CN107417752B - Compound with anticancer activity and preparation method and application thereof - Google Patents
Compound with anticancer activity and preparation method and application thereof Download PDFInfo
- Publication number
- CN107417752B CN107417752B CN201710618269.XA CN201710618269A CN107417752B CN 107417752 B CN107417752 B CN 107417752B CN 201710618269 A CN201710618269 A CN 201710618269A CN 107417752 B CN107417752 B CN 107417752B
- Authority
- CN
- China
- Prior art keywords
- compound
- platinum
- reaction
- anticancer activity
- lactosamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a compound with anticancer activity and a preparation method and application thereof, relating to the technical field of chemical synthetic drugs. The compound has a structure shown in a formula (I) or (II). The lactose with liver targeting and water solubility provided by the invention is subjected to condensation reaction with a platinum (IV) compound to finally prepare a monomolecular compound which is stimulus-responsive and can be self-assembled and has anticancer activity. The compound provided by the invention improves the water solubility of the platinum (IV) compound by introducing the water-soluble lactose molecule with a liver targeting function, thereby forming a monomolecular platinum (IV) compound capable of self-assembling, reducing the cytotoxicity of the platinum (IV) compound, simultaneously enabling the synthesized tetravalent platinum prodrug to have amphipathy, and improving the accumulation degree of the tetravalent platinum prodrug in liver cancer cells.
Description
Technical Field
The invention relates to the technical field of chemical synthetic drugs, in particular to a compound with anticancer activity and a preparation method and application thereof.
Background
Since the discovery of cisplatin as an anticancer active ingredient in 1967, the research and use of platinum-based anticancer drugs has been greatly developed, and several thousand platinum-series compounds have been screened, several dozen of which have been clinically studied and several approved.
Among them, platinum (II) has been widely used in chemotherapy, such as cis-dichlorodiammineplatinum (II), also called cisplatin (cissplatin), which is a periodic nonspecific drug and is the most clinically used bivalent platinum drug. Although clinical practice proves that the cisplatin has the characteristics of wide anticancer spectrum, strong effect, synergistic effect with various antitumor drugs, no cross drug resistance and the like, and is widely used for treating solid tumors such as ovarian cancer, prostatic cancer, testicular cancer, lung cancer, nasopharyngeal carcinoma, esophageal cancer, malignant lymphoma, breast cancer and the like. However, cisplatin has severe digestive tract reaction, myelosuppression, acoustic neurotoxicity, irreversible damage to the kidney and other toxic and side effects, and the improvement of the therapeutic index of cisplatin is limited. Meanwhile, low water solubility and high toxic and side effects are common problems of other bivalent platinum drugs. In addition, platinum (II) has high reactivity and thus low stability under physiological conditions, and is often inactivated by binding with bioactive molecules such as GSH, metallothionein, etc., in large part before platinum (II) reaches target cancer cells. The use of platinum (II) compounds is limited for a variety of reasons.
In recent years, platinum (IV) compounds have received much attention as compared with platinum (II) compounds because they form octahedral structures in space, are kinetically inert, have low reactivity, and have less toxic and side effects. In addition, by modifying the structure of the vertical axis, the reduction potential of the platinum (IV) compound can be changed, so that the platinum (II) can be rapidly reduced under the condition of cells, and the anticancer effect can be exerted. Although many platinum (IV) compounds have been synthesized and tested for their activity, the most representative tetravalent platinum drug is Satraplatin, which can be administered orally. The drug was developed by Bristol-Squibb, Inc. in the United states, Johnson Matthey, and cancer institute, and entered clinical trials in 1992, now in clinical stage III. However, the therapeutic effect is far from that of cisplatin and carboplatin because platinum (IV) compounds hardly reach the lesion site due to their early reduced erratic movement in blood circulation, and thus the platinum (IV) compounds have poor solubility, which causes problems in clinical application, and thus further modification is necessary to improve the solubility, therapeutic effect, and amount of accumulation reaching the lesion site.
To increase the amount of drug accumulated at the tumor site, much work has been done on the tumor microenvironment in detail. Among them, it has been found that asialoglycoprotein receptor (ASGPR) exists at a high concentration on the surface of the hepatic cell membrane, and glycoprotein having a non-reducing galactose or N-acetylgalactosan as the sugar chain terminal has specific recognition and binding properties, and thus is also called hepatic cell galactose receptor. Thus, a ligand that specifically binds to the receptor can achieve a specific effect on hepatocytes. Galactose or lactose can both achieve targeting of this receptor. Meanwhile, lactose or galactose, which is one of the saccharides, has the commonalities of the saccharides: the water solubility is good. Therefore, the lactose is combined with the tetravalent platinum prodrug molecule, so that the accumulation amount of the platinum drug at the liver tumor part can be increased, the hydrophilicity of platinum can be improved, the solubility of platinum can be improved, and nano self-assembly can be carried out.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a compound with anticancer activity, and a preparation method and an application thereof, wherein the prepared compound has high antitumor activity and low cytotoxicity. The invention firstly provides a compound with anticancer activity, which has a structure shown in a formula (I) or (II):
(I) or (II) above
Is selected from
The invention also provides a preparation method of the compound with anticancer activity, which comprises the following steps:
A) reacting a platinum (II) compound with hydrogen peroxide to obtain a platinum (IV) compound;
B) reacting the platinum (IV) compound obtained in the step A) with succinic anhydride to obtain a platinum (IV) complex containing one carboxyl or two carboxyl in the axial direction;
C) dehydrating lactobionic acid in a reaction solvent to obtain lactolactone;
D) reacting lactosucrose obtained in the step C) with ethylenediamine to obtain lactosucrose;
E) reacting the platinum (IV) complex obtained in the step B) with the lactosamine obtained in the step D) in the presence of a condensing agent to obtain a compound represented by the structure of formula (I) or (II);
(I) or (II) above
Is selected from
Preferably, the platinum (II) compound is selected from
Preferably, the reaction temperature of the step B) is 25-75 ℃, and the reaction time is 12-24 h.
Preferably, in the step D), the molar ratio of lactolactone to ethylenediamine is 1: (10-100).
Preferably, the reaction temperature of the step D) is 65-75 ℃, and the reaction time is 5-8 h.
Preferably, in said step E), the molar ratio of platinum (IV) compound, lactosamine and condensing agent is 1: (1-4): (2-5).
Preferably, the condensing agent is selected from N, N ' -carbonyldiimidazole, N- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or 2- (7-benzotriazol oxide) -N, N, N ', N ' -tetramethyluronium hexafluorophosphate.
Preferably, the reaction temperature of the step E) is 25-35 ℃, and the reaction time is 12-24 h.
The invention also provides the application of the compound in preparing anticancer drugs.
The invention has the advantages of
The invention provides a compound with anticancer activity, a preparation method and application thereof, wherein the compound has a structure shown in a formula (I) or (II). Compared with the prior art, the lactose with liver targeting and water solubility provided by the invention is subjected to condensation reaction with a platinum (IV) compound to finally prepare a monomolecular compound which is stimulus-responsive and can be self-assembled and has anticancer activity. The compound provided by the invention improves the water solubility of the platinum (IV) compound, namely the hydrophilic-hydrophobic water balance, by introducing the water-soluble lactose molecule with the liver targeting function, so that a monomolecular platinum (IV) compound capable of self-assembling is formed, the cytotoxicity of the platinum (IV) compound is reduced, the synthesized tetravalent platinum prodrug has amphipathy, the accumulation degree of the synthesized tetravalent platinum prodrug on liver cancer cells can be improved, and the activation and release of the platinum compound are facilitated under the condition of external light stimulation or intracellular reduction due to the existence of platinum, so that the compound has higher antitumor activity.
The cytotoxicity experiment result shows that the compound provided by the invention has small killing property on normal mouse fibroblast L929 cells, has good killing effect and maximum drug accumulation on cancer cells such as human cervical cancer HeLa cells, human lung adenocarcinoma A549 cells and human liver cancer HepG2 cells, particularly on HepG2, and has the strongest killing effect on subcutaneous liver cancer animal models. Therefore, the lactose molecule with hydrophilicity and targeting is introduced into the platinum (IV) in the axial direction, so that the self-assembly morphology of the platinum (IV) can be regulated, the toxicity of the platinum (IV) to normal cells can be reduced, the killing capability of the platinum (IV) to a liver cancer model can be enhanced, and the solubility and the anticancer effect of platinum (IV) and other drugs can be improved.
Drawings
FIG. 1 shows IR absorption spectra of compound and lactosamine prepared in examples 2 and 4 of the present invention, respectively;
FIG. 2 shows the NMR spectra of the compounds prepared in examples 2 and 4 of the present invention;
FIG. 3 is a mass spectrum of the compound prepared in examples 2 and 4 of the present invention and lactosamine, respectively;
fig. 4 is a transmission electron microscope picture and an atomic force scanning electron microscope picture of the compounds prepared in examples 2 and 4 of the present invention, respectively.
Detailed Description
The invention firstly provides a compound with anticancer activity, which has a structure shown in a formula (I) or (II):
in the formula (I) or (II), the
Is selected from
The compound provided by the invention improves the water solubility, namely the hydrophilic-hydrophobic water balance, of the platinum (IV) compound by introducing the water-soluble lactose molecule with the liver targeting function, so that the monomolecular platinum (IV) compound capable of being self-assembled is formed, the cytotoxicity of the platinum (IV) compound is reduced, and the compound is beneficial to the activation and release of the platinum compound under the condition of external light stimulation or intracellular reduction due to the existence of platinum, so that the compound has higher antitumor activity. The result of a cytotoxicity experiment shows that the platinum (IV) complex provided by the invention has small killing property on normal mouse fibroblast L929 cells, has good killing effect on cancer cells such as human cervical cancer HeLa cells, human lung adenocarcinoma A549 cells and human liver cancer HepG2 cells, particularly on HepG2, and can still obtain anticancer activity equivalent to that of cisplatin while reducing the system toxicity.
The invention also provides a preparation method of the compound with anticancer activity, which comprises the following steps:
A) reacting a platinum (II) compound with hydrogen peroxide to obtain a platinum (IV) compound;
B) reacting the platinum (IV) compound obtained in the step A) with succinic anhydride to obtain a platinum (IV) complex containing one carboxyl or two carboxyl in the axial direction;
C) dehydrating lactobionic acid in a reaction solvent to obtain lactolactone;
D) reacting lactosucrose obtained in the step C) with ethylenediamine to obtain amino functionalized lactose, namely lactosamine;
E) reacting the platinum (IV) complex obtained in the step B) with the lactosamine obtained in the step D) in the presence of a condensing agent to obtain compounds represented by the structures of formula (I) and (II);
according to the invention, the compound shown in the formula (I) provided by the invention is synthesized by three steps, and firstly, a platinum (II) compound reacts with hydrogen peroxide to obtain a platinum (IV) compound.
In the present invention, the source of the platinum (II) compound is not particularly limited, and may be generally commercially available or simply synthesized. Among them, the platinum (II) compound is preferably
The invention has no special requirement on the hydrogen peroxide, and the hydrogen peroxide is preferably 30 percent; the molar ratio of the volume of the hydrogen peroxide to the platinum (II) compound is preferably (5mL-15 mL): (1mmol-3 mmol); the reaction temperature is preferably room temperature, the reaction time is preferably 5-8h, and the reaction is preferably carried out in a dark place; after the reaction is finished, purifying the product, preferably, removing the excessive hydrogen peroxide by a filtering method to obtain yellow powder of the product.
The structure of the reaction product corresponds to that of a platinum (IV) compound
According to the present invention, after obtaining the platinum (IV) compound, it is reacted with succinic anhydride in a reaction solvent, preferably in a molar ratio of 1: (1-1.1), more preferably 1: 1; the reaction solvent is preferably dimethyl sulfoxide or N, N-dimethylformamide. The reaction temperature is preferably 25 ℃ to 35 ℃ and the reaction time is preferably 12h to 24h, and the single carboxyl modified platinum (IV) compound is obtained, correspondingly
According to the present invention, lactosamine synthesis is described, lactobionic acid is first dehydrated in a reaction solvent under the catalysis of trifluoroacetic acid to form lactolactolactonic lactone, said lactobionic acid and trifluoroacetic acid preferably being in a molar ratio of 1: (0.01-0.05), more preferably 1: (0.01-0.03); the reaction solvent is preferably methanol, the reaction temperature is preferably 65-75 ℃, and the reaction time is preferably 5-8 h; after the reaction is finished, the preferable condition for obtaining the lactonase is to drain methanol.
For further synthesis of lactosamine, lactolactone is preferably dissolved directly in methanol at 35-45 ℃ and reacted with ethylenediamine, said lactolactone and ethylenediamine preferably being present in a molar ratio of 1: (10-100), the temperature of the reaction is preferably 25-35 ℃, and the time of the reaction is preferably 12-24 h; after the reaction is finished, the product is purified, preferably, acetone is directly used for sedimentation, and after a filter cake is filtered and vacuum-dried, the lactosamine product is obtained and is white powder.
The reaction formula is as follows:
the structure of lactosamine is shown as formula (III),
according to the present invention, said lactosamine is subjected to a condensation reaction with a platinum (IV) compound modified with a monocarboxylic group in the presence of a condensing agent and a reaction solvent to obtain a platinum (IV) complex containing one lactose molecule in the axial direction.
The molar ratio of the monocarboxyl-modified platinum (IV) compound to lactosamine is preferably 1: (1-3), more preferably 1: (1-2); the solvent of the reaction is preferably N, N' -Dimethylformamide (DMF) or dimethyl sulfoxide, the temperature of the reaction is preferably 25-35 ℃, and the time of the reaction is preferably 12-24 h; after the reaction is finished, the product is purified, preferably, the product is directly precipitated by acetone, a filter cake is dissolved by a small amount of water and then passes through a Sephadex G-15 column to obtain the product, and the product is light yellow powder after being freeze-dried.
The source of the condensing agent is not particularly limited in the present invention, and may be a general commercial product. The condensing agent is preferably N, N ' -carbonyldiimidazole, N- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or 2- (7-benzotriazole oxide) -N, N, N ', N ' -tetramethylurea hexafluorophosphate. The molar ratio of the platinum (IV) complex to the condensing agent is preferably 1: (2-2.5), more preferably 1: (2-2.25).
The prepared compound with the structure of the formula (I) is subjected to infrared absorption, nuclear magnetic resonance and electrospray mass spectrometry, and the result shows that the lactose derivative and the carboxyl modified platinum (IV) are successfully condensed to obtain the compound with the structure of the formula (I).
The compound shown in the formula (II) structure provided by the invention is synthesized by three steps, and firstly, a platinum (II) compound reacts with hydrogen peroxide to obtain a platinum (IV) compound.
The source of the compound is not particularly required, and the compound can be generally commercially available or simply synthesized. Among them, the platinum (II) compound is preferably
The invention has no special requirement on the hydrogen peroxide, and the hydrogen peroxide is preferably 30 percent; the molar ratio of the volume of the hydrogen peroxide to the platinum (II) compound is preferably (5mL-15 mL): (1mmol-3 mmol); the reaction temperature is preferably room temperature, the reaction time is preferably 5-8h, and the reaction is preferably carried out in a dark place; after the reaction is finished, purifying the product, preferably, removing the excessive hydrogen peroxide by a filtering method to obtain yellow powder of the product.
The structure of the reaction product corresponds to that of a platinum (IV) compound
According to the present invention, after obtaining the platinum (IV) compound, it is reacted with succinic anhydride in a reaction solvent, preferably in a molar ratio of 1: (2-5), more preferably 1: 4; the reaction solvent is preferably dimethyl sulfoxide or N, N-dimethylformamide. The reaction temperature is preferably 45-75 ℃, the reaction time is preferably 12-24h, and the dicarboxyl modified platinum (IV) compound is obtained, correspondingly
According to the present invention, lactosamine synthesis is described, lactobionic acid is first dehydrated in a reaction solvent under the catalysis of trifluoroacetic acid to form lactolactolactonic lactone, said lactobionic acid and trifluoroacetic acid preferably being in a molar ratio of 1: (0.01-0.05), more preferably 1: (0.01-0.03); the reaction solvent is preferably methanol, the reaction temperature is preferably 65-75 ℃, and the reaction time is preferably 5-8 h; after the reaction is finished, the preferable condition for obtaining the lactonase is to drain methanol.
For further synthesis of lactosamine, lactolactone is preferably dissolved directly in methanol at 35-45 ℃ and reacted with ethylenediamine, said lactolactone and ethylenediamine preferably being present in a molar ratio of 1: (10-100), the temperature of the reaction is preferably 25-35 ℃, and the time of the reaction is preferably 12-24 h; after the reaction is finished, the product is purified, preferably, acetone is directly used for sedimentation, and after a filter cake is filtered and vacuum-dried, the lactosamine product is obtained and is white powder.
The reaction formula is as follows:
the structure of lactosamine is shown as formula (III),
according to the invention, said lactosamine is subjected to a condensation reaction with a platinum (IV) compound modified with a dicarboxy group to give a platinum (IV) complex containing two lactose molecules in the axial direction.
The molar ratio of the dicarboxy-modified platinum (IV) compound to lactosamine is preferably 1: (2-4), more preferably 1: (2-3); the solvent of the reaction is preferably N, N' -Dimethylformamide (DMF) or dimethyl sulfoxide, the temperature of the reaction is preferably 25-35 ℃, and the time of the reaction is preferably 12-24 h; after the reaction is finished, the product is purified, preferably, the product is directly precipitated by acetone, a filter cake is dissolved by a small amount of water and then passes through a Sephadex G-15 column to obtain the product, and the product is light yellow powder after being freeze-dried.
The source of the condensing agent is not particularly limited in the present invention, and may be a general commercial product. The condensing agent is preferably N, N ' -carbonyldiimidazole, N- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or 2- (7-benzotriazole oxide) -N, N, N ', N ' -tetramethylurea hexafluorophosphate.
The molar ratio of the platinum (IV) complex to the condensing agent is preferably 1: (4-5), more preferably 1: (4-4.5).
The prepared compound with the structure of the formula (II) is subjected to infrared absorption, nuclear magnetic resonance and electrospray mass spectrometry, and the result shows that the lactose derivative and the carboxyl modified platinum (IV) are successfully condensed to obtain the compound with the structure of the formula (II).
The compound with anticancer activity provided by the invention can form a monomolecular nano assembly, and is obtained by carrying out condensation reaction on a carboxyl modified platinum (IV) compound and lactose derivative lactosamine, and finally the platinum (IV) compound containing one or two lactose molecules in the axial direction is prepared. The platinum (IV) complex provided by the invention improves the water solubility of the platinum (IV) compound by introducing one or two lactose molecules, so that the platinum (IV) compound can be assembled into nanoparticles, and simultaneously, the cytotoxicity of the platinum (IV) compound is reduced, and the platinum (IV) complex has higher antitumor activity.
The invention also provides the application of the compound in preparing anticancer drugs, the prepared compound is subjected to cytotoxicity test, L929, HeLa, A549 and HepG2 cells are respectively taken as models, the survival rate of the cells is observed, and experimental results show that the lactose-modified platinum (IV) complex provided by the invention has small killing effect on normal mouse fibroblast L929 cells, and has good killing effect on cancer cells such as human cervical carcinoma Hela cells, human lung adenocarcinoma A549 cells and human hepatoma HepG2 cells, especially HepG2 cells, and the anticancer activity equivalent to cisplatin can be obtained while the system toxicity is reduced.
In order to further illustrate the present invention, the compounds having anticancer activity and the preparation method thereof provided by the present invention will be described in detail with reference to examples.
Example 1
Synthesis of compound shown in formula (I)
Placing cisplatin (600mg, 2mmol) in a reaction bottle, adding 30% hydrogen peroxide solution 10mL, stirring at room temperature in the dark for 5h, filtering to remove hydrogen peroxide solution to obtain cissplatin (IV) (NH)3)2-(OH)2A yellow powder of (4).
The obtained Cisplatin (IV) (NH)3)2-(OH)2(334mg,1mmol) and succinic anhydride (100mg, 1mmol) were dispersed in dry DMSO solvent and reacted at 30 ℃ with stirring thoroughly for 12h, then precipitated with diethyl ether, filtered to give a solid which was vacuum dried to give Cisplatin (IV) (NH) as a pale yellow solid powder3)2-(OH)(COOH)。
Lactobionic acid (1g) is dispersed in 40mL of methanol, 0.1mL of trifluoroacetic acid is added, the lactosucrose is dehydrated at 65 ℃ for 8h to form lactosucrose, the methanol is dried, the lactosucrose is dissolved in 40mL of methanol, 10mL of ethylenediamine is added, the reaction is carried out at room temperature for 24h, then acetone is used for sedimentation, and white solid powder, namely the lactosamine, is obtained through filtration.
The obtained Cisplatin (IV) (NH)3)2- (OH) (COOH) (434mg, 1mmol) and lactosamine (400.1mg,1mmol) were dissolved in dry DMF, the condensing agent 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (760.48mg, 2mmol) was added and the reaction was stirred well at 25 ℃ for 24h, directly precipitated with acetone, the filter cake was dissolved with a small amount of water after filtration, passed through a Sephadex G-15 gel column and the aqueous solution after the column was lyophilized to give 215mg of yellow solid powder.
The reaction formula is as follows:
example 2
Synthesis of compound shown in formula (I)
Placing cisplatin (600mg, 2mmol) in a reaction bottle, adding silver nitrate (679.48 mg, 4mmol) with two times of equivalent, reacting at 65 ℃ for 12h, filtering the white precipitate, adding sodium azide (520mg, 8mmol) with 4 times of equivalent into the filtrate, reacting at room temperature for 4h, filtering to obtain a filter cake, dispersing with 10mL of water, adding 30% hydrogen peroxide10mL of Cisplatin (IV) (N) was obtained by stirring the mixture at room temperature for 8 hours in the dark and then filtering off hydrogen peroxide3)2-(OH)2A yellow powder of (4).
The obtained cissplatin (IV) (N)3)2-(OH)2(347mg,1mmol) and succinic anhydride (100mg, 1mmol) in dry DMSO and stirred well at 35 ℃ for 12h, then precipitated with ether, filtered to give a solid and vacuum dried to give Cisplatin (IV) (N) as a pale yellow solid powder3)2-(OH)(COOH)。
Lactobionic acid (1g) is dispersed in 40mL of methanol, 0.1mL of trifluoroacetic acid is added, lactol is formed by dehydration for 5h at 70 ℃, the methanol is dried, the lactol is dissolved in 40mL of methanol, 10mL of ethylenediamine is added, the reaction is carried out for 24h at room temperature, then acetone is used for sedimentation, and white solid powder, namely lactosamine, is obtained by filtration.
The obtained cissplatin (IV) (N)3)2- (OH) (COOH) (447mg, 1mmol) and lactosamine (400.1mg,1mmol) were dissolved in dry DMF and the condensing agent 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (760.48mg, 2mmol) was added and the reaction was stirred well at 30 ℃ for 16h, directly precipitated with acetone, the filter cake was dissolved with a small amount of water after filtration, passed through a Sephadex G-15 gel column and the aqueous solution after the column was lyophilized to give 234mg of yellow solid powder.
The reaction formula is as follows:
example 3
Synthesis of compound shown in formula (I)
Potassium chloroplatinite (415mg, 1mmol) was placed in a reaction flask, then 10mL of water was added to dissolve, pyridine (1.5mL) was added to react at 85 ℃ for 1.5h, then the reaction solvent was drained, 15mL of 2M HCl was added, and the reaction was continued at 70 ℃ for 24 h. After cooling, the pale yellow solid, i.e., Pt (Py)2(Cl)2. Mixing Pt (Py)2(Cl)2(423mg, 1mmol) was placed in a reaction flask, dispersed in 10mL water, and silver nitrate (340mg, 2mmol) was addedAnd reacting for 12 hours at 65 ℃ in the absence of light. Filtering the white precipitate, adding 4 times equivalent of sodium azide (260mg, 4mmol) into the filtrate, reacting at room temperature for 4 hours, filtering to obtain a filter cake, dispersing with 10mL of water, adding 10mL of 30% hydrogen peroxide, stirring at room temperature in dark place for 8 hours, filtering to remove hydrogen peroxide to obtain Pt (Py)2(Cl)2-(OH)2A yellow powder of (4).
The obtained Pt (Py)2(Cl)2-(OH)2(471mg,1mmol) and succinic anhydride (100mg, 1mmol) in dry DMSO and stirred well at 25 ℃ for 24h, then settled with ether, filtered to give a solid and vacuum dried to give a pale yellow solid powder Pt (Py)2(Cl)2-(OH)(COOH)。
Lactobionic acid (1g) was dispersed in 40mL of methanol, 0.1mL of trifluoroacetic acid was added, and lactosucrose was dehydrated at 75 ℃ for 5h to form lactosucrose. After methanol is pumped to dryness, lactosucrose is dissolved by 40mL of methanol, 10mL of ethylenediamine is added to react for 12h at room temperature, then acetone is used for sedimentation, and white solid powder, namely lactosamine, is obtained by filtration.
The obtained Pt (Py)2(Cl)2- (OH) (COOH) (571mg, 1mmol) and lactosamine (400.1mg,1mmol) were dissolved in dry DMSO, N-Carbonyldiimidazole (CDI) (324.3mg, 2mmol) was added and the reaction stirred well at 35 ℃ for 12h, precipitated directly with acetone, the filter cake was dissolved with a small amount of water after filtration, passed through a Sephadex G-15 gel column and the aqueous solution after passing through the column was lyophilized to obtain 258mg of yellow solid powder.
The reaction formula is as follows:
example 4
Synthesis of compound shown as formula (II)
Placing cisplatin (600mg, 2mmol) in a reaction bottle, adding silver nitrate (679.48 mg, 4mmol) with two times of equivalent, reacting at 65 deg.C for 12h, filtering the white precipitate, adding sodium azide (520mg, 8mmol) with 4 times of equivalent to the filtrate, reacting at room temperature for 4h, filtering to obtain a filter cake, dispersing with 10mL water, adding 30%10mL of hydrogen peroxide, stirring at room temperature for 8h in the dark, filtering to remove hydrogen peroxide to obtain Cisplatin (IV) (N)3)2-(OH)2A yellow powder of (4).
The obtained cissplatin (IV) (N)3)2-(OH)2(347mg,1mmol) and succinic anhydride (400mg, 4mmol) in dry DMF and stirred well at 45 ℃ for 24 h. DMF was dried by suction, dissolved in 2mL of methanol, precipitated with diethyl ether, filtered to give a solid, and vacuum-dried to give Cisplatin (IV) (N) as a pale yellow solid powder3)2(COOH)2。
Lactobionic acid (1g) is dispersed in 40mL of methanol, 0.1mL of trifluoroacetic acid is added, lactol is formed by dehydration for 5h at 70 ℃, the methanol is dried, the lactol is dissolved in 40mL of methanol, 10mL of ethylenediamine is added, the reaction is carried out for 24h at room temperature, then acetone is used for sedimentation, and white solid powder, namely lactosamine, is obtained by filtration.
The obtained cissplatin (IV) (N)3)2(COOH)2(547mg, 1mmol) and lactosamine (800.2 mg,2mmol) were dissolved in dry DMF and the condensing agent 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (1520.96mg, 4mmol) was added and the reaction was stirred well at 25 ℃ for 12h, directly precipitated with acetone, the filter cake was dissolved with a small amount of water after filtration, passed through a Sephadex G-15 gel column and the aqueous solution after passage through the column was lyophilized to give 320mg of yellow solid powder.
The reaction formula is as follows:
example 5
Synthesis of compound shown as formula (II)
Placing cisplatin (600mg, 2mmol) in a reaction bottle, adding 30% hydrogen peroxide solution 10mL, stirring at room temperature in the dark for 5h, filtering to remove hydrogen peroxide solution to obtain cissplatin (IV) (NH)3)2-(OH)2A yellow powder of (4).
The obtained Cisplatin (IV) (NH)3)2-(OH)2(334mg,1mmol) and succinic anhydride (400mg, 4mmol)Dispersing in dry DMF solvent, stirring at 75 deg.C for 12 hr, precipitating with diethyl ether, filtering to obtain solid, and vacuum drying to obtain light yellow solid powder Cisplatin (IV) (NH)3)2-(COOH)2。
Lactobionic acid (1g) is dispersed in 40mL of methanol, 0.1mL of trifluoroacetic acid is added, lactol is formed by dehydration for 5h at 65 ℃, methanol is dried, lactol is dissolved in 40mL of methanol, 10mL of ethylenediamine is added, reaction is carried out for 24h at room temperature, then acetone is used for sedimentation, and white solid powder, namely lactosamine, is obtained by filtration.
The obtained Cisplatin (IV) (NH)3)2-(COOH)2(534mg, 1mmol) and lactosamine (800.2 mg,2mmol) were dissolved in dry DMF and the condensing agent 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (1520.96mg, 4mmol) was added and the reaction was stirred well at 25 ℃ for 24h, directly precipitated with acetone, the filter cake was dissolved with a small amount of water after filtration, passed through a Sephadex G-15 gel column and the aqueous solution after passage through the column was lyophilized to give 215mg of yellow solid powder.
The reaction formula is as follows:
example 6
Synthesis of compound shown as formula (II)
Cisplatin (300mg, 1mmol) was placed in a reaction flask, then 10mL of water was added for dissolution, pyridine (10mmol) was added for reaction at 75 ℃ for 8h, then the reaction solvent was dried by spinning, 15mL of 2M HCl was added, and the reaction was continued at 75 ℃ for 72 h. After cooling, the pale yellow solid, i.e. Pt (Py) (NH), was filtered3)(Cl)2. Reacting Pt (Py) (NH)3)(Cl)2(362mg, 1mmol) was placed in a reaction flask, dispersed in 10mL of water, and silver nitrate (340mg, 2mmol) was added to react at 65 ℃ under the exclusion of light for 12 hours. Filtering the white precipitate, adding 4 times equivalent of sodium azide (260mg, 4mmol) into the filtrate, reacting at room temperature for 4 hours, filtering to obtain filter cake, dispersing with 10mL water, adding 10mL of 30% hydrogen peroxide, stirring at room temperature in dark place for 8 hours, filtering to remove hydrogen peroxide to obtain the final productTo Pt (Py) (NH)3)(Cl)2-(OH)2A yellow powder of (4).
The obtained Pt (Py) (NH)3)(Cl)2-(OH)2(409mg,1mmol) and succinic anhydride (400mg, 4mmol) in dry DMSO and stirred well at 60 deg.C for 14h, then settled with ether, filtered to give a solid and vacuum dried to give pale yellow solid powder Pt (Py) (NH)3)(Cl)2-(COOH)2。
Lactobionic acid (1g) is dispersed in 40mL of methanol, 0.1mL of trifluoroacetic acid is added, lactol is formed by dehydration for 5h at 70 ℃, the methanol is dried, the lactol is dissolved in 40mL of methanol, 10mL of ethylenediamine is added, the reaction is carried out for 12h at room temperature, then acetone is used for sedimentation, and white solid powder, namely lactosamine, is obtained by filtration.
The obtained Pt (Py) (NH)3)(Cl)2-(COOH)2(609mg, 1mmol) and lactosamine (800.1 mg,2mmol) were dissolved in dry DMSO, the condensing agent 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (1520.96mg, 4mmol) was added and the reaction was stirred well at 35 ℃ for 12h, directly precipitated with acetone, the filter cake was dissolved with a small amount of water after filtration, it was passed through a Sephadex G-15 gel column and the aqueous solution after passing through the column was lyophilized to obtain 277mg of yellow solid powder.
The reaction formula is as follows:
the prepared compounds I and II are characterized by infrared spectrum, nuclear magnetic resonance, mass spectrum and transmission electron microscope, and the characterization results are shown in figure 1, figure 2, figure 3 and figure 4.
FIG. 1 shows IR absorption spectra of compound and lactosamine prepared in examples 2 and 4 of the present invention, respectively; wherein curve A represents Cisplatin (IV) (N)3)2(OH) (COOH), curve B represents Cisplatin (IV) (N)3)2(Lac), Curve C represents Cisplatin (IV) (N)3)2(COOH)2Curve D represents Cisplatin (IV) (N)3)2(Lac)2Curve E represents Lac-NH2. As can be seen in FIG. 1, compounds I and II were successfully prepared in accordance with the present invention.
FIG. 2 shows the NMR spectra of the compounds prepared in examples 2 and 4 of the present invention; wherein A represents Cisplatin (IV) (N)3)2(Lac) and B in the figure represents Cisplatin (IV) (N)3)2(Lac)2Wherein the peak assignments for each protic hydrogen are well defined and the ratios are matched, thus again demonstrating the successful synthesis of compounds 1 and II.
FIG. 3 is a mass spectrum of lactosamine and the compound prepared in examples 2 and 4, respectively, of the present invention, wherein A represents lactosamine and B represents Cisplatin (IV) (N)3)2(Lac) where C represents Cisplatin (IV) (N)3)2(Lac)2As can be seen from fig. 3, the mass spectrum is consistent with the corresponding molecular weight. FIG. 4 shows transmission electron microscope images and atomic force scanning electron microscope images of the compounds prepared in examples 2 and 4 of the present invention, wherein A is Cisplatin (IV) (N)3)2(Lac) morphology by transmission electron microscopy, in which B is Cisplatin (IV) (N)3)2(Lac) morphology by atomic force scanning electron microscopy, wherein C is Cisplatin (IV) (N)3)2(Lac) atomic force scanning electron microscope height map; in the figure, D is Cisplatin (IV) (N)3)2(Lac)2The morphology of the transmission electron microscope; in the figure, E is Cisplatin (IV) (N)3)2(Lac)2The shape of the atomic force scanning electron microscope; in the figure, F is Cisplatin (IV) (N)3)2(Lac)2The successful grafting of lactose and the amphiphilic existence of the compound can be proved from figure 4.
Example 7
Cytotoxicity tests are carried out on the compounds I and II prepared in the examples 1 and 4 of the invention, L929, HeLa, A549 and HepG2 cells are taken as models, the compounds I and II provided in the examples 1 and 4 are taken as substances to be detected, after the substances to be detected act on the cells, the survival rate of the cells is observed, and the cytotoxicity of the platinum complex disclosed by the invention is examined by a thiazole blue (MTT) method, and the specific operation steps are as follows:
1) collecting the logarithmic phase cells, adjusting the concentration of the cell suspension, adding the cells into a 96-well plate, adding 100 mu l of the cells into each well, and counting about 5 thousand cells in each well;
2) subjecting the above test sample to CO2Culturing for 12 hours in a cell culture box with the concentration of 5% at the temperature of 37 ℃ under the saturated humidity condition to ensure that cells are attached to the wall fully;
3) diluting compounds I and II according to certain gradient multiple with concentration of 216 μ M, 108 μ M, 54 μ M, 27 μ M, 13.5 μ M, 6.75 μ M, and 3.375 μ M, respectively, adding into 96-well plate with cells, setting three multiple wells for each concentration, sucking out the medicine after four hours of endocytosis, changing new culture medium, and performing light irradiation and dark irradiation (365nm, 10 mW/cm)2) Culturing for 15min in dark for 24h,48h and 72 h; the dark group is always in a dark condition and the culture time of the dark group is consistent with that of the light group;
4) adding 20 μ l MTT solution (5mg/ml, i.e. 0.5% MTT) into each well, culturing for 4h, removing the culture medium by suction, adding 150 μ l DMSO into each well, and shaking at low speed for 10min by shaking table to dissolve the crystals completely;
5) detecting the light absorption value of each hole at 490nm of an enzyme-labeling instrument;
6) the cell viability was calculated by setting the zero-setting wells (medium, MTT, DMSO) and the control (cells, medium, MTT, DMSO) simultaneously according to the following formula:
wherein abs (sample) is the absorbance of the cells in the sample set; abs (blank) is the absorbance of the liquid in the blank control culture wells; abs (control) is the absorbance of untreated experimental cells.
The results are shown in Table 1, Table 1 shows the results of examples 1 and 4 of the present invention and comparative example 1, wherein Compound I, Compound II and Cisplatin (IV) (OH)2IC of HeLa, A549 and HepG2 cells treated for 24h,48h and 72h respectively50And summarizing value data.
TABLE 1 Compound I, Compound II and Cisplatin (IV) (OH)2Are respectively to HIC after eLa, A549 and HepG2 cell treatment50The value is obtained.
As can be seen from the above examples and comparative examples, the compounds I and II provided by the present invention have high antitumor activity and low cytotoxicity.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (10)
1. A compound with anticancer activity is characterized by having a structure shown in a formula (I) or (II):
(I) or (II) above
Is selected from
2. The process for the preparation of a compound having anticancer activity according to claim 1, comprising:
A) reacting a platinum (II) compound with hydrogen peroxide to obtain a platinum (IV) compound;
B) reacting the platinum (IV) compound obtained in the step A) with succinic anhydride to obtain a platinum (IV) complex containing one carboxyl or two carboxyl in the axial direction;
C) dehydrating lactobionic acid in a reaction solvent to obtain lactolactone;
D) reacting lactosucrose obtained in the step C) with ethylenediamine to obtain lactosucrose;
E) reacting the platinum (IV) complex obtained in the step B) with the lactosamine obtained in the step D) in the presence of a condensing agent to obtain a compound represented by the structure of formula (I) or (II);
(I) or (II) above
Is selected from
3. The process for the preparation of a class of compounds having anticancer activity according to claim 2, characterized in that said platinum (II) compound is selected from
4. The method for preparing compounds with anticancer activity as claimed in claim 2, wherein the reaction temperature of step B) is 25-75 ℃ and the reaction time is 12-24 h.
5. The process for preparing compounds having anticancer activity according to claim 2, wherein the molar ratio of lactolactone to ethylenediamine in step D) is 1: (10-100).
6. The method for preparing compounds with anticancer activity as claimed in claim 2, wherein the reaction temperature of step D) is 65-75 ℃ and the reaction time is 5-8 h.
7. The process according to claim 2, wherein the molar ratio of platinum (IV) compound, lactosamine and condensing agent in step E) is 1: (1-4): (2-5).
8. The method for preparing a compound with anticancer activity as claimed in claim 2, wherein the condensing agent is selected from N, N '-carbonyldiimidazole, N- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or 2- (7-benzotriazole oxide) -N, N' -tetramethylurea hexafluorophosphate.
9. The method for preparing compounds with anticancer activity as claimed in claim 2, wherein the reaction temperature of step E) is 25-35 ℃ and the reaction time is 12-24 h.
10. Use of a compound of claim 1 for the preparation of an anti-cancer agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710618269.XA CN107417752B (en) | 2017-07-26 | 2017-07-26 | Compound with anticancer activity and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710618269.XA CN107417752B (en) | 2017-07-26 | 2017-07-26 | Compound with anticancer activity and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107417752A CN107417752A (en) | 2017-12-01 |
| CN107417752B true CN107417752B (en) | 2020-05-05 |
Family
ID=60431083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710618269.XA Active CN107417752B (en) | 2017-07-26 | 2017-07-26 | Compound with anticancer activity and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107417752B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109293702B (en) * | 2018-08-27 | 2020-05-29 | 河南大学 | Tetravalent platinum polyamine complex, preparation method and application thereof |
| CN110898229B (en) * | 2019-12-16 | 2021-07-13 | 福州大学 | Preparation method of double-response nano prodrug for cancer synergistic treatment |
| CN113072594A (en) * | 2021-04-20 | 2021-07-06 | 南开大学 | Carbon glycoside glycosylated tetravalent platinum compound, synthetic method and application thereof |
| CN115590879B (en) * | 2021-06-28 | 2024-03-22 | 沈阳药科大学 | Platinum drug lipid derivative and application thereof |
| CN114249773B (en) * | 2021-12-06 | 2022-12-30 | 苏州大学 | Tetravalent platinum compound capable of releasing nitric oxide and preparation and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101259284A (en) * | 2008-04-15 | 2008-09-10 | 华东师范大学 | Liver target anticancer nano prodrug system based on tree shaped polymer, preparation and use |
| CN105705152A (en) * | 2013-06-14 | 2016-06-22 | 成事在人肿瘤学公司 | Lipid-based platinum compounds and nanoparticles |
| CN105906667A (en) * | 2016-04-26 | 2016-08-31 | 中国科学院长春应用化学研究所 | Chemical substance with anticancer activity and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7138520B2 (en) * | 2003-01-13 | 2006-11-21 | Massachusetts Institute Of Technology | Coordination complexes having tethered therapeutic agents and/or targeting moieties, and methods of making and using the same |
-
2017
- 2017-07-26 CN CN201710618269.XA patent/CN107417752B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101259284A (en) * | 2008-04-15 | 2008-09-10 | 华东师范大学 | Liver target anticancer nano prodrug system based on tree shaped polymer, preparation and use |
| CN105705152A (en) * | 2013-06-14 | 2016-06-22 | 成事在人肿瘤学公司 | Lipid-based platinum compounds and nanoparticles |
| CN105906667A (en) * | 2016-04-26 | 2016-08-31 | 中国科学院长春应用化学研究所 | Chemical substance with anticancer activity and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| Oral delivery of a platinum anticancer drug using lipid assisted polymeric nanoparticles;Qinqin Cheng，等;《The Royal Society of Chemistry》;20151231;第51卷;第17536-17539页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107417752A (en) | 2017-12-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107417752B (en) | Compound with anticancer activity and preparation method and application thereof | |
| CN102988999A (en) | Curcumin-polysaccharide conjugate as well as preparation method and application thereof | |
| CN105906667B (en) | A kind of chemical substance with active anticancer and preparation method and application | |
| CN109303780B (en) | Reduction response type amphiphilic polymer prodrug of 7-ethyl-10-hydroxycamptothecin and preparation method thereof | |
| CN101831000A (en) | Purification method of acetyl pullulan polysaccharide folate conjugate and preparation method of nanometer particles thereof | |
| JP2019123878A (en) | Novel cationic polyphosphazene compounds, polyphosphazene-drug conjugate compounds and methods for preparing the same | |
| CN108553647A (en) | A kind of preparation method of Ginsenoside compound K-chitosan micelle nanoparticle | |
| CN111494411A (en) | In-situ self-assembled tetravalent platinum drug and preparation method and application thereof | |
| CN103881088B (en) | A kind of responsive polymer micelle medicine carrying system and preparation method thereof | |
| CN107537039B (en) | Targeting lignin-based nano drug-loaded particle | |
| Xie et al. | Targeted nanoparticles from xyloglucan–doxorubicin conjugate loaded with doxorubicin against drug resistance | |
| CN108743963B (en) | Anti-cancer conjugate containing tetravalent platinum and preparation method and application thereof | |
| CN108395543B (en) | Modified polyrotaxane, medicine-carrying micelle based on polyrotaxane and preparation method and application of medicine-carrying micelle | |
| CN107951839B (en) | Polyion micelle shielding system with reversible charges and preparation method thereof | |
| CN107929261B (en) | pH-sensitive targeted nanoparticle preparation loaded with chemotherapeutic drugs and preparation method thereof | |
| CN108774301A (en) | The preparation method and applications of sour responsive polymer drug of the one kind based on glucan | |
| CN104761732A (en) | Tumor cell targeted nano gel and preparation method thereof as well as tumor cell targeted drug-loaded nano-particles | |
| CN105254867B (en) | Main chain contains double anticarcinogen amphipathy macromolecule, preparation method and its nano-micelles | |
| CN104758244B (en) | A kind of nanogel, its preparation method and anti-tumor nano gel medicine-carried system and preparation method thereof | |
| JP5155388B2 (en) | Cyclic phosphazene trimer-platinum (II) complex conjugate anticancer agent having cancer tissue selectivity and biodegradability and method for producing the same | |
| CN105879051A (en) | Preparation and application of self-assembled nano-drug of core-shell structure | |
| CN115572302A (en) | Podophyllotoxin modified polyoxometallate hybrid compound and preparation method and application thereof | |
| CN112137986B (en) | Responsive nanoparticle with mitochondrial targeting function, and preparation method and application thereof | |
| CN108721636B (en) | Drug delivery material with dual responsiveness connected by diselenide bond and preparation method and application thereof | |
| CN110368500B (en) | Amphiphilic copolymer prodrug, preparation method and calcipotriol-entrapped nanoparticles |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |