CN112940044A - Berberine coupled cis-platinum compound and preparation method and application thereof - Google Patents
Berberine coupled cis-platinum compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of pharmaceutical chemicals, in particular to a berberine coupling cis-platinum compound and a preparation method and application thereof. The invention provides a berberine coupling cis-platinum compound which has a structure shown in a formula I. The results of the examples show that the berberine coupling cis-platinum compound provided by the invention can effectively inhibit the proliferation activity of intestinal cancer cells and obviously reduce the killing property of cis-platinum on normal intestinal epithelial cells, and the in vivo experiments of mice prove that the berberine coupling cis-platinum chemical compound has better tumor inhibition effect than the cis-platinum.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a berberine coupling cis-platinum compound and a preparation method and application thereof.
Background
Colorectal cancer is the fourth most common malignant tumor and the fifth most lethal malignant tumor in China, and seriously harms the life health of people. At present, surgical excision is mainly adopted in treatment in combination with chemoradiotherapy, but the effective improvement of the life cycle of intestinal cancer patients is limited by high postoperative recurrence rate and serious toxic and side effects of patients. Therefore, the development of new highly effective and low-toxic anti-intestinal cancer targeted drugs has become a very interesting and urgent task at present.
Platinum drugs, one of the most representative drugs in the field of chemotherapeutic drugs, play an irreplaceable role in the clinical treatment of various cancers. Cisplatin, as a first-generation platinum drug, is one of three most widely used antitumor drugs in the world, but has the defects of lack of selectivity on cancer cells, serious toxic and side effects on normal cells and lack of sensitivity on digestive tract tumors, so that the further clinical application of cisplatin is limited.
Disclosure of Invention
In view of the above, the invention provides a berberine coupling cis-platinum compound and a preparation method and application thereof, the berberine coupling cis-platinum compound provided by the invention can effectively inhibit intestinal cancer cell proliferation activity and obviously reduce the killing property of cis-platinum on normal intestinal epithelial cells, and mouse in vivo experiments prove that the berberine coupling cis-platinum compound has a better tumor inhibition effect than the cis-platinum.
The invention provides a berberine coupling cis-platinum compound which has a structure shown in a formula I:
the invention provides a preparation method of a berberine coupling cisplatin compound in the technical scheme, which comprises the following steps:
carrying out hydroxylation reaction on the berberine to obtain hydroxylated berberine;
carrying out nucleophilic substitution reaction on the hydroxylated berberine, butyl bromoacetate and an organic basic catalyst in a first polar organic solvent to obtain berberine with protected hydroxyl;
carrying out deprotection and carboxylation reactions on the hydroxyl protected berberine and trifluoroacetic acid in a second polar organic solvent to obtain carboxylated berberine;
performing oxidation reaction on cisplatin and hydrogen peroxide to obtain tetravalent cisplatin;
and carrying out condensation reaction on the carboxylated berberine, tetravalent cisplatin and a condensation reaction catalyst in a polar organic solvent of the condensation reaction to obtain the berberine coupling cisplatin compound.
Preferably, the molar ratio of the hydroxylated berberine to the butyl bromoacetate to the organic basic catalyst is 2 (2.4-3) to 2-4.
Preferably, the organic basic catalyst comprises N, N-diisopropylethylamine and/or triethylamine; the temperature of the nucleophilic substitution reaction is room temperature, and the time is 8-12 h.
Preferably, the volume ratio of the mass of the hydroxyl-protected berberine to the trifluoroacetic acid is (50-100) mg: 1 mL;
the volume ratio of the trifluoroacetic acid to the second polar organic solvent is 1 (2-3).
Preferably, the molar ratio of the carboxylated berberine to the tetravalent cisplatin is 6: 5.
Preferably, the condensation reaction catalyst comprises triethylamine and O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate;
the molar ratio of the triethylamine to the O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroborate is (1-1.5): (1-1.5).
Preferably, the condensation reaction is carried out at 60 ℃ for 12 h.
Preferably, the first polar organic solvent and the second polar organic solvent independently comprise dichloromethane, N-dimethylformamide, or acetonitrile; the polar organic solvent for the condensation reaction includes DMSO or N, N-dimethylformamide.
The invention provides an application of the berberine coupling cis-platinum compound in the technical scheme or the berberine coupling cis-platinum compound obtained by the preparation method in the technical scheme in the preparation of anti-intestinal cancer drugs.
The invention provides a berberine coupling cis-platinum compound which has a structure shown in a formula I, wherein the berberine coupling cis-platinum compound is used for coupling berberine and tetravalent cis-platinum and can be reduced into berberine and cis-platinum under the action of a reducing medium. The berberine coupling cis-platinum compound provided by the invention is reduced in cytoplasm after entering cancer cells and releases cis-platinum and berberine, and cis-platinum is combined with cell genome DNA to form an adduct after entering the cells, so that the transcription and replication of the cancer cell DNA are influenced, and the double-strand break and apoptosis of the cancer cell DNA are finally induced; berberine inhibits intestinal cancer cell proliferation by inhibiting Wnt signal pathway protein to finally cause intestinal cancer cell cycle block. In addition, the berberine and the cisplatin are coupled, so that the response of intestinal cancer cells to the cisplatin is changed, the selectivity of the intestinal cancer cells to the cisplatin is improved, the accumulation amount of platinum in the cancer cells is further improved, the killing effect of the intestinal cancer cells is enhanced, and the toxic and side effect of the intestinal cancer cells to normal intestinal epithelial cells is reduced. The berberine coupling cis-platinum compound provided by the invention obviously improves the anti-intestinal cancer activity of cis-platinum through the above way. The results of the examples show that the berberine coupling cis-platinum compound provided by the invention can effectively inhibit the proliferation activity of intestinal cancer cells and obviously reduce the killing property of cis-platinum on normal intestinal epithelial cells, and the mouse in vivo experiments prove that the berberine coupling cis-platinum compound has better tumor inhibition effect and tumor selectivity than the cis-platinum.
Drawings
FIG. 1 is a mass spectrum of a berberine coupled cis-platinum compound prepared in example 1;
FIG. 2 is a NMR chart of a berberine coupled cisplatin compound prepared in example 1;
FIG. 3 is a comparative HPLC chart showing the berberine coupled cisplatin compound, berberine, cisplatin and the product of test example 3 prepared in example 1;
FIG. 4 is a graph comparing immunofluorescence assays of berberine coupled cisplatin compounds, berberine and cisplatin mixture, berberine and cisplatin prepared in example 1 after 24h treatment of HCT116 cells;
FIG. 5 is a graph comparing the results of the berberine coupled cisplatin compound, berberine and cisplatin mixture, berberine and cisplatin Westen Blot experiments prepared in example 1;
FIG. 6 is a graph comparing the results of the cell cycle assays using single stain assays for berberine conjugate cisplatin compounds, berberine and cisplatin mixtures, berberine and cisplatin PI, prepared in example 1;
FIG. 7 is a comparison graph of the results of detecting apoptosis by double staining method of berberine coupled cis-platinum compound, mixture of berberine and cisplatin, berberine and cisplatin Annexin V/PI prepared in example 1;
FIG. 8 is a graph comparing intracellular platinum levels in the berberine coupled cisplatin compound, berberine and cisplatin mixture and cisplatin treated SW620 and HCT116 cells prepared in example 1;
FIG. 9 is a graph comparing intracellular platinum levels in the berberine coupled cisplatin compound, berberine and cisplatin mixture and cisplatin treated HIEC-6 cells prepared in example 1;
FIG. 10 is a graph showing the effect of the berberine compound and cisplatin prepared in example 1 on the transplanted tumor in nude mice.
Detailed Description
The invention provides a berberine coupling cis-platinum compound which has a structure shown in a formula I:
the berberine coupling cis-platinum compound provided by the invention couples berberine and tetravalent cis-platinum, and can be reduced into berberine and cis-platinum under the action of a reducing medium. The berberine can inhibit Wnt signal path so as to inhibit the growth of intestinal cancer, and the berberine only has lethality to intestinal cancer cells and has no toxicity to normal intestinal epithelial cells; cisplatin enters cells and then forms an adduct through being combined with cell genome DNA, so that the transcription and the replication of the DNA are influenced, and the double-strand break and the apoptosis of the DNA are finally induced; the berberine coupling cisplatin compound changes the response of intestinal cancer cells to cisplatin, and further improves the accumulation amount of intracellular platinum so as to enhance the killing effect of the intestinal cancer cells to tumor cells. The berberine coupling cis-platinum compound obviously improves the anti-intestinal cancer activity of the cis-platinum through the above way.
The invention provides a preparation method of a berberine coupling cisplatin compound in the technical scheme, which comprises the following steps:
carrying out hydroxylation reaction on the berberine to obtain hydroxylated berberine;
carrying out nucleophilic substitution reaction on the hydroxylated berberine, butyl bromoacetate and an organic basic catalyst in a first polar organic solvent to obtain berberine with protected hydroxyl;
carrying out deprotection and carboxylation reactions on the hydroxyl protected berberine and trifluoroacetic acid in a second polar organic solvent to obtain carboxylated berberine;
performing oxidation reaction on cisplatin and hydrogen peroxide to obtain tetravalent cisplatin;
and carrying out condensation reaction on the carboxylated berberine, tetravalent cisplatin and a condensation reaction catalyst in a polar organic solvent of the condensation reaction to obtain the berberine coupling cisplatin compound.
In the present invention, the starting materials are all commercially available products well known to those skilled in the art unless otherwise specified.
The specific synthetic route of the preparation method of the berberine coupling cisplatin compound provided by the invention is as follows:
the method comprises the steps of carrying out hydroxylation reaction on berberine to obtain hydroxylated berberine; in the present invention, the hydroxylation reaction is preferably referred to as "Antibacterial activity and structure-activity relationships of bergenine analogues. Eur J Med Chem (1996)31, 469-; in the invention, the hydroxylation reaction comprises the following specific steps: in N2Under protection, 1g of berberine is addedReacting at 190 ℃ for 15min, cooling to room temperature, and adding 100mL of a mixture with a volume ratio of 1:1, washing the washed precipitate by using a mixed solution of ethanol and methanol, and separating and purifying the washed precipitate by using a high performance liquid chromatography to obtain the hydroxylated berberine, wherein an eluent used by the high performance liquid chromatography is a mixed solution of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 20: 1.
After obtaining the hydroxylated berberine, butyl bromoacetate and an organic basic catalyst are subjected to nucleophilic substitution reaction in a first polar organic solvent to obtain the hydroxyl-protected berberine.
In the invention, the organic basic catalyst preferably comprises N, N-diisopropylethylamine and/or triethylamine, more preferably comprises N, N-diisopropylethylamine or triethylamine, and most preferably comprises N, N-diisopropylethylamine, wherein the molar ratio of the hydroxylated berberine, butyl bromoacetate and the organic basic catalyst is preferably 2 (2.4-3) to 2-4, more preferably 2 (2.5-2.6) to (2.2-3.8), and most preferably 2:2.4: 1; in the present invention, the first polar organic solvent preferably includes dichloromethane, N-dimethylformamide or acetonitrile, more preferably includes dichloromethane, and the present invention has no special requirement on the amount of the first polar organic solvent, and can achieve dissolution of reaction raw materials, and in a specific embodiment of the present invention, the mass-to-volume ratio of the hydroxymethylberberine to the first polar organic solvent is preferably 1 g: 50 mL.
In the invention, the temperature of the nucleophilic substitution reaction is preferably room temperature, and the time is preferably 8-12 h. In the present invention, the affinity substitution reaction is preferably performed under stirring, and the present invention does not require any particular embodiment of the stirring, and the reaction can be performed in a manner well known to those skilled in the art.
In the present invention, the post-treatment is preferably performed on the reaction solution after the nucleophilic substitution reaction is finished, the post-treatment preferably comprises solvent removal and separation and purification, in the present invention, the solvent removal manner is preferably reduced pressure distillation, the temperature of the reduced pressure distillation is preferably room temperature, the time of the reduced pressure distillation is not particularly required, the first polar organic solvent is completely evaporated, the equipment of the reduced pressure distillation is not particularly required, and in a specific embodiment of the present invention, the reduced pressure distillation is performed in a rotary evaporator. The invention preferably performs separation and purification on the crude solid product after the solvent is removed, in the invention, the separation and purification mode is preferably high performance liquid chromatography, the invention has no special requirement on the specific implementation mode of the high performance liquid chromatography, in the specific implementation example of the invention, the high performance liquid chromatography is stage elution, the used chromatographic column is a silica gel column, the eluent is a mixed solution of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 100:1 and 50: 1.
After obtaining the berberine with protected hydroxyl, carrying out deprotection and carboxylation reactions on the berberine with protected hydroxyl and trifluoroacetic acid in a second polar organic solvent to obtain carboxylated berberine; in the present invention, the second polar organic solvent preferably comprises dichloromethane, N-dimethylformamide or acetonitrile, more preferably comprises dichloromethane, and the volume ratio of the mass of the hydroxy-protected berberine to trifluoroacetic acid is preferably (50 to 100) mg: 1mL, and the volume ratio of the trifluoroacetic acid to the second organic solvent is preferably 1: 3.
In the present invention, the temperature of the deprotection and carboxylation reaction is preferably room temperature, and the time is preferably 3 hours. In the present invention, the hydroxyl group-protected berberine is preferably dissolved in trifluoroethylene and a second polar organic solvent to perform a deprotection reaction, and in the present invention, the deprotection reaction and the carboxylation reaction are preferably performed under stirring conditions, and the present invention does not particularly require a specific stirring embodiment, and can be performed in a manner well known to those skilled in the art.
In the present invention, the post-treatment is preferably performed on the reaction solution after the deprotection and carboxylation reactions are finished, the post-treatment preferably comprises solvent removal, precipitation and separation purification, in the present invention, the solvent removal is preferably performed by reduced pressure distillation, the temperature of the reduced pressure distillation is preferably room temperature, the time of the reduced pressure distillation is not particularly required, the second polar organic solvent is completely evaporated, the equipment of the reduced pressure distillation is not particularly required, and in a specific embodiment of the present invention, the reduced pressure distillation is performed in a rotary evaporator. In the present invention, the reaction solution after the solvent is removed is preferably subjected to precipitation, in the present invention, the precipitation solvent for precipitation is preferably anhydrous diethyl ether, in the present invention, the solid crude product obtained after precipitation is preferably subjected to separation and purification, in the present invention, the separation and purification mode is preferably high performance liquid chromatography, in the present invention, no special requirement is imposed on the specific implementation mode of the reversed phase high performance liquid chromatography, in the specific embodiment of the present invention, the high performance liquid chromatography is stage elution, the used chromatographic column is a silica gel column, the eluent is a mixed solution of dichloromethane and methanol, and the volume ratio of dichloromethane and methanol is 100:1 and 50: 1.
The invention carries out oxidation reaction on cisplatin and hydrogen peroxide to obtain tetravalent cisplatin; in the present invention, the mass concentration of the hydrogen peroxide is preferably 15%, and in the present invention, the hydrogen peroxide having a mass concentration of 15% is preferably obtained by diluting a commercially available hydrogen peroxide having a mass concentration of 30% with water. The mass volume ratio of the cisplatin to the hydrogen peroxide is preferably 30 mg: 1 mL. In the present invention, the oxidation reaction is preferably carried out under stirring, and the present invention does not require special embodiments of the stirring, and can be carried out in a manner well known to those skilled in the art.
After the carboxylated berberine and the tetravalent cis-platinum are obtained, the carboxylated berberine, the tetravalent cis-platinum and a condensation reaction catalyst are mixed in an organic solvent for condensation reaction to obtain the berberine coupling cis-platinum compound.
In the invention, the mole ratio of the carboxylated berberine to the tetravalent cisplatin is preferably 6: 5; the condensation reaction catalyst preferably comprises triethylamine and O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroborate, and the molar ratio of the triethylamine to the O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroborate is preferably (1-1.5): (1-1.5). In the present invention, the polar organic solvent for the condensation reaction preferably includes DMSO or N, N-dimethylformamide, and more preferably includes DMSO. In the present invention, the mass-to-volume ratio of the total mass of the carboxyberberine and the tetravalent cisplatin to the polar organic solvent of the condensation reaction is preferably 15 mg: 1 mL.
In the present invention, the condensation reaction preferably comprises the steps of: first mixing the carboxylated berberine with a polar organic solvent of partial condensation reaction to obtain a carboxylated berberine solution;
carrying out second mixing on tetravalent cisplatin, a condensation reaction catalyst and the residual polar organic solvent for the condensation reaction to obtain a tetravalent cisplatin mixed solution;
and carrying out third mixing on the tetravalent cisplatin mixed solution and the carboxylated berberine solution.
In the present invention, the volume ratio of the polar organic solvent for partial condensation reaction to the polar organic solvent for residual condensation reaction is preferably 1:1, in the present invention, the third mixing manner is preferably dropwise adding, in a specific embodiment of the present invention, the tetravalent cisplatin mixed solution is dropwise added to the carboxylated berberine solution. The present invention has no particular requirement on the rate of the dropwise addition.
In the present invention, the temperature of the condensation reaction is preferably 60 ℃ and the time is preferably 12 hours, in the present invention, the condensation reaction is preferably carried out under stirring, and the present invention has no special requirement on the specific embodiment of the stirring, and the condensation reaction can be carried out by adopting a manner well known to those skilled in the art.
After the condensation reaction is finished, the invention preferably carries out post-treatment on the condensation reaction liquid cooled to room temperature, the post-treatment preferably comprises solvent removal, separation and purification and drying, in the invention, the solvent removal mode is preferably reduced pressure distillation, the temperature of the reduced pressure distillation is preferably room temperature, the invention has no special requirement on the time of the reduced pressure distillation and can completely evaporate the polar organic solvent of the condensation reaction, the invention has no special requirement on equipment of the reduced pressure distillation, and in the specific embodiment of the invention, the reduced pressure distillation is carried out in a rotary evaporator. The invention preferably performs separation and purification on the solid crude product obtained after the solvent is removed, in the invention, the separation and purification mode is preferably reverse phase high performance liquid chromatography, the invention has no special requirements on the specific implementation mode of the reverse phase high performance liquid chromatography, in the specific implementation mode of the invention, the reverse phase high performance liquid chromatography is stage elution, a used chromatographic column is a C-18 column, and an eluent is a mixed solution of water and acetonitrile. After separation and purification, the pure berberine coupling cis-platinum product is preferably dried in a freeze-drying mode, wherein the freeze-drying temperature is preferably 0 ℃ and the time is preferably 12 hours.
The preparation method provided by the invention can ensure that the berberine coupling cis-platinum is synthesized with higher efficiency and better yield, the pure berberine coupling cis-platinum is light yellow solid powder, and the ratio of the amount of the berberine coupling cis-platinum compound to the amount of the berberine compound is 1: 20.
The invention provides an application of the berberine coupling cis-platinum compound in the technical scheme or the berberine coupling cis-platinum compound obtained by the preparation method in the technical scheme in the preparation of anti-colorectal cancer drugs.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention.
Example 1
Reference is made to "Antibacterial activity and structure-activity relationships of bergenine analogues. Eur J Med Chem (1996)31, 469-478", at N2Under protection, 1000mg of berberine is reacted for 15min at 190 ℃, then cooled to room temperature, and then added with 100ml of berberine with the volume ratio of 1:1, washing the mixed solution of ethanol and methanol, and separating and purifying by high performance liquid chromatography, wherein an eluent used by the high performance liquid chromatography is the mixed solution of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 20:1 to obtain the hydroxylated berberine;
carrying out affinity substitution reaction on 320mg of hydroxylated berberine and 234mg of tert-butyl bromoacetate in 10mL of dichloromethane solution containing 260mg of N, N-diisopropylethylamine at room temperature under stirring for 8h, removing dichloroethane from the reaction solution after the nucleophilic substitution reaction at room temperature by using a rotary evaporator to obtain a solid crude product, and separating and purifying the solid crude product by using high performance liquid chromatography and silica gel column, and mixed solution of dichloromethane and methanol (the volume ratio of dichloromethane to methanol is 100:1 and 50:1) as an eluent by using stepwise elution to obtain the hydroxyl-protected berberine;
dissolving 100mg of carboxyl-protected berberine and 3mL of trifluoroacetic acid in 1mL of dichloromethane, carrying out deprotection reaction for 3h at room temperature under the stirring condition, removing dichloroethane from the reaction solution after the deprotection reaction at room temperature by adopting a rotary evaporator, adding anhydrous ether to obtain a solid crude product, and separating and purifying the solid crude product by adopting high performance liquid chromatography and using a silica gel column, and a mixed solution of dichloromethane and methanol (the volume ratio of dichloromethane to methanol is 100:1 and 50:1) as an eluent by adopting stepwise elution to obtain carboxylated berberine;
carrying out oxidation reaction on 300mg of cisplatin and 10mL of hydrogen peroxide with the mass concentration of 15% under the stirring condition to obtain tetravalent cisplatin;
300mg of carboxylation berberine and 10ml of DMSO are mixed under the condition of stirring for the first time to obtain a carboxylation berberine solution, 330mg of cis-platinum, 120mg of triethylamine, 456mg of O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate and 10ml of DMSO are mixed under the condition of stirring for the second time to obtain a tetravalent cis-platinum mixed solution, the tetravalent cis-platinum mixed solution is dripped into the carboxylation berberine solution to carry out condensation reaction under the condition of stirring, the reaction temperature is 60 ℃, after 12 hours, DMSO is removed from the condensation reaction liquid cooled to room temperature by a rotary evaporator to obtain a solid crude product, reversed phase high performance liquid chromatography is adopted, a C-18 chromatographic column is used, the cis-platinum mixed solution is used as an eluent, the solid crude product is separated and purified by a stepwise elution mode, after separation and purification, the obtained berberine coupling pure product is subjected to freeze drying for 12 hours at 0 ℃, 90mg of berberine coupled cisplatin compound was obtained.
FIG. 1 is a mass spectrum of a berberine coupled cis-platinum compound prepared in example 1;
FIG. 2 is a NMR chart of a berberine coupled cisplatin compound prepared in example 1;
as can be seen from the nuclear magnetic spectrum mass spectrogram in FIG. 1, the actually measured molecular weight of the berberine coupling cisplatin compound prepared in the embodiment 1 of the invention is 696.0, which is consistent with the theoretically calculated molecular weight of 690.06; as can be seen from the NMR chart of FIG. 2, the chemical shift assignments of the H atoms of the berberine coupling cisplatin compound prepared in the embodiment 1 of the present invention are clear and can correspond to each other.
Example 2
Reference is made to "Antibacterial activity and structure-activity relationships of bergenine analogues. Eur J Med Chem (1996)31, 469-478", at N2Under protection, 1g of berberine reacts for 15min at 190 ℃, then the temperature is reduced to room temperature, and 100ml of berberine with the volume ratio of 1:1, washing the mixed solution of ethanol and methanol, and separating and purifying by high performance liquid chromatography, wherein an eluent used by the high performance liquid chromatography is the mixed solution of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 20:1 to obtain the hydroxylated berberine;
carrying out affinity substitution reaction on 320mg of hydroxylated berberine and 234mg of tert-butyl bromoacetate in 10mL of dichloromethane solution containing 260mg of N, N-diisopropylethylamine at room temperature under stirring for 8h, removing dichloroethane from the reaction solution after the nucleophilic substitution reaction at room temperature by using a rotary evaporator to obtain a solid crude product, and separating and purifying the solid crude product by using high performance liquid chromatography and silica gel column, and mixed solution of dichloromethane and methanol (the volume ratio of dichloromethane to methanol is 100:1 and 50:1) as an eluent by using stepwise elution to obtain the hydroxyl-protected berberine;
dissolving 100mg of carboxyl-protected berberine and 3mL of trifluoroacetic acid in 1mL of dichloromethane, carrying out deprotection reaction for 3h at room temperature, removing dichloroethane from the reaction solution after the deprotection reaction at room temperature by adopting a rotary evaporator, adding anhydrous ether to obtain a solid crude product, and separating and purifying the solid crude product by adopting high performance liquid chromatography and using a silica gel column, and a mixed solution of dichloromethane and methanol (the volume ratio of dichloromethane to methanol is 100:1 and 50:1) as an eluent by adopting stepwise elution to obtain carboxylated berberine;
carrying out oxidation reaction on 300mg of cisplatin and 10mL of hydrogen peroxide with the mass concentration of 15% under the stirring condition to obtain tetravalent cisplatin;
carrying out first mixing on 300mg of carboxylation berberine and 10mL of DMSO under the stirring condition to obtain a carboxylation berberine solution, carrying out second mixing on 330mg of cis-platinum, 120mg of triethylamine, 456mg of O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate and 10mL of DMSO under the stirring condition to obtain a tetravalent cis-platinum mixed solution, dropwise adding the tetravalent cis-platinum mixed solution into the carboxylation berberine solution to carry out condensation reaction under the stirring condition, carrying out condensation reaction at the reaction temperature of 60 ℃ for 12h, removing the DMSO from the condensation reaction solution cooled to room temperature by using a rotary evaporator to obtain a solid crude product, carrying out reversed-phase high performance liquid chromatography by using a C-18 chromatographic column and using a mixed solution of water and acetonitrile as an eluent, carrying out separation and purification on the solid crude product by using a stepwise elution mode, carrying out freeze drying on the obtained berberine coupling pure product at 0 ℃ for 12h after separation and purification, 90mg of berberine coupled cisplatin compound was obtained.
The mass spectrum and nuclear magnetic resonance image of the berberine coupling cis-platinum compound prepared in the example 2 are similar to those of the product in the example 1.
Example 3
Reference is made to "Antibacterial activity and structure-activity relationships of bergenine analogues. Eur J Med Chem (1996)31, 469-478", at N2Under protection, 1g of berberine reacts for 15min at 190 ℃, then the temperature is reduced to room temperature, and 100ml of berberine with the volume ratio of 1:1, washing the mixed solution of ethanol and methanol, and separating and purifying by high performance liquid chromatography, wherein an eluent used by the high performance liquid chromatography is the mixed solution of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 20:1 to obtain the hydroxylated berberine;
carrying out affinity substitution reaction on 320mg of hydroxylated berberine and 234mg of tert-butyl bromoacetate in 10mL of dichloromethane solution containing 260mg of N, N-diisopropylethylamine at room temperature under stirring for 8h, removing dichloroethane from the reaction solution after the nucleophilic substitution reaction at room temperature by using a rotary evaporator to obtain a solid crude product, and separating and purifying the solid crude product by using a silica gel column, and a mixed solution of dichloromethane and methanol (the volume ratio of dichloromethane to methanol is 100:1 and 50:1) as an eluent by using stepwise elution to obtain the hydroxyl-protected berberine by using a high performance liquid chromatography method;
dissolving 100mg of carboxyl-protected berberine and 3mL of trifluoroacetic acid in 1mL of dichloromethane, carrying out deprotection reaction for 3h at room temperature under the stirring condition, removing dichloroethane from the reaction solution after the deprotection reaction at room temperature by adopting a rotary evaporator, adding anhydrous ether to obtain a solid crude product, and separating and purifying the solid crude product by adopting high performance liquid chromatography and using a silica gel column, and a mixed solution of dichloromethane and methanol (the volume ratio of dichloromethane to methanol is 100:1 and 50:1) as an eluent by adopting stepwise elution to obtain carboxylated berberine;
carrying out oxidation reaction on 300mg of cisplatin and 10mL of hydrogen peroxide with the mass concentration of 15% under the stirring condition to obtain tetravalent cisplatin;
300mg of carboxylation berberine and 10ml of DMSO are mixed under the condition of stirring for the first time to obtain a carboxylation berberine solution, 330mg of cis-platinum, 120mg of triethylamine, 456mg of O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate and 10ml of DMSO are mixed under the condition of stirring for the second time to obtain a tetravalent cis-platinum mixed solution, the tetravalent cis-platinum mixed solution is dripped into the carboxylation berberine solution to carry out condensation reaction under the condition of stirring, the reaction temperature is 60 ℃, after 12 hours, DMSO is removed from the condensation reaction liquid cooled to room temperature by a rotary evaporator to obtain a solid crude product, reversed phase high performance liquid chromatography is adopted, a C-18 chromatographic column is used, the cis-platinum mixed solution is used as an eluent, the solid crude product is separated and purified by a stepwise elution mode, after separation and purification, the obtained berberine coupling pure product is subjected to freeze drying for 12 hours at 0 ℃, 90mg of berberine coupled cisplatin compound was obtained.
The mass spectrum and nuclear magnetic resonance image of the berberine coupling cis-platinum compound prepared in the example 3 are similar to those of the product in the example 1.
Test example 1
The berberine coupling cisplatin compound prepared in the example 1 is subjected to reduction reaction in a reduction medium, wherein the reduction medium is sodium ascorbate, the reaction time is 12 hours, the reaction temperature is 37 ℃, a product after the reduction reaction is detected by a high performance liquid chromatography, and the berberine coupling cisplatin compound, berberine and cisplatin are used as comparison, wherein the berberine coupling cisplatin compound is recorded as: B-D, carboxylated berberine: b-1, cisplatin labeled DDP, and in order to make cisplatin detectable in the HPLC chromatogram, cisplatin was chelated with a chelating agent DDTC labeled Pt (DDTC)2The hplc chromatogram is shown in fig. 3, and it can be seen from fig. 3 that the berberine coupled cisplatin compound obtained in example 1 of the present application can be successfully cleaved in a reducing medium, and carboxylated berberine and cisplatin can be released with higher efficiency.
Test example 2
The MTT method is used for detecting the cytotoxicity of the berberine coupling cis-platinum compound prepared in the embodiment 1 of the invention on human colon cancer cells HCT116/SW620 and human normal intestinal epithelial cells HIEC-6. The specific experiment is divided into five groups, namely a berberine independent medicinal group (Ber group), a berberine coupling cis-platinum compound medicinal group (B-D group), a cis-platinum independent medicinal group (DDP group) and a berberine and cis-platinum combined medicinal group (B + D group), after the cells are treated by different medicinal groups for 24 hours, the MTT experiment detects the inhibition effect of the medicaments on cell proliferation and calculates the corresponding IC50The specific experimental data are shown in table 1, and the IC50 result of MTT shows that the berberine-conjugated cis-platinum compound has better effect on the proliferation inhibition of tumor cells compared with either berberine or a cis-platinum single drug group or a berberine and cis-platinum combined drug group, and the cytotoxicity of the berberine-conjugated cis-platinum compound on normal intestinal epithelial cells (HIEC-6) is far lower than that of cis-platinum. The berberine coupling cis-platinum compound prepared in the embodiment 1 of the invention shows selectivity to tumor cells compared with normal cells.
TABLE 1 inhibition of cell proliferation by different drug treatment groups
| Cellline | Ber(μM) | DDP(μM) | B+D(μM) | B-D(μM) |
| HCT116 | 57.76 | 32.29 | 30.22 | 3.99 |
| SW620 | 41.74 | 31.26 | 30.75 | 5.22 |
| HIEC-6 | ＞200 | 25 | 36.54 | ＞200 |
Test example 3
An immunofluorescence experiment is used for detecting the action mechanism of the berberine coupling cisplatin compound prepared in the embodiment 1 of the invention on human colon cancer cells HCT 116. The results of immunofluorescence detection after HCT116 cells are treated for 24 hours by respectively using a blank control group (control), a berberine independent drug group (Ber group), a berberine coupled cis-platinum compound drug group (B-D group), a cis-platinum independent drug group (DDP group) and a berberine and cis-platinum combined drug group (B + D group) are shown in figure 4, and it can be seen from figure 4 that the expression level of gamma H2A protein (DNA damage marker protein) in the B-D group prepared in example 1 is obviously increased, which indicates that the berberine coupled cis-platinum compound prepared in example 1 can interfere DNA replication after treating the cells, so that DNA damage is broken and the proliferation of tumor cells is influenced.
Test example 4
The Westen Blot experiment is used for detecting the action mechanism of the berberine coupling cis-platinum compound prepared in the embodiment 1 of the invention to human colon cancer cells HCT 116. HCT116 cells are treated by a blank control group (control), a berberine independent drug group (Ber group), a berberine coupled cis-platinum compound drug group (B-D group), a cis-platinum independent drug group (DDP group) and a berberine and cis-platinum combined drug group (B + D group) for 24 hours respectively, Westen Blot experiment results show that the expression level of gamma H2A protein (DNA damage marker protein) in the B-D group is obviously increased, as shown in figure 5, and Westen Blot experiments also show that related protein Caspase-3, PARP shear activation and P53 expression which can obviously induce HCT116 cell apoptosis after B-D group treatment are up-regulated, which shows that the berberine coupled compound prepared in example 1 of the invention can induce cell DNA breakage and cell apoptosis after treating the cells, so that cell cycle block is caused to influence the proliferation of tumor cells.
Test example 5
The action mechanism of the berberine coupling cis-platinum compound prepared in the embodiment 1 of the invention on human colon cancer cells HCT116 is detected by a PI single staining method. HCT116 cells are treated by a blank control group (control), a berberine independent drug group (Ber group), a berberine coupled cis-platinum compound drug group (B-D group), a cis-platinum independent drug group (DDP group) and a berberine and cis-platinum combined drug group (B + D group) for 24 hours respectively, and the result of a PI single staining cell cycle arrest detection experiment shows that the cells are arrested in the S phase after the B-D group treatment, as shown in the table 2 and the figure 6, the berberine coupled cis-platinum compound prepared in the embodiment 1 of the invention can cause cell cycle arrest to further influence the proliferation of tumor cells after the cells are treated.
TABLE 2 experiment results of PI single staining method for detecting cell cycle arrest of different drug treatment groups
Test example 6
The Annexin V/PI double staining method is used for detecting the action mechanism of the berberine coupling cisplatin compound prepared in the embodiment 1 of the invention on human colon cancer cells HCT 116. HCT116 cells are treated by a blank control group (control), a berberine independent drug group (Ber group), a berberine coupled cis-platinum compound drug group (B-D group), a cis-platinum independent drug group (DDP group) and a berberine and cis-platinum combined drug group (B + D group) for 24 hours respectively, and the cell apoptosis result of Annexin V/PI double staining shows that the B-D group induces 52.4 percent of HCT116 cell apoptosis rate which is far higher than that of the cis-platinum under the same concentration, as shown in a table 3 and a figure 7, the berberine coupled cis-platinum compound prepared in the embodiment 1 of the invention can induce cell apoptosis to further influence the proliferation of tumor cells after treating the cells.
TABLE 3 AnnexinV/PI double staining test results for apoptosis test of different drug treatment groups
| HCT116 cells | Control | Ber(μM) | DDP(μM) | B+D(μM) | B-D(μM) |
| The apoptosis rate% | 5.33 | 4.93 | 7.82 | 61.3 | 4.92 |
Test example 7
The intake conditions of the berberine coupling cis-platinum compound prepared in the embodiment 1 of the invention on human colon cancer HCT116 and SW620 cells and human normal intestinal epithelial cells HIEC-6 on B-D are determined by an inductively coupled plasma mass spectrometry (ICP-MS) experimental method. Treating HCT116 cells and SW620 cells with a blank control group (control), a group of berberine-coupled cis-platinum compound (group B-D), a group of cis-platinum alone (group DDP) and a group of berberine-and cis-platinum combination (group B + D) for 6h respectively; treating HIEC-6 cells with blank control group (control), group of berberine-coupled cisplatin compounds (group B-D), and group of cisplatin alone (group DDP) for 6 hr; the ICP-MS experiment is used for detecting the intracellular platinum accumulation amount, the experiment result is shown in the table 4, the figure 8 and the figure 9, the ingestion amount of the tested tumor cells to the B-D is obviously higher than that to the cisplatin, and the ingestion amount of the tested tumor cells to the cisplatin is respectively 13.27 times and 6.85 times of that of the cells to the cisplatin; there was also a large difference in platinum uptake by normal cells for B-D and cisplatin. Test results show that the great increase of accumulation amount of the berberine coupling cis-platinum compound prepared in the embodiment 1 in HCT116 and SW620 cells is one of the important reasons for the enhancement of cytotoxicity of B-D; whereas, the selectivity in tumor cells is related to the difference in uptake and intracellular accumulation between tumor cells and normal cells.
TABLE 4 intracellular platinum levels following treatment of HCT116, SW620 and HIEC-6 cells with different drug treatment groups
Test example 8
Nude mice with transplanted tumors were administered with a blank control group (control), a group of cisplatin alone (DDP group) and a group of berberine-conjugated cisplatin compound (groups B-D) continuously for 16 days, and the body weight statistics (shown as D in fig. 9) and the growth of the transplanted tumors, including the volume statistics (shown as a in fig. 10) and the weight statistics (shown as c in fig. 10) of the transplanted tumors, of the nude mice were recorded, and the nude mice were sacrificed 16 days after administration to take pictures of the transplanted tumors (shown as B in fig. 10); the analysis in fig. 10 shows that the tumor volume of the control group grows rapidly, and the growth of the tumor is significantly inhibited although the tumor volumes of the DDP group and B-D group are also increasing; analysis from c in figure 10 shows that DDP group treated mice inhibited tumor growth to some extent, while B-D group significantly inhibited tumor growth, where statistical significance was analyzed by two-way anova using GraphPad Prism software. Statistical significance was expressed as p <0.05, p <0.01 and p < 0.001. The statistical result shows that B-D has obvious function of inhibiting the growth of in vivo tumor cells; and the body weight statistical chart of the mice (shown as D in figure 10) shows that the body weight of the mice in the DDP group slightly decreases, but the mice in the B-D group have no obvious change, and the safety of the B-D in the mice is reflected to a certain extent; analysis from B in FIG. 10 shows that the tumor volumes of DDP and B-D groups were significantly smaller than those of the control group and those of B-D group were significantly smaller than those of DDP group 16 days after administration, and the difference was statistically significant.
In conclusion, the berberine coupling cis-platinum compound provided by the invention is superior to cis-platinum in three aspects of enhancing the inhibitory activity of intestinal cancer cells, reducing the toxicity to normal cells and inhibiting the tumor in a nude mouse body.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A berberine coupling cis-platinum compound has a structure shown in a formula I:
2. a process for the preparation of a berberine coupled cisplatin compound as claimed in claim 1 comprising the steps of:
carrying out hydroxylation reaction on the berberine to obtain hydroxylated berberine;
carrying out nucleophilic substitution reaction on the hydroxylated berberine, butyl bromoacetate and an organic basic catalyst in a first polar organic solvent to obtain berberine with protected hydroxyl;
carrying out deprotection and carboxylation reactions on the hydroxyl protected berberine and trifluoroacetic acid in a second polar organic solvent to obtain carboxylated berberine;
performing oxidation reaction on cisplatin and hydrogen peroxide to obtain tetravalent cisplatin;
and carrying out condensation reaction on the carboxylated berberine, tetravalent cisplatin and a condensation reaction catalyst in a polar organic solvent of the condensation reaction to obtain the berberine coupling cisplatin compound.
3. The method according to claim 2, wherein the molar ratio of the hydroxylated berberine to the butyl bromoacetate to the organic basic catalyst is 2 (2.4-3) to (2-4).
4. The production method according to claim 2 or 3, wherein the organic basic catalyst comprises N, N-diisopropylethylamine and/or triethylamine; the temperature of the nucleophilic substitution reaction is room temperature, and the time is 8-12 h.
5. The method according to claim 2, wherein the ratio of the mass of the hydroxy-protected berberine to the volume of trifluoroacetic acid is (50-100) mg: 1 mL;
the volume ratio of the trifluoroacetic acid to the second polar organic solvent is 1 (2-3).
6. The method according to claim 2, wherein the molar ratio of the carboxylated berberine to the tetravalent cisplatin is 6: 5.
7. The preparation method according to claim 2, wherein the condensation reaction catalyst comprises triethylamine and O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate;
the molar ratio of the triethylamine to the O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroborate is (1-1.5): (1-1.5).
8. The process according to claim 2, 6 or 7, wherein the condensation reaction is carried out at a temperature of 60 ℃ for a period of 12 hours.
9. The method of claim 2, wherein the first and second polar organic solvents independently comprise dichloromethane, N-dimethylformamide, or acetonitrile; the polar organic solvent for the condensation reaction includes DMSO or N, N-dimethylformamide.
10. The use of a berberine coupling cis-platinum compound as defined in claim 1 or a berberine coupling cis-platinum compound obtained by the preparation method as defined in claims 2-9 in the preparation of anti-intestinal cancer drugs.
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