrence, these virtually increase patient pressure, and some patients are had to take into account that in medication " with still not having to ".With
This is directed to invalid and Problems Concerning Their Recurrence simultaneously, scientists also further research and probe, for example improves PD- by conjoint therapy
The effective percentage of 1/PD-L1 immunotherapy extends curative effect lasting time, improves therapeutic effect.
In consideration of it, inventing or finding that one kind can be realized simultaneously tumor cytotoxicity and PD-1/PD-L1 immunotherapy joint
The small-molecule drug for the treatment of is the research topic with great practical application value and direction of a urgent need to resolve.
Summary of the invention
Present invention discover that iron chelator and its officinal salt can be effectively reduced kinds of tumor cells surface PD-L1's
Expression is different from the new application for treating certain diseases or symptom because caused by excessively being built up internal iron ion.
Therefore, according to the present invention, iron chelator and its officinal salt is provided to solve in preparation for tumor patient
The purposes on immunosuppressive drug mediated except PD-1/PD-L1.
Iron chelator includes any with medicinal usage, the controlling as chelated iron in the patient for needing iron to chelate
Treat agent.
Further preferably La Luosi (Deferasirox), deferoxamine mesylate (Desferrioxamine), Deferiprone,
L1NA11, Deferitrin or their officinal salt.
Shown in the Deferasirox and its main structure of derivative such as formula (I):
Wherein R1And R5Simultaneously or it is independent of each other be hydrogen, halogen, hydroxyl, low alkyl group, Halo-lower alkyl, lower alkyl
Oxygroup, halogen-lower alkoxy, carboxyl, carboxyl, carbamoyl, N- elementary alkyl amido methanoyl, N, bis--lower alkyl of N-
Base carbamoyl or nitrile；R2And R4Simultaneously or it is independent of each other be hydrogen, unsubstituted or substituted low-grade alkane acidyl or aroyl or
The group that person can remove in physiological conditions；R3It is hydrogen, low alkyl group, hydroxy lower alkyl, Halo-lower alkyl, carboxylic
Base-low alkyl group, elementary alkoxy carbonyl-low alkyl group, R6R7N-C (O)-low alkyl group, unsubstituted or substituted aryl or virtue
Base-low alkyl group or unsubstituted or substituted heteroaryl or heteroarylalkyl；R6And R7Simultaneously or it is independent of each other be hydrogen, it is rudimentary
Alkyl, hydroxy lower alkyl, alkoxy-lower alkyl groups, hydroxy alkoxy base-low alkyl group, Amino-lower alkyl, N- lower alkyl
Base Amino-lower alkyl, N, N- bis--lower alkylamino-lower alkyl, N- (hydroxy lower alkyl) Amino-lower alkyl,
(hydroxy lower alkyl) Amino-lower alkyl of N, N- bis- or the nitrogen-atoms being bonded with them are formed together azepine alicyclic ring.
Further preferably Deferasirox (4- [3,5- bis- (2- hydroxy phenyl) -1,2,4- triazol-1-yl] benzoic acid).
Contain any one or more of iron chelator and officinal salt described above as therapeutic component, is prepared
Medicinal preparation for oral administration or liposome, albumin, high molecular polymer, inorganic nanoparticles auxiliary preparation Nano medication inject system
Agent or application or spray formulation, or with the united composition of other drugs.
Patient to be treated can suffer from melanoma, bladder cancer, non-small cell lung cancer, bladder cancer head and neck cancer, Huo Qijin
The highly expressed tumour of the PD-L1/PD-1 access such as lymthoma, clear-cell carcinoma or Merkel cell cancer.
The beneficial effects of the present invention are:
Present invention discover that iron chelator and its officinal salt can be effectively reduced kinds of tumor cells surface PD-L1's
Expression, release that PD-1/PD-L1 mediates includes melanoma, bladder cancer, non-small cell lung cancer, bladder cancer head and neck cancer, suddenly
Application in the immunosupress of kinds of tumors such as odd gold lymthoma, clear-cell carcinoma, Merkel cell cancer, be different from treatment it is certain because
Internal iron ion excessively build up caused by disease or symptom new application.
Detailed description of the invention
Invention is further described in detail with reference to the accompanying drawings and detailed description.
Fig. 1 is for various concentration Deferasirox at 6 hours and 24 hours to B16F10 cell killing toxicity figure.
Fig. 2 is the expression schematic diagram that Deferasirox reduces B16F10 Cellular immunity suppression checkpoint PD-L1.
Fig. 3 be control group and medication group murine melanoma treatment results figure, wherein A be intravenously administrable Deferasirox and
Mouse weight and time of measuring figure after vein PBS, B are mouse tumor volume and survey after intravenously administrable Deferasirox and vein PBS
Time diagram is measured, C is the melanoma HE colored graph of mouse after vein PBS, and D is the melanin of mouse after intravenously administrable Deferasirox
Tumor HE colored graph.
Fig. 4 be treatment end after take respectively the HE tissue paraffin section de of control group and medication group mouse different organs tissue with
The HE tissue paraffin section de comparison diagram of healthy mice.
Fig. 5 measures its every biochemical indicator test chart to take control group and medication group mouse blood respectively after treatment end.
Fig. 6 is that tumor tissues PD-L1 immunohistochemistry and CD8+ cellular immunofluorescence analyze result figure.
Fig. 7 is the double melanoma tumor model Inhibition test figures of mouse.
Specific embodiment
The present invention is illustrated with following embodiment.
Embodiment Deferasirox (4- [3,5- bis- (2- hydroxy phenyl) -1,2,4- triazol-1-yl] benzoic acid) is used for black
Plain tumor test
1, vitro cytotoxicity is tested
After digesting B16F10 cell with pancreatin, it is made into 105A/mL cell suspension, every 100 μ L of hole are inoculated into 96 orifice plates,
After culture 18-24 hours, different final concentration (120/60/30/15/0 μM) Deferasirox are separately added into, continue culture 6 hours, benefit
With thiazolyl blue (MTT) colorimetric determination cell survival rate (survival rate (%)=(test hole OD value/control wells OD value) ×
100%), in triplicate.
2, Western Blot detects the influence that Deferasirox expresses PD-L1 on B16F10 cell
B16F10 cell after being digested with pancreatin, every hole 2mL are inoculated into 6 orifice plates, and 30 μM of ends are separately added into after 18-24 hours
Concentration Deferasirox continues culture 6 hours, and after PBS is cleaned 2-3 times, 100 μ L cell pyrolysis liquids are added in every hole, gently with cell scraper
Scraping, is put in EP pipe with liquid-transfering gun taking-up, places sufficiently cracking in 15 minutes, 1.2*10 on ice4Rpm/min low-temperature centrifugation
10min, after taking supernatant, BCA protein detection kit to measure concentration, packing is stored in -20 DEG C.When carrying out Western Blot,
It keeping under the protein content unanimous circumstances of each hole electrophoresis duct, PD-L1 antibody handles pvdf membrane, after HRP secondary antibody is incubated for, developing solution
Processing, Multifunctional imaging instrument shoot photo, analyze data using ImageJ.
3, the building of melanoma tumors model
To be generated when growing to 80%-90% by B16F10 cell inoculation in 10cm Tissue Culture Dish, PBS is cleaned 2-3 time, use
Pancreatin is digested into centrifuge tube, and PBS is cleaned 2-3 times, is counted, being made into concentration with PBS is 5*107The cell suspension of/mL.It chooses
The BALB/c female mice of 18-20g, locally after depilation, the cell suspension that 100 μ L are prepared is subcutaneously injected in back, to long to 300-
400mm3Start to treat.The every other day variation of measurement mouse weight and tumor size.
Double tumor models are to inject the cell suspension that 100 μ L are prepared respectively at left and right back, to long to 300-400mm3It opens
Begin to treat.Only in left side intratumor injection drug.
4, histology
In treatment end, major organs (heart, liver, spleen, lungs, kidney and swollen are harvested from every group of mouse
Tumor), and be fixed on formalin in 5% neutral buffered liquid, paraffin embedding is cut into the slice with a thickness of 5 μm, hematoxylin and she
Red (H&E) dyeing, passes through microexamination histopathology.
5, biochemical index
Each group mice serum biochemical indicator is detected after treatment end, takes blood (about 0.5mL/ sample) to collect by mouse orbit
Blood sample.It is put into centrifuge tube, stands 20 minutes at room temperature, with 3000rpm/min centrifugation 10 minutes, separate upper serum sample
Product and the sample cell being transferred to after label.Biochemical Indices In Serum includes alanine aminotransferase (ALT), and aspartic acid amino turns
It moves enzyme (AST), blood urea nitrogen (BUN), albumin (ALB) and kreatinin (CER), microelement (Ca, K, Fe, P, Mg, Zn, Cl)
Automatic biochemistry analyzer is measured by Hitachi7020.
6, tumor tissues PD-L1 immunohistochemistry and CD8+ cellular immunofluorescence are analyzed
Drug treatment after a week, is taken each group mouse tumor, is cleaned up, and filter paper suck dry moisture is put in mold, with suitable
It measures OCT embedding medium and embeds tumor tissues, be put in after being rapidly frozen in liquid nitrogen, be transferred to -80 DEG C of refrigerators and save.Frozen section
Afterwards, the variation of histogenic immunity fluorescence analysis active t cell quantity is done with AF647-CD8+ antibody respectively, pays attention to being protected from light in the process；With
After PD-L1 antibody and HRP-IgG secondary antibody are incubated for, ABC color development treatment is used for immunohistochemical analysis, measures in tumor tissues
The variation of PD-L1 expression quantity, the print handled well are observed under the microscope.
Fig. 1 is for various concentration Deferasirox at 24 hours to B16F10 cell killing toxicity figure.As shown in Figure 1: drawing on ground
Sieve department can inhibit B16F10 cell to grow.
Fig. 2 is the expression schematic diagram that Deferasirox reduces B16F10 Cellular immunity suppression checkpoint PD-L1.As shown in Figure 2:
Deferasirox can reduce the expression of B16F10 Cellular immunity suppression checkpoint PD-L1.
Fig. 3 be control group and medication group murine melanoma treatment results figure, wherein A be intravenously administrable Deferasirox and
Mouse weight and time of measuring figure after vein PBS, B are mouse tumor volume and survey after intravenously administrable Deferasirox and vein PBS
Time diagram is measured, C is the melanoma HE colored graph of mouse after vein PBS, and D is the melanin of mouse after intravenously administrable Deferasirox
Tumor HE colored graph.As shown in Figure 3: mouse list melanoma tumor model is established, to tumour in 300mm3When left and right, start to be injected intravenously
Treatment, about 0.98mg/kg, is every other day injected once every time, and totally six times, administration process has not significant impact mouse weight,
Tumour starts to be suppressed after being administered second, volume start it is smaller, until the 14th day tumour disappears substantially after treatment, with skin
It flushes.The melanoma HE coloration result of comparison injection PBS and Deferasirox, it can be seen that the tissue of medication group tumour is broken
It is bad, from mouse test results it can be seen that Deferasirox has a good therapeutic effect for late tumor tool.
Fig. 4 be treatment end after take respectively the HE tissue paraffin section de of control group and medication group mouse different organs tissue with
The HE tissue paraffin section de comparison diagram of healthy mice.As shown in Figure 4: mouse list melanoma tumor model after treatment end, takes respectively
Different control groups and experimental mice organs and tissues prepare HE tissue paraffin section de, control as can be seen from the results through Deferasirox
After treatment, each mice organs are without clearly visible damage.
Fig. 5 measures its every biochemical indicator test chart to take control group and medication group mouse blood respectively after treatment end.
As shown in Figure 5: mouse list melanoma tumor model inhibits to test, and after treatment end, takes different control groups and experimental mice respectively
Blood measures its every biochemical indicator, and after treating as can be seen from the results through Deferasirox, each mouse ALT, ALB, CRE are equal
Within critical field, illustrate that treat institute's dosage main organs each for mouse influences without significant organic again.It considers
Deferasirox is a kind of metal ion chelation agent, we have detected each treatment group's mice serum trace element change, by comparing
It was found that illustrating the safety of medication again from another point of view without more apparent variation for Ca, Fe, K, Mg, Zn, Na, Cl, P
Property and very little toxic side effect.
Fig. 6 is that tumor tissues PD-L1 immunohistochemistry is analyzed with CD8+ cellular immunofluorescence as a result, passing through as can be seen from the results
After Deferasirox treatment, tumor tissues PD-L1 expression quantity is significantly reduced, and CD8+ quantity increases, and illustrates the use of Deferasirox
PD-L1 is inhibited to express, the immunosupress for having blocked tumour PD-L1/PD-1 access to mediate has activated immunological effect, T lymph is exempted from
Epidemic disease cell is recruited and activates.
Fig. 7 is the double melanoma tumor model Inhibition test figures of mouse.As shown in Figure 7: the double melanoma tumor models of mouse inhibit real
It tests, left side intratumor injection drug, after the intratumor injection drug of left side, right side tumor shows the effect of the inhibition as the tumor of left side
Fruit can speculate that the medicine excites the immunity function of body again.
Obviously, the above embodiments are merely examples for clarifying the description, and does not limit the embodiments.It is right
For those of ordinary skill in the art, can also make on the basis of the above description it is other it is various forms of variation or
It changes.There is no necessity and possibility to exhaust all the enbodiments.And it is extended from this it is obvious variation or
It changes still within the protection scope of the invention.
Claims (7)
1. iron chelator and its officinal salt are in preparation for tumor patient in the immune suppression for releasing PD-1/PD-L1 mediation
Purposes on pharmacy object.
2. purposes according to claim 1, which is characterized in that the iron chelator includes any with medicinal usage
, the therapeutic agent in the patient for needing iron to chelate as chelated iron.
3. purposes according to claim 1, which is characterized in that the iron chelator is Deferasirox, methanesulfonic acid is gone
Sideramines, Deferiprone, L1NA11, Deferitrin or their officinal salt.
4. purposes according to claim 3, which is characterized in that the Deferasirox and its main structure of officinal salt such as formula
(I) shown in:
Wherein R1And R5Simultaneously or it is independent of each other be hydrogen, halogen, hydroxyl, low alkyl group, Halo-lower alkyl, rudimentary alcoxyl
Base, halogen-lower alkoxy, carboxyl, carbonyl, carbamoyl, N- elementary alkyl amido methanoyl, N, bis--low alkyl group of N-
Carbamoyl or nitrile；R2And R4Simultaneously or it is independent of each other be hydrogen, unsubstituted or substituted low-grade alkane acidyl or aroyl or
The group that can remove in physiological conditions；R3It is hydrogen, low alkyl group, hydroxy lower alkyl, Halo-lower alkyl, carboxyl-
Low alkyl group, elementary alkoxy carbonyl-low alkyl group, R6R7It is N-C (O)-low alkyl group, unsubstituted or substituted aryl, unsubstituted
Or aryl lower alkyl, unsubstituted or substituted heteroaryl or the unsubstituted or substituted heteroarylalkyl replaced；R6And R7Together
When or it is independent of each other be hydrogen, low alkyl group, hydroxy lower alkyl, alkoxy-lower alkyl groups, hydroxy alkoxy base-lower alkyl
Base, Amino-lower alkyl, N- lower alkylamino-lower alkyl, N, N- bis--lower alkylamino-lower alkyl, N- (hydroxyl
Base-low alkyl group) Amino-lower alkyl, N, it N- bis- (hydroxy lower alkyl) Amino-lower alkyl or is bonded with them
Nitrogen-atoms is formed together azepine alicyclic ring.
5. purposes according to claim 1, which is characterized in that the iron chelator is Deferasirox (4- [3,5- bis-
(2- hydroxy phenyl) -1,2,4- triazol-1-yl] benzoic acid).
6. purposes according to claim 3 or 4, which is characterized in that contain any one or more of iron ion described above
Chelating agent and officinal salt as therapeutic component, the medicinal preparation for oral administration or liposome that are prepared, albumin, high molecular polymer,
The Nano medication ejection preparation or application or spray formulation of inorganic nanoparticles auxiliary preparation, or with united group of other drugs
Close object.
7. purposes according to claim 1, which is characterized in that the tumor patient is with melanoma, bladder cancer, non-
Small Cell Lung Cancer, bladder cancer head and neck cancer, Hodgkin lymphoma, clear-cell carcinoma or Merkel cell cancer it is immune by PD-L1/PD-1
The patient of inhibition.
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Cited By (4)
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| CN111450085A (en) * | 2020-05-22 | 2020-07-28 | 颜廷良 | Broad-spectrum anti-tumor medicine and preparation method and application thereof |
| CN112773777A (en) * | 2020-12-30 | 2021-05-11 | 中国科学院长春应用化学研究所 | cRGD-DFX-BSA-NPS nano particle and preparation method and application thereof |
| CN115057827A (en) * | 2022-07-20 | 2022-09-16 | 河南大学 | Deferasirox derivative, synthesis method thereof and application thereof in preparation of medicines for diagnosing and treating iron-overload hepatocellular carcinoma |
| CN115429881A (en) * | 2022-09-02 | 2022-12-06 | 中国医学科学院基础医学研究所 | Iron chelators for treatment of tumors with beta-catenin activating mutations |
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| CN111450085A (en) * | 2020-05-22 | 2020-07-28 | 颜廷良 | Broad-spectrum anti-tumor medicine and preparation method and application thereof |
| CN112773777A (en) * | 2020-12-30 | 2021-05-11 | 中国科学院长春应用化学研究所 | cRGD-DFX-BSA-NPS nano particle and preparation method and application thereof |
| CN115057827A (en) * | 2022-07-20 | 2022-09-16 | 河南大学 | Deferasirox derivative, synthesis method thereof and application thereof in preparation of medicines for diagnosing and treating iron-overload hepatocellular carcinoma |
| CN115429881A (en) * | 2022-09-02 | 2022-12-06 | 中国医学科学院基础医学研究所 | Iron chelators for treatment of tumors with beta-catenin activating mutations |
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