CN113456797B - Application of vinblastine derivatives in preparation of medicines for treating osteosarcoma and/or soft tissue sarcoma - Google Patents
Application of vinblastine derivatives in preparation of medicines for treating osteosarcoma and/or soft tissue sarcoma Download PDFInfo
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- CN113456797B CN113456797B CN202110679780.7A CN202110679780A CN113456797B CN 113456797 B CN113456797 B CN 113456797B CN 202110679780 A CN202110679780 A CN 202110679780A CN 113456797 B CN113456797 B CN 113456797B
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- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical class C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 title claims abstract description 52
- 201000008968 osteosarcoma Diseases 0.000 title claims abstract description 45
- 206010039491 Sarcoma Diseases 0.000 title claims abstract description 43
- 208000021712 Soft tissue sarcoma Diseases 0.000 title claims abstract description 42
- 239000003814 drug Substances 0.000 title claims abstract description 23
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- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims abstract description 41
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- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 abstract description 4
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- VZUNGTLZRAYYDE-UHFFFAOYSA-N N-methyl-N'-nitro-N-nitrosoguanidine Chemical compound O=NN(C)C(=N)N[N+]([O-])=O VZUNGTLZRAYYDE-UHFFFAOYSA-N 0.000 description 1
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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
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of vinblastine derivatives in preparation of medicines for treating osteosarcoma and/or soft tissue sarcoma. The vinblastine derivative comprises vinblastine dipeptide and physiologically acceptable salts thereof; the vinblastine dipeptide is a compound obtained by condensing a hydrazinolysis vinblastine compound and N-benzyloxycarbonyl dipeptide; the hydrazinolysis vinblastine compound is a compound obtained by reacting a vinblastine compound with hydrazine hydrate; the vinblastine compound is vinblastine, vinorelbine, vinflunine or vincristine. The vinblastine dipeptide and its physiologically acceptable salts can remarkably inhibit proliferation, invasion and migration of osteosarcoma and soft tissue sarcoma cells in vitro, inhibit in-situ growth and pulmonary metastasis of osteosarcoma and soft tissue sarcoma cells in vivo, and can be used for treating osteosarcoma and soft tissue sarcoma patients.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of a vinblastine derivative in preparation of medicines for treating osteosarcoma and/or soft tissue sarcoma.
Background
Osteosarcoma and soft tissue sarcoma are malignant tumors originating in mesenchymal tissue, and have extremely high metastasis and recurrence rates. Surgery and chemotherapy are the primary treatments for osteosarcomas and soft tissue sarcomas. Cisplatin, cyclophosphamide, doxorubicin and methotrexate are first-line drugs for osteosarcoma chemotherapy, whereas doxorubicin and ifosfamide constitute the two major stones for soft tissue sarcoma chemotherapy. The chemotherapy can improve the survival rate of patients with osteosarcoma to 60-70% within 5 years, while the survival rate of patients with soft tissue sarcoma is still lower than 10%. Osteosarcoma and soft tissue sarcoma are mainly transferred to the lung by hematogenous metastasis, with survival rates of less than 20% in 5 years for patients with lung metastasis. The large dose of the chemotherapeutic drug can cause adverse reactions such as nausea, vomiting, bone marrow suppression, cardiotoxicity and the like to patients, which leads to poor patient compliance and low quality of life. Therefore, the development of low-toxicity and high-efficiency targeted therapeutic drugs has important significance in the treatment of osteosarcoma and soft tissue sarcoma.
The enzyme-activated prodrug can improve the targeting of the parent drug to the enzyme expression cells and reduce the toxic and side effects of the parent drug to the organism. The specific principle is as follows: the active group of the parent drug is blocked by the polypeptide to form an inactive form of the prodrug, which is a hydrolysis substrate for a specific enzyme, and when the prodrug encounters a specific enzyme highly expressed by a cell, the prodrug is hydrolyzed to release the active parent drug, thereby killing the cell expressing the enzyme. Fibroblast activation protein alpha (fibroblast activation protein alpha, FAP alpha) is a type II serine protease, which is one of the dipeptidyl peptidase family members, has dipeptidyl peptidase hydrolyzing activity, and uniquely has restriction endonuclease activity, and can specifically hydrolyze substrates coupled to N-terminal benzyloxy carbonyl (Z) -blocked Gly-Pro (Z-GP). It was found that fapα is not or is low expressed in normal bone and soft tissue, but is continuously highly expressed on bone and soft tissue tumor cells (Dohi O et al histopath.2009, 55 (4): 432-40); tumor cells from osteosarcoma patients highly express FAP alpha and are positively correlated with their prognosis and metastasis (Yuan et al J Surg Oncol.2013,108 (3): 157-62;Zhang et al.Clin Exp Med.2020,20 (1): 121-30). The above studies indicate that fapα can be an effective target for osteosarcoma and soft tissue sarcoma treatment, and fapα enzyme-activated prodrugs are expected to be a good design strategy for osteosarcoma and soft tissue sarcoma treatment drugs.
The vinblastine compounds are known bisindole alkaloids and derivatives thereof isolated from herba Catharanthi rosei of Apocynaceae, and include vinblastine, vinorelbine, vinflunine, vincristine, vinblastine or vindoline. The applicant and south university application and published Chinese patent application (CN 201310138241.8) disclose a class of vinblastine derivatives obtained by hydrazinolysis and dipeptide derivatization of vinblastine compounds and application of the vinblastine derivatives in preparation of antitumor drugs. The entire contents of this patent application will be incorporated into this application by reference.
Pharmacological studies have shown that vinca alkaloids and analogues or derivatives thereof belong to cytotoxic drugs, which inhibit mainly the polymerization of tubulin, thus interfering with the formation of spindle microtubules and blocking the nuclear division in the metaphase (Martino E, et al Bioorg Med Chem Lett.2018,28 (17): 2816-26). Vinblastine and its derivatives have been clinically used alone or in combination with osteosarcoma first-line therapies since the 70 s of the 20 th century, but have not achieved satisfactory therapeutic results (Claudia MH et al pharmacogenomics.2016,17 (18): 2097-114; veronique MC et al Eur J cancer.2012,48 (15): 2409-16). In addition, vinblastine and its derivatives have adverse effects such as myelosuppression, limiting their long-term and large-dose applications. In view of the above, there is a need for effective therapeutic agents for osteosarcoma and soft tissue sarcoma.
Disclosure of Invention
The primary aim of the invention is to overcome the defects and shortcomings of the prior art and provide the application of the vinblastine derivatives in preparing the medicines for treating osteosarcoma and/or soft tissue sarcoma.
The aim of the invention is achieved by the following technical scheme:
the application of the vinblastine derivative in preparing medicaments for treating osteosarcoma and/or soft tissue sarcoma comprises vinblastine dipeptide and physiologically acceptable salts thereof.
The application is preferably the application in preparing medicines for inhibiting proliferation, invasion, migration, in-situ growth or lung metastasis of osteosarcoma cells and/or soft tissue sarcoma cells.
The vinblastine dipeptide is a compound obtained by condensing a hydrazinolysis vinblastine compound with N-benzyloxycarbonyl dipeptide (namely, the vinblastine dipeptide is a compound obtained by condensing a hydrazinolysis vinblastine compound formed by reacting a vinblastine compound with hydrazine hydrate with N-benzyloxycarbonyl dipeptide); preferably one or more of vinblastine dipeptide (BX-CCJ), vinorelbine dipeptide (BX-CCRB), vinflunine dipeptide (BX-CCFN) and vincristine dipeptide (BX-CCXJ), and its structural formula is shown in formula II-V:
wherein Z-GP represents benzyloxycarbonyl glycyl prolyl.
The synthetic route of the vinblastine derivative is as follows:
the hydrazinolysis vinblastine compound is a compound obtained by reacting a vinblastine compound with hydrazine hydrate, and is preferably hydrazinolysis vinblastine (JJ-CCJ), hydrazine Jie Changchun rebaudibine (JJ-CCRB), hydrazinolysis vinflunine (JJ-CCFN) or hydrazinolysis vincristine (JJ-CCXJ).
The vinblastine compound is preferably vinblastine (CCJ), vinorelbine (CCRB), vinflunine (CCFN) or vincristine (CCXJ).
The N-carbobenzoxy dipeptide is preferably N-carbobenzoxy glycyl proline (Z-GP-OH); the structural formula of the N-carbobenzoxy glycyl proline is shown as formula I:
the osteosarcoma cells include, but are not limited to, cells of the following osteosarcoma cell lines: osteosarcoma cell line SJSA-1, osteosarcoma cell line 143B, osteosarcoma cell line MNNG/HOS, osteosarcoma cell line U2OS, osteosarcoma cell line Saos-2, osteosarcoma cell line HOS, osteosarcoma cell line MG-63;
the soft tissue sarcoma cells include, but are not limited to, cells of the soft tissue sarcoma cell line: soft tissue sarcoma cell line a673, soft tissue sarcoma cell line RD-ES, soft tissue sarcoma cell line TC-32, soft tissue sarcoma cell line SW982, soft tissue sarcoma cell line SW684, soft tissue sarcoma cell line SK-PN-DW, soft tissue sarcoma cell line HT-1080.
The physiologically acceptable salts include, but are not limited to, hydrochloride, sulfate, acetate, tartrate, citrate.
Compared with the prior art, the invention has the following advantages and effects:
the invention designs a vinblastine compound which is designed aiming at the characteristic that tumor cells of osteosarcoma and/or soft tissue sarcoma highly express FAP alpha, and the vinblastine compound is subjected to hydrazinolysis and dipeptide derivatization to form FAP alpha enzyme activated prodrug, so that the vinblastine compound has good activity of resisting tumor growth and lung metastasis in vivo and in vitro, reduces toxic and side effects of vinblastine and derivatives thereof, and enhances the treatment effect of the vinblastine compound.
The vinblastine dipeptide and the physiologically acceptable salt thereof can obviously inhibit proliferation, invasion and migration capacity of osteosarcoma and/or soft tissue sarcoma cells in vitro, obviously inhibit in-situ growth and pulmonary metastasis of osteosarcoma and/or soft tissue sarcoma cells in vivo, have better effect than vinorelbine, and can be applied to treatment of patients with osteosarcoma and soft tissue sarcoma.
Drawings
Fig. 1 is a graph showing the inhibition of the migration capacity of the vinblastine derivatives BX-CCJ and vinorelbine against SJSA-1,143b, a-673 and HT-1080 cells (< 0.05, <0.01 and <0.001vs blank).
Fig. 2 is a graph showing the inhibition of the invasiveness of the vinblastine derivatives BX-CCJ and vinorelbine to SJSA-1,143b, a-673 and HT-1080 cells (< 0.05 and <0.001vs placebo).
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the present invention are not limited thereto.
The vinblastine compounds related in the embodiment of the invention are sequentially vinblastine (CCJ), vinorelbine (CCRB), vinflunine (CCFN) and vincristine (CCXJ), and the hydrazinolysis of the vinblastine compounds is carried out; the hydrazinolysis vinblastine compound is: vinblastine hydrazinolysis (JJ-CCJ), jie Changchun rebaudine hydrazinol (JJ-CCRB), vinflunine hydrazinolysis (JJ-CCFN), and vincristine hydrazinolysis (JJ-CCXJ);
the vinblastine dipeptide related in the embodiment of the invention is a hydrazinolysis vinblastine compound formed by the reaction of a vinblastine compound and hydrazine hydrate, and is condensed with N-benzyloxycarbonyl dipeptide (N-benzyloxycarbonyl glycyl proline (Z-GP-OH)); the vinblastine dipeptide is vinblastine dipeptide (BX-CCJ), vinorelbine dipeptide (BX-CCRB), vinflunine dipeptide (BX-CCFN), and vincristine dipeptide (BX-CCXJ);
the structure and nomenclature of the compounds are shown below:
EXAMPLE 1 inhibition of proliferation potency of vinblastine derivatives BX-CCJ on human osteosarcoma cells and soft tissue sarcoma cells
The experimental method comprises the following steps: cells in the logarithmic growth phase were inoculated into 96-well plates at an inoculation density of 5X 10 3 After overnight incubation in the incubator, the old medium was removed, and each well was filled with medium containing inactivated serum at different drug concentrations, and an equal volume of PBS was added as a negative control well, and an equal volume of complete medium without drug was added as a positive control well. After 72h of cell culture, the old cell culture medium was removed, 30. Mu.L of MTT was added to each well, incubated at 37℃for 4h, the recovered MTT solution was removed, 100. Mu.L of DMSO was added to each well, and after complete dissolution of the formazan reaction product by shaking the shaker, the OD value of each well was measured using a fluorescent multifunctional microplate reader (wavelength 590 nm). The formula for calculating cell viability is as follows: cell viability% = (mean OD value of dosing treatment group-mean OD value of blank wells)/(mean OD value of control group-mean OD value of blank wells) ×100%. The results are shown in Table 1.
From the experimental results shown in the table, it can be seen that: the vinblastine derivative BX-CCJ can inhibit proliferation of osteosarcoma cells and soft tissue sarcoma cells, and has antiproliferative effect superior to that of vinorelbine.
TABLE 1 statistical results of cell viability
EXAMPLE 2 inhibition of the cell migration Capacity of human osteosarcoma cells and Soft tissue sarcoma cells by Vinca derivatives BX-CCJ
The experimental method comprises the following steps: cells in logarithmic growth phase were centrifuged, and the cells were resuspended in serum-free medium at 1X 10 4 Cells/well were inoculated into a Transwell-nested upper chamber with a pore size of 8.0. Mu.m, the volume of the inoculated cell suspension was 100. Mu.L, and 500. Mu.L of a medium containing 10% FBS and a specific concentration (0 nmol/L, 2nmol/L, 4 nmol/L) of BX-CCJ or vinorelbine was added to the lower chamber, and 3 multiplex wells were placed in each group. After incubation at 37℃for 48h in the incubator, all the medium in the upper and lower chambers was removed, the cells were fixed with 4% paraformaldehyde at room temperature for 50min, washed 2 times, and 500. Mu.L of 0.1% crystal violet solution was added to the lower chamber and stained for 3min. The cells were washed with PBS and gently rubbed with a cotton swab to remove cells that did not migrate to the lower chamber in the nested upper chamber. After the Transwell nested cells were naturally dried, the cells that had migrated to the lower layers of the nested cells were observed and photographed using an inverted microscope, 5 fields of view were randomly selected for each nest to photograph, and the number of migrated cells was counted using IPP software. The cell invasion experiment was performed in the same manner as the migration experiment except that 20. Mu.L of matrigel was spread in advance in the Transwell nest upper chamber and coagulated at 37℃for 30min at a matrigel concentration of 2.5mg/mL. The results are shown in FIG. 1.
From the experimental results shown in the figures, it can be seen that: compared with a blank control group, the vinblastine derivative BX-CCJ can obviously inhibit migration capacity of SJSA-1,143B, A-673 and HT-1080 cells, and the effect is better than that of vinorelbine.
EXAMPLE 3 inhibition of the ability of vinblastine derivatives BX-CCJ to invade human osteosarcoma cells and soft tissue sarcoma cells
The experimental method comprises the following steps: cells in logarithmic growth phase were centrifuged, and the cells were resuspended in serum-free medium at 1X 10 4 Cells/well were inoculated into a Transwell-nested upper chamber with a pore size of 8.0. Mu.m, 20. Mu.L of 2.5mg/mL Matrigel (BD Co.) and the cell suspension volume was inoculated at 100. Mu.L, and 500. Mu.L of BX-CCJ or vinorelbine medium containing 10% FBS and specific concentrations (0 nmol/L, 2nmol/L, 4 nmol/L) was added to the lower chamber, and 3 multiplex wells were set per group. After incubation at 37℃for 48h in the incubator, all the medium in the upper and lower chambers was removed, the cells were fixed with 4% paraformaldehyde at room temperature for 50min, washed 2 times, and 500. Mu.L was added to the lower chamber0.1% crystal violet solution, staining for 3min. The cells were washed with PBS and gently rubbed with a cotton swab to remove cells that did not migrate to the lower chamber in the nested upper chamber. After the Transwell nested cells were naturally dried, the cells that had migrated to the lower layers of the nested cells were observed and photographed using an inverted microscope, 5 fields of view were randomly selected for each nest to photograph, and the number of migrated cells was counted using IPP software. The results are shown in FIG. 2.
From the experimental results shown in the figures, it can be seen that: compared with a blank control group, the vinblastine derivative BX-CCJ can obviously inhibit invasion capacity of SJSA-1,143B, A-673 and HT-1080 cells, and the effect is better than that of vinorelbine.
EXAMPLE 4 inhibition of growth and pulmonary metastasis of vinblastine derivatives BX-CCJ on in situ transplantation of human osteosarcoma cells and soft tissue sarcoma cells in nude mice
The experimental method comprises the following steps: digesting and collecting SJSA-1 and 143B cells in logarithmic phase, washing with PBS for 3 times, centrifuging, mixing cell precipitate with precooled PBS, blowing uniformly, and adjusting cell density to 4×10 7 And each mL. Cell suspensions were injected into the proximal tibia of 4-6 week old male BALB/C nude mice at a volume of 0.05 mL/mouse with an islet syringe.
Taking A-673 and HT-1080 cells growing in logarithmic phase, washing with PBS for 3 times, and adjusting cell concentration to 4×10 7 cells/mL, quadriceps femoris of each BALB/c Nu/Nu mouse was inoculated with 0.1mL. After the tumor volume gradually increases to 80-100 mm 3 About, tumor-bearing mice were randomly divided into solvent control, BX-CCJ and vinorelbine dosing groups of 6 animals each. The administration mode is as follows: BX-CCJ or vinorelbine 1mg/kg was injected intravenously at the tail once a couple of days. Body weight of nude mice was recorded and tumor diameters were measured. The volumetric calculation formula of osteosarcoma is expressed as: v=4/3 pi [1/4 (a+b)] 2 Wherein a and b are the long and short diameters of the tumor perpendicular to the tibia, respectively. The volume calculation formula of soft tissue sarcoma is: v=1/2 (a×b 2 ) Wherein a and b represent the major and minor diameters of the tumor, respectively. The results are shown in Table 2. After 20 days of drug administration, mice were sacrificed and tumors and lung tissues were dissected. Tumor tissue was weighed and photographed. Tumors and lung tissue were sectioned with 4% paraformaldehyde fixation, embedding, H&E dyeing backHistological analysis was performed. The results are shown in Table 3.
From the experimental results shown in the table, it can be seen that: the vinblastine derivative BX-CCJ can remarkably inhibit the growth capacities of 143B, SJSA-1, A-673 and HT-1080 transplanted tumors, the tumor inhibition rates are 93.10%,88.92%,91.20% and 90.55%, the tumor inhibition rate of Yu Changchun rebaudibines is high (59.31%, 65.46%,54.67% and 56.73%), and the weight of nude mice is not obviously affected. BX-CCJ can remarkably reduce the number and the area of 143B and HT-1080 cell lung metastases, and the effect is superior to that of vinorelbine.
TABLE 2 statistical results of tumor weights and tumor suppression rates
TABLE 3 statistics of the number and area of lung metastases
*P<0.05,**P<0.01,***P<0.001VS saline group; # P<0.05, ## P<0.01VS vinorelbine group
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (4)
1. The application of the vinblastine derivative in preparing the medicament for treating osteosarcoma and/or soft tissue sarcoma is characterized in that:
the vinblastine derivative comprises vinblastine dipeptide and physiologically acceptable salts thereof;
the vinblastine dipeptide is vinblastine and dipeptide, and the structural formula is shown in formula II:
；
wherein Z-GP represents benzyloxycarbonyl glycyl prolyl.
2. The use of a vinblastine derivative according to claim 1 for the manufacture of a medicament for the treatment of osteosarcoma and/or soft tissue sarcoma, characterized in that:
the application is the application in preparing the medicines for inhibiting proliferation, invasion, migration or in-situ growth of osteosarcoma cells and/or soft tissue sarcoma cells.
3. The use of a vinblastine derivative according to claim 2 for the manufacture of a medicament for the treatment of osteosarcoma and/or soft tissue sarcoma, characterized in that:
the migration is lung metastasis.
4. Use of a vinblastine derivative according to claim 1 or 2 for the preparation of a medicament for the treatment of osteosarcoma and/or soft tissue sarcoma, characterized in that:
the physiologically acceptable salts include hydrochloride, sulfate, acetate, tartrate or citrate.
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