CN113456797A - Application of vinblastine derivative in preparation of medicine for treating osteosarcoma and/or soft tissue sarcoma - Google Patents
Application of vinblastine derivative in preparation of medicine for treating osteosarcoma and/or soft tissue sarcoma Download PDFInfo
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- CN113456797A CN113456797A CN202110679780.7A CN202110679780A CN113456797A CN 113456797 A CN113456797 A CN 113456797A CN 202110679780 A CN202110679780 A CN 202110679780A CN 113456797 A CN113456797 A CN 113456797A
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- vinblastine
- soft tissue
- osteosarcoma
- tissue sarcoma
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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 63
- 201000008968 osteosarcoma Diseases 0.000 title claims abstract description 59
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- 208000021712 Soft tissue sarcoma Diseases 0.000 title claims abstract description 58
- 239000003814 drug Substances 0.000 title claims abstract description 28
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- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses application of vinblastine derivatives in preparation of a medicine for treating osteosarcoma and/or soft tissue sarcoma. The vinblastine derivative comprises vinblastine dipeptide and physiologically acceptable salt thereof; the vinblastine dipeptide is a compound obtained by condensing a vinblastine hydrazinolysis compound and N-benzyloxycarbonyl dipeptide; the catharanthine hydrazinolysis compound is a compound obtained by reacting a catharanthine compound with hydrazine hydrate; the vinblastine compound is vinblastine, vinorelbine, vinflunine or vincristine. The vinblastine dipeptide and its physiologically acceptable salt can remarkably inhibit proliferation, invasion and migration of osteosarcoma and soft tissue sarcoma cells in vitro, inhibit in-situ growth and lung 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 vinblastine derivatives in preparation of medicines for treating osteosarcoma and/or soft tissue sarcoma.
Background
Osteosarcoma and soft tissue sarcoma are malignant tumors originating from mesenchymal tissues, and have a very high rate of metastasis and recurrence. Surgery and chemotherapy are the primary treatment for osteosarcoma and soft tissue sarcoma. Cisplatin, cyclophosphamide, doxorubicin and methotrexate are first-line agents of osteosarcoma chemotherapy, while doxorubicin and ifosfamide constitute the two major cornerstones of soft tissue sarcoma chemotherapy. The survival rate of osteosarcoma patients can be improved to 60-70% within 5 years by chemotherapy, and the survival rate of soft tissue sarcoma patients is still lower than 10% by chemotherapy. Osteosarcoma and soft tissue sarcoma metastasize to the lung mainly by hematogenous metastases, with a survival rate of less than 20% in 5 years for patients with lung metastases. Large doses of chemotherapeutic drugs can cause nausea, vomiting, bone marrow suppression, cardiotoxicity and other adverse reactions in patients, resulting in poor patient compliance and poor 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 property of the parent drug to enzyme expression cells and reduce the toxic and side effects of the parent drug to organisms. The specific principle is as follows: the active group of the parent drug is blocked by the polypeptide to form an inactive form of prodrug, the prodrug is a hydrolysis substrate of a specific enzyme, and when the prodrug meets a specific enzyme highly expressed by cells, the prodrug is hydrolyzed to release the active parent drug, so that the cells expressing the enzyme are killed. Fibroblast activation protein alpha (FAP alpha) is a type ii serine protease belonging to one of the members of the dipeptidyl peptidase family, having dipeptidase hydrolysis activity and uniquely having restriction endonuclease activity, and specifically hydrolyzing a substrate coupled with N-terminal benzoyl (Z) -blocked Gly-Pro (Z-GP). The research shows that FAP alpha is not expressed or is low expressed in normal bone and soft tissue, but is continuously high expressed on bone and soft tissue tumor cells (Dohi O et al. histopathology.2009,55(4): 432-40); tumor cells of osteosarcoma patients highly express FAP alpha and have positive correlation with 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 research shows that FAP alpha can be used as an effective target for treating osteosarcoma and soft tissue sarcoma, and the FAP alpha enzyme activated prodrug is expected to be a good design strategy for treating osteosarcoma and soft tissue sarcoma.
The vinblastine compound is a known bisindole alkaloid separated from Catharanthus roseus of Apocynaceae and its derivatives, including vinblastine, vinorelbine, vinflunine, vincristine, vinblastine or vindoline. The applicant of river-south university and the published Chinese invention patent application (CN201310138241.8) disclose vinblastine derivatives of vinblastine compounds subjected to hydrazinolysis and dipeptide derivatization and application thereof in preparation of antitumor drugs. The entire contents of this patent application are incorporated into this application by reference.
Pharmacological studies have shown that vinblastine and its analogues or derivatives belong to cytotoxic drugs, mainly inhibiting the polymerization of tubulin, thus preventing the formation of spindle microtubules, and arresting nuclear division in the metaphase (Martino E, et al bioorg Med Chem lett.2018,28(17): 2816-26). Since the 70's of the 20 th century, vinblastine and its derivatives were used clinically alone or in combination with first-line osteosarcoma therapeutics, but the therapeutic effects were not satisfactory (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 reactions such as bone marrow suppression, and limit its long-term and large-dose application. In conclusion, there is a great clinical need for effective therapeutic agents for osteosarcoma and soft tissue sarcoma.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides the application of the vinblastine derivative in preparing the medicine for treating osteosarcoma and/or soft tissue sarcoma.
The purpose of the invention is realized by the following technical scheme:
the application of vinblastine derivatives in preparing medicines for treating osteosarcoma and/or soft tissue sarcoma is provided, wherein the vinblastine derivatives comprise vinblastine dipeptide and physiologically acceptable salts thereof.
The application is preferably the application in preparing the medicine 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 vinblastine hydrazinolysis compound and N-benzyloxycarbonyl dipeptide (namely, the vinblastine dipeptide is a compound obtained by condensing the vinblastine hydrazinolysis compound formed by the reaction of the vinblastine compound and hydrazine hydrate and then condensing the vinblastine hydrazinolysis compound and the N-benzyloxycarbonyl dipeptide); preferably one or more of vinblastine plus dipeptide (BX-CCJ), vinorelbine plus dipeptide (BX-CCRB), vinflunine plus dipeptide (BX-CCFN) and vincristine plus dipeptide (BX-CCXJ), and the structural formula is shown in formulas II-V:
wherein Z-GP represents benzyloxycarbonyl glycyl prolyl.
The synthetic route of the vinblastine derivative is as follows:
the catharanthine hydrazinolysis compound is a compound obtained by reacting a catharanthine compound with hydrazine hydrate, and is preferably catharanthine hydrazinolysis (JJ-CCJ), vinorelbine hydrazinolysis (JJ-CCRB), vinflunine hydrazinolysis (JJ-CCFN) or vincristine hydrazinolysis (JJ-CCXJ).
The vinblastine compound is preferably vinblastine (CCJ), vinorelbine (CCRB), vinflunine (CCFN) or vincristine (CCXJ).
The N-benzyloxycarbonyl dipeptide is preferably N-benzyloxycarbonyl glycyl proline (Z-GP-OH); the structural formula of the N-benzyloxycarbonyl glycyl proline is shown as a formula I:
such 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 following soft tissue sarcoma cell lines: 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 vinblastine compound designed aiming at the characteristic of high expression of FAP alpha in osteosarcoma and/or soft tissue sarcoma tumor cells forms FAP alpha enzyme activated prodrug by hydrazinolysis and dipeptide derivatization, has good activity of resisting tumor growth and lung metastasis in vitro and in vivo, reduces the toxic and side effects of vinblastine and derivatives thereof, and enhances the treatment effect.
The vinblastine dipeptide and the physiologically acceptable salt thereof can obviously inhibit the proliferation, invasion and migration capacity of osteosarcoma and/or soft tissue sarcoma cells in vitro, obviously inhibit the in-situ growth and lung metastasis of the osteosarcoma and/or soft tissue sarcoma cells in vivo, have better effect than vinorelbine, and can be applied to the treatment of patients with bone tumors and soft tissue sarcoma.
Drawings
Figure 1 is a graph of the inhibitory effect of vinblastine derivatives BX-CCJ and vinorelbine on the migratory capacity of SJSA-1,143B, a-673 and HT-1080 cells (P <0.05, P <0.01 and P <0.001vs blank).
Figure 2 is a graph of the inhibitory effect of vinblastine derivatives BX-CCJ and vinorelbine on the invasive capacity of SJSA-1,143B, a-673 and HT-1080 cells (pp <0.05 and pp <0.001vs blank).
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.
The vinblastine compounds related in the embodiment of the invention are vinblastine (CCJ), vinorelbine (CCRB), vinflunine (CCFN) and vincristine (CCXJ) in turn, and the vinblastine compounds are hydrazinolyzed to obtain the vinblastine compounds; the catharanthine hydrazinolysis compound is as follows: catharanthine hydrazinolysis (JJ-CCJ), vinorelbine hydrazinolysis (JJ-CCRB), vinflunine hydrazinolysis (JJ-CCFN) and vincristine hydrazinolysis (JJ-CCXJ);
the vinblastine dipeptide related in the embodiment of the invention is a compound which is obtained by reacting a vinblastine compound with hydrazine hydrate to form a hydrazinolysis vinblastine compound and then condensing the hydrazinolysis vinblastine compound 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 as follows:
example 1 inhibitory Effect of vinblastine derivative BX-CCJ on the proliferative Capacity of human osteosarcoma cells and Soft tissue sarcoma cells
The experimental method comprises the following steps: cells in logarithmic growth phase were digested and seeded into 96-well plates at a seeding density of 5X 103Cells/wells cultured in incubatorAfter night, the old medium was removed and medium containing inactivated serum at different drug concentrations was added to each well, 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 72 hours of cell culture, the old cell culture medium was discarded, 30. mu.L of MTT was added to each well, and after incubation at 37 ℃ for 4 hours, the recovered MTT solution was removed, 100. mu.L of DMSO was added to each well, and the reaction product formazan was completely dissolved by shaking a shaker, and then the OD value of each well was measured using a fluorescent multi-functional microplate reader (wavelength 590 nm). The formula for calculating cell viability is as follows: the cell survival rate [% ], [% ] (mean OD value in the administration treatment group-mean OD value in blank wells)/(mean OD value in the control group-mean OD value in blank wells) × 100%. The results are shown in Table 1.
As can be seen from the experimental results shown in the table: the vinblastine derivative BX-CCJ can inhibit the proliferation capacity of osteosarcoma cells and soft tissue sarcoma cells, and the anti-proliferation capacity of the vinblastine derivative BX-CCJ is superior to that of vinorelbine.
TABLE 1 statistics of cell viability
Example 2 inhibitory Effect of vinblastine derivative BX-CCJ on cell migration ability of human osteosarcoma cells and soft tissue sarcoma cells
The experimental method comprises the following steps: digesting and centrifuging the cells in the logarithmic growth phase, and resuspending the cells in a serum-free medium at 1X 104Cells/well were seeded into Transwell nested upper chambers of 8.0 μm pore size, with a cell suspension volume of 100 μ L, and 500 μ L of medium containing 10% FBS and specified concentrations (0nmol/L, 2nmol/L, 4nmol/L) of BX-CCJ or vinorelbine was added to the lower chamber, with 3 duplicate wells per set. After incubation in an incubator at 37 ℃ for 48h, all media in the upper and lower chambers were removed, 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 3 min. The chamber was washed with PBS and the cells that did not migrate to the lower chamber in the nested upper chamber were gently wiped off with a cotton swab. After the Transwell nested chamber is naturally dried, the chamber is invertedCells that had migrated to the lower layers of the nests were observed microscopically and photographed, 5 fields were randomly picked for each nest to be photographed, and the number of migrated cells was counted using IPP software. The cell invasion experiment was performed as in the migration experiment except that 20. mu.L of matrigel was previously placed in the Transwell nested chamber and allowed to set at 37 ℃ for 30min at a matrigel concentration of 2.5 mg/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 the migration capacity of SJSA-1,143B, A-673 and HT-1080 cells, and the effect is superior to that of vinorelbine.
Example 3 inhibitory Effect of vinca alkaloid derivative BX-CCJ on the cell invasion ability of human osteosarcoma cells and soft tissue sarcoma cells
The experimental method comprises the following steps: digesting and centrifuging the cells in the logarithmic growth phase, and resuspending the cells in a serum-free medium at 1X 104Cells/well were seeded into a Transwell nested upper chamber of 8.0 μm pore size plated with 20 μ L of 2.5mg/mL Matrigel matrix gel (BD Corp.) and a cell suspension volume of 100 μ L was seeded, and 500 μ L of medium containing 10% FBS and BX-CCJ or vinorelbine at specified concentrations (0nmol/L, 2nmol/L, 4nmol/L) was added to the lower chamber, with 3 duplicate wells per set. After incubation in an incubator at 37 ℃ for 48h, all media in the upper and lower chambers were removed, 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 3 min. The chamber was washed with PBS and the cells that did not migrate to the lower chamber in the nested upper chamber were gently wiped off with a cotton swab. After the Transwell nested chamber is naturally dried, observing the cells which have migrated to the lower layer of the nested chamber by using an inverted microscope and taking pictures, randomly selecting 5 visual fields for taking pictures for each nest, and counting the number of the migrated cells by 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 the invasion capacity of SJSA-1,143B, A-673 and HT-1080 cells, and the effect is superior to that of vinorelbine.
Example 4 inhibitory Effect of Vinca alkaloid derivative BX-CCJ on the growth and Lung metastasis of nude mouse orthotopic transplantation human osteosarcoma cells and Soft tissue sarcoma cells
The experimental method comprises the following steps: digesting and collecting SJSA-1 and 143B cells in logarithmic growth phase, washing with PBS 3 times, centrifuging, mixing cell precipitate with precooled PBS, blowing uniformly, and adjusting cell density to 4 × 107one/mL. The cell suspension was injected into the proximal tibia of 4-6 week old male BALB/C nude mice using an islet syringe in a volume of 0.05 mL/mouse.
Collecting logarithmic phase-grown A-673 and HT-1080 cells, washing with PBS 3 times, and adjusting cell concentration to 4 × 107cells/mL, 0.1mL per quadriceps femoris of BALB/c Nu/Nu mice. Gradually increasing the tumor volume to 80-100 mm3On the left and right, tumor-bearing mice were randomly divided into a solvent control group, a BX-CCJ group and a vinorelbine administration group, and 6 mice were administered to each group. The administration mode comprises the following steps: BX-CCJ or vinorelbine is injected into the tail vein at the rate of 1mg/kg once every two days. Body weight of nude mice was recorded and tumor size was measured. The calculation formula of the volume of osteosarcoma is shown as follows: v-4/3 pi [1/4(a + b)]2Wherein a and b are respectively the major diameter and the minor diameter of the tumor perpendicular to the tibia. The volume calculation formula for soft tissue sarcoma is: 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 treatment, mice were sacrificed and tumor and lung tissue were dissected out. Tumor tissues were weighed and photographed. Tumor and lung tissues were fixed with 4% paraformaldehyde, embedded and sectioned, H&Histological analysis was performed after E staining. The results are shown in Table 3.
As can be seen from the experimental results shown in the table: the vinblastine derivative BX-CCJ can obviously inhibit the growth capacity 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% respectively, and are higher than the tumor inhibition rates of vinorelbine (59.31%, 65.46%, 54.67% and 56.73%), and the weight of a nude mouse is not obviously influenced. BX-CCJ can obviously reduce the number and area of 143B and HT-1080 cell lung metastasis foci, and the effect is superior to that of vinorelbine.
TABLE 2 statistical results of tumor weight and tumor inhibition
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 embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. The application of the vinblastine derivative in preparing the medicine for treating osteosarcoma and/or soft tissue sarcoma is characterized in that:
the vinblastine derivative comprises vinblastine dipeptide and physiologically acceptable salt thereof.
2. The use of vinblastine derivatives according to claim 1, for the preparation of a medicament for the treatment of osteosarcoma and/or soft tissue sarcoma, characterized in that:
the application is the application in preparing the medicine for inhibiting proliferation, invasion, migration, in-situ growth or lung metastasis of osteosarcoma cells and/or soft tissue sarcoma cells.
3. Use of vinblastine derivatives 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 vinblastine dipeptide is a compound obtained by condensing a catharanthine hydrazinolysis compound and N-benzyloxycarbonyl dipeptide.
4. Use of vinblastine derivatives according to claim 3 for the preparation of a medicament for the treatment of osteosarcoma and/or soft tissue sarcoma, characterized in that:
the vinblastine hydrazinolysis compound is a compound obtained by reacting vinblastine compound with hydrazine hydrate.
5. Use of vinblastine derivatives according to claim 3 for the preparation of a medicament for the treatment of osteosarcoma and/or soft tissue sarcoma, characterized in that:
the catharanthine hydrazinolysis compound is catharanthine hydrazinolysis, vinorelbine hydrazinolysis, vinflunine hydrazinolysis or vincristine hydrazinolysis.
6. The use of vinblastine derivatives according to claim 4, for the preparation of a medicament for the treatment of osteosarcoma and/or soft tissue sarcoma, characterized in that:
the vinblastine compound is vinblastine, vinorelbine, vinflunine or vincristine.
7. Use of vinblastine derivatives according to claim 3 for the preparation of a medicament for the treatment of osteosarcoma and/or soft tissue sarcoma, characterized in that:
the N-benzyloxycarbonyl dipeptide is N-benzyloxycarbonyl glycyl proline, and the structural formula of the N-benzyloxycarbonyl glycyl proline is shown as the formula I:
8. the use of vinblastine derivatives according to claim 1, for the preparation of a medicament for the treatment of osteosarcoma and/or soft tissue sarcoma, characterized in that:
the vinblastine dipeptide is one or more of vinblastine plus dipeptide, vinorelbine plus dipeptide, vinflunine plus dipeptide and vincristine plus dipeptide, and the structural formula is shown as formulas II-V:
9. the use of vinblastine derivatives according to claim 2, for the preparation of a medicament for the treatment of osteosarcoma and/or soft tissue sarcoma, characterized in that:
such 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 following soft tissue sarcoma cell lines: 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.
10. Use of vinblastine derivatives 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, but are not limited to, hydrochloride, sulfate, acetate, tartrate, citrate.
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