CN110041375A - Compound, preparation method and its application in preparation of anti-tumor drugs with asymmetric monosubstituted naphthalimide tetravalence platinum structure - Google Patents
Compound, preparation method and its application in preparation of anti-tumor drugs with asymmetric monosubstituted naphthalimide tetravalence platinum structure Download PDFInfo
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- CN110041375A CN110041375A CN201910407366.3A CN201910407366A CN110041375A CN 110041375 A CN110041375 A CN 110041375A CN 201910407366 A CN201910407366 A CN 201910407366A CN 110041375 A CN110041375 A CN 110041375A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
The present invention proposes that a kind of compound, preparation method and its application in preparation of anti-tumor drugs with asymmetric monosubstituted naphthalimide tetravalence platinum structure, the structural formula of the compound are as follows:The compound has the effect of excellent anticancer and antitumor.
Description
Technical Field
The invention belongs to the field of organic chemistry and pharmaceutical chemistry, and particularly relates to a compound with an asymmetric mono-substituted naphthalimide tetravalent platinum structure, a preparation method and application thereof in preparation of antitumor drugs.
Background
Cancer is one of the main causes of abnormal human death, and is a worldwide medical problem to be overcome urgently. The design and synthesis of anti-cancer drugs are always hot spots in the field of medicine, and through years of development, the research and development of anti-cancer drugs make a lot of important progress. The platinum medicine occupies an important position in the field of tumor chemotherapy, and the action mechanism of the platinum medicine is to interfere the normal physiological function of cells by interfering the DNA replication and transcription of tumor cells, so as to induce the apoptosis of the tumor cells and finally generate the anti-tumor effect. However, with the wide clinical application of these drugs, the serious problems of toxic side effects and drug resistance become major obstacles in the clinical treatment of platinum drugs. The retrieval of historical documents shows that the tetravalent platinum drug as a bivalent platinum drug prodrug has the advantages of low toxic and side effects compared with the parent drug, and the drug resistance of the bivalent platinum drug is overcome. Meanwhile, other fragments with a DNA damage mechanism are introduced into a platinum drug system, so that the drug effect can be effectively improved, the existing drug resistance problem is overcome, and the method is an effective way for developing novel platinum drugs.
Disclosure of Invention
In view of the above, the present invention aims to provide a compound having an asymmetric mono-substituted naphthalimide tetravalent platinum structure, a preparation method thereof, and an application thereof in the preparation of antitumor drugs, wherein the compound has excellent anticancer and antitumor effects.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
an asymmetric mono-substituted naphthalimide tetravalent platinum compound with anticancer activity, which has the following structural formula (1):
wherein,is cisplatin, carboplatin, heptaplatin, nedaplatin, oxaliplatin, lobaplatin, miboplatin, picoplatin, NDDP or
R3Is methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene or hexadecylene;
R4is Cl, Br or OH;
R5in the 2, 3 or 4 position of the naphthalimide structure, amino, nitryl, hydrogen, bromine, dimethylamino, methoxyl or acetamido is adopted.
The preparation method of the asymmetric mono-substituted naphthalimide tetravalent platinum compound with anticancer activity comprises the following steps:
the asymmetric mono-substituted naphthalimide tetravalent platinum compound with the general formula 1 has the following reaction formula:
wherein the feeding molar ratio of the compound 4 to the compound 5 to the TBTU to the triethylamine is 1: (1.0-1.3): (1.0-1.3): (1.0-1.3), the charge relationship of Compound 4 and DMF was 1 g: (30-80 mL).
Further, an asymmetric mono-group of the formula 1The preparation method of the substituted naphthalimide modified tetravalent platinum compound comprises the following steps: adding TBTU and naphthalimide derivative 5 (compound 5) into a reaction vessel, replacing air in the system with nitrogen, adding dry DMF, stirring and reacting for about 10min at room temperature, adding dried triethylamine into the reaction system, stirring and reacting for about 10min at room temperature, finally adding tetravalent platinum compound 4 (compound 4) into the reaction system, and using N again2Replacing air in the flask, placing the reaction system at 25-120 ℃ in the dark for reaction for 12-72h, removing the solvent under reduced pressure, and performing column chromatography to obtain the asymmetric monosubstituted naphthalimide modified tetravalent platinum compound with the general formula 1.
Further, R in the compound 44Is Cl, Br or OH, and has the general formula:
specifically, the reaction formula of compound 4a is as follows:
the preparation method of the tetravalent platinum compound with the general formula 4a comprises the following steps: adding a compound with a general formula 3 into a reaction vessel, adding 30mL of distilled water into every 1.0g of the compound with the general formula 3, stirring to disperse the compound, slowly dropwise adding 50mL of 30% hydrogen peroxide into the reaction system, raising the temperature to 60 ℃, stirring to react for 4h, stopping the reaction, standing at-4 ℃ for crystallization for 12 h, filtering and separating to obtain a yellow solid, adding a proper amount of distilled water, heating to 80 ℃ to dissolve and clear, standing at 4 ℃ for crystallization for 12 h, and filtering to obtain a compound with a general formula 4 a.
Specifically, the reaction formula of compound 4b is as follows:
the preparation method of the tetravalent platinum compound with the general formula 4b comprises the following steps: adding the compound with the general formula 3 into a reaction container, adding 150mL of distilled water into every 1.0g of the compound with the general formula 3, stirring to disperse the compound, adding 0.46g of N-bromosuccinimide (NBS) into the reaction system, stirring the system overnight in a dark place, filtering out a solid, and performing reduced pressure spin drying on the solution to obtain a yellow solid. Washing the solid with ethanol and ether, drying and filtering to obtain the compound with the general formula 4 b.
Specifically, the reaction formula of compound 4c is as follows:
the preparation method of the tetravalent platinum compound with the general formula 4c comprises the following steps: adding the compound with the general formula 3 into a reaction vessel, adding 150mL of distilled water into every 1.0g of the compound with the general formula 3, stirring to disperse the compound, adding 0.34g of N-chlorosuccinimide (NCS) into the reaction system, stirring the system overnight in a dark place, filtering out a solid, and performing reduced pressure spin drying on the solution to obtain a yellow solid. Washing the solid with ethanol and ether, drying and filtering to obtain the compound with the general formula 4 c.
An application of a compound with a structural formula (1) in preparing an anti-tumor medicament.
The invention also provides application of the compound with the structural formula (1) in preparation of anti-human ovarian cancer, anti-human cervical cancer, anti-human lung adenocarcinoma, anti-cisplatin-resistant human lung adenocarcinoma and anti-mouse colon cancer.
In addition, the invention also provides a pharmaceutical composition, which comprises an effective treatment amount of the compound shown in the structural formula (1) and pharmaceutically acceptable auxiliary materials.
Furthermore, the administration dosage form of the pharmaceutical composition is tablets, capsules, aerosols, dispersible tablets, oral liquids, suppositories, dropping pills, large infusion solutions, small needles, freeze-dried powder injections, ointments or liniments.
The invention also provides a tumor therapeutic agent, which contains an effective therapeutic amount of the compound shown in the structural formula (1) and pharmaceutically acceptable auxiliary materials.
Furthermore, the tumor therapeutic agent is tablets, capsules, aerosol, dispersible tablets, oral liquid, suppositories, dropping pills, large transfusion, small needles, freeze-dried powder injection, ointment or liniments.
Compared with the prior art, the asymmetric mono-substituted naphthalimide tetravalent platinum compound with the anticancer activity has the following advantages:
according to the invention, naphthalimide molecules are introduced into a tetravalent platinum parent nucleus, a series of novel asymmetric mono-substituted naphthalimide modified tetravalent platinum compounds are designed and synthesized, and the anti-cancer and anti-tumor capabilities of the novel asymmetric mono-substituted naphthalimide modified tetravalent platinum compounds are investigated; the series of original innovative researches hopefully obtain a plurality of effective lead molecules for tumors, provide new candidate drug molecules for overcoming the defects of the traditional bivalent platinum drugs, and open up a new way for the modification of tetravalent platinum compounds; the research of innovative medicaments at the source has important theoretical value and practical significance to national economy, social development, people's health and the like.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate an embodiment of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
FIG. 1 is a graph showing the results of the uptake of an asymmetric mono-substituted naphthalimide tetravalent platinum compound 1-1 in SKOV-3 cells;
FIG. 2 is a graph showing the result of the uptake of an asymmetric mono-substituted naphthalimide tetravalent platinum compound 1-1 in DNA in SKOV-3 cells;
FIG. 3 is a graph of tumor growth over time;
FIG. 4 is a graph of the change in body weight of mice during treatment;
FIG. 5 is a graph of tumor weight for each group at the end of the experiment;
FIG. 6 is a graph of HE staining of normal tissues of heart, lung, liver, spleen and kidney;
FIG. 7 is a graph of HE staining of tumor tissue;
fig. 8 is a graph of tumors at the end of the experiment, where P <0.05, P <0.01, P <0.001, ns: there was no significant difference compared to the control group.
Detailed Description
Unless otherwise defined, terms used herein have meanings that are conventionally understood by those skilled in the art, and some terms used herein are defined as follows in order to facilitate understanding of the present invention.
As used in the specification and in the claims, the singular form of "a", "an", and "the" include plural references unless the context clearly dictates otherwise. For example, the term "cell" includes a plurality of cells, including mixtures thereof.
All numerical designations such as pH, temperature, time, concentration, including ranges, are approximations. It is to be understood, although not always explicitly stated that all numerical designations are preceded by the term "about". It is also to be understood that, although not always explicitly recited, the reagents described herein are merely exemplary and equivalents thereof are known in the art.
An asymmetric mono-substituted naphthalimide tetravalent platinum compound with anticancer activity, which has the following structural formula (1):
wherein,is cisplatin, carboplatin, heptaplatin, nedaplatin, oxaliplatin, lobaplatin, miboplatin, picoplatin, NDDP or
R3 is methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene or hexadecylene;
r4 is Cl, Br or OH;
r5 is amino, nitro, hydrogen, bromine, dimethylamino, methoxy or acetylamino at the 2-, 3-or 4-position of the naphthalimide structure.
Further, the preparation method of the asymmetric mono-substituted naphthalimide tetravalent platinum compound with anticancer activity comprises the following steps:
the asymmetric mono-substituted naphthalimide tetravalent platinum compound with the general formula 1 has the following reaction formula:
the preparation method of the asymmetric mono-substituted naphthalimide tetravalent platinum compound with the general formula 1 comprises the following steps: oxidizing bivalent platinum compounds with the general formula 3 by hydrogen peroxide at the temperature of 60-70 ℃, and reacting for 1-8 hours to prepare dihydroxyl tetravalent platinum compounds with the general formula 4 a; the divalent platinum compound with the general formula 3 is reacted for 6 to 18 hours at the temperature of between 10 and 40 ℃ by N-bromosuccinimide (NBS)/N-chlorosuccinimide (NCS) to prepare the bromine/chlorohydroxy tetravalent platinum compound with the general formula 4b/4 c.
TBTU and naphthalimide derivative 5 (i.e., compound 5) are added into a reaction vessel, and the mixture is placed under nitrogenChanging air in the system, adding dry DMF, stirring at room temperature for reaction for about 10min, adding dried triethylamine into the reaction system, stirring at room temperature for reaction for about 10min, finally adding tetravalent platinum compound 4 (namely compound 4) into the reaction system, and using N again2Replacing air in the flask, placing the reaction system at 25-120 ℃ in the dark for reaction for 12-72h, removing the solvent under reduced pressure, and performing column chromatography to obtain the asymmetric monosubstituted naphthalimide modified tetravalent platinum compound with the general formula 1.
Wherein the feeding mol ratio of the compounds 4 and 5, TBTU and triethylamine is 1 (1.0-1.3) to (1.0-1.3), the relationship between the compound 4 and DMF is 1 g: (30-80 mL).
The target compound is obtained by adopting the synthetic route and the method, and the synthetic method is simple and convenient.
The asymmetric mono-substituted naphthalimide tetravalent platinum compound can be prepared into a pharmaceutical preparation for treating cancers, and the preparation contains a therapeutically effective amount of the compound as an active ingredient and one or more pharmaceutically acceptable carriers. The compound is used as a drug effect component to prepare a pharmaceutical preparation for treating cancer, and can be independently used. The pharmaceutically acceptable carrier refers to a pharmaceutical carrier which is conventional in the pharmaceutical field, such as pharmaceutically acceptable adjuvants, diluents, excipients and the like.
The asymmetric mono-substituted naphthalimide tetravalent platinum compound can be administrated in a unit dosage form, and the administration route can be intestinal tract and parenteral tract, such as oral administration, muscle administration, subcutaneous administration, nasal administration and the like.
The administration route of the asymmetric mono-substituted naphthalimide tetravalent platinum compound can be intravenous administration. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, acupoint injection, etc.
The administration dosage form of the asymmetric mono-substituted naphthalimide tetravalent platinum compound can be tablet, capsule, aerosol, dispersible tablet, oral liquid, suppository, dripping pill, infusion solution, small needle, freeze-dried powder injection, ointment or liniment and other dosage forms of medicaments, and comprises various sustained-release, controlled-release dosage forms or nano preparations which are prepared by adopting the conventional accepted common sense of pharmacy.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following detailed description of representative embodiments of the present invention is given without being limited thereto.
Example 1: preparation of asymmetric mono-substituted naphthalimide tetravalent platinum compound shown in general formula 1
1. Synthesis of hydroxy cis-platinum (IV)4a-1
1.0g of cisplatin and 30mL of distilled water are added into a 250mL round-bottom flask, stirred to be dispersed, 50mL of 30% hydrogen peroxide is slowly dropped into a reaction system, and the temperature is raised to 60 ℃ to be stirred and reacted for 4 hours. Stopping reaction, standing at-4 deg.C for crystallization for 12 hr, filtering to obtain yellow solid, adding appropriate amount of distilled water, heating to 80 deg.C for dissolving, standing at 4 deg.C for crystallization for 12 hr, and filtering to obtain yellow crystal (0.82g, 74%) of compound 4 a-1.
2. Synthesis of hydroxyoxaliplatin (IV)4a-2
Adding 1.0g of oxaliplatin and 30mL of distilled water into a 250mL round-bottom flask, stirring to disperse the oxaliplatin, slowly dropwise adding 50mL of 30% hydrogen peroxide into the reaction system, and raising the temperature to 60 ℃ to stir and react for 4 hours. Stopping reaction, standing at-4 deg.C for crystallization for 12 hr, filtering to obtain yellow solid, adding appropriate amount of distilled water, heating to 80 deg.C for dissolving, standing at 4 deg.C for crystallization for 12 hr, and filtering to obtain compound 4a-2 white crystal (0.85g, 78%).
2. Synthesis of hydroxyoxaliplatin (IV)4c-1
1.15g (2.67mmol) of oxaliplatin are placed in a reaction flask, and 172.5mL of distilled water are added and stirred uniformly. 0.392g (2.94mmol) of N-chlorosuccinimide (NCS) was dissolved in 150mL of distilled water and slowly added to the oxaliplatin solution, the system was stirred overnight in the dark, the solid was filtered off and the solution was dried under reduced pressure to give a yellow solid. The solid was washed with ethanol and ether, respectively, and dried to give 4c-1(1.07g, 89%) as a final pale yellow product.
3. Preparation of product 1
Adding TBTU and naphthalimide derivative 5 into a 50mL round-bottom flask, replacing air in the system with nitrogen, adding dry DMF, stirring and reacting for about 10min at room temperature, adding dried triethylamine into the reaction system, stirring and reacting for about 10min at room temperature, finally adding tetravalent platinum compound 4 into the reaction system, and using N again2Replacing air in the flask, placing the reaction system at 50 ℃ in a dark place for reaction for 48 hours, stopping the reaction, removing the solvent under reduced pressure, and carrying out column chromatography to obtain the compound 1.
In the synthesis of the compounds having the structural formulas 1-1 to 1-5, the amounts of the compounds 4/5 and the yields of the products are shown in Table 1.
TABLE 1 raw materials, amounts and yields for the synthesis of Compounds 1-1 to 1-5
1-1: a white solid;1H NMR(400MHz,DMSO-d6)δ8.47(t,J＝7.1Hz,4H), 7.89(d,J＝7.6Hz,2H),4.24(s,2H),2.71–2.57(m,4H),2.06(dd,J＝30.6, 11.5Hz,2H),1.45(dd,J＝44.3,8.8Hz,4H),1.15(s,2H).13C NMR(100MHz, DMSO-d6)δ178.39,163.83,163.76,134.80,131.74,131.11,127.84,127.65, 122.55,62.01,61.47,36.75,35.12,31.30,31.04,24.03,23.97.
1-2: a white solid;1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝7.1Hz,2H), 8.40(d,J＝8.0Hz,2H),7.84(t,J＝7.6Hz,2H),4.26–3.98(m,2H),3.26– 2.61(m,2H),2.38(d,J＝6.6Hz,2H),2.20(d,J＝12.1Hz,1H),1.92(s,3H), 1.56(s,4H),1.22(d,J＝7.1Hz,2H).13CNMR(100MHz,DMSO-d6)δ180.71, 163.98,163.59,134.77,131.71,131.17,127.82,127.66,122.47,61.88,61.72, 46.12,34.11,31.36,31.14,24.24,24.00,23.86.
1-3: a white solid;1H NMR(400MHz,DMSO-d6)δ8.50–8.43(m,4H),7.87 (t,J＝7.7Hz,2H),4.14–4.00(m,2H),3.18(d,J＝5.1Hz,1H),2.57(s,1H), 2.35(t,J＝7.1Hz,2H),2.05(dd,J＝34.0,11.8Hz,2H),1.70–1.39(m,7H), 1.37–1.03(m,3H).13C NMR(100MHz,DMSO-d6)δ181.17,163.83,163.58, 134.73,131.72,131.14,127.64,122.47,61.94,49.04,36.63,31.35,31.03,27.57, 23.93,23.34.
1-4: a yellow solid;1H NMR(400MHz,DMSO-d6)δ9.46(d,J＝2.2Hz,1H), 8.93(d,J＝2.2Hz,1H),8.76(d,J＝8.0Hz,1H),8.65(d,J＝6.4Hz,1H),8.05(t, J＝7.8Hz,1H),4.10(dq,J＝19.1,6.4Hz,2H),2.73(s,1H),2.61(s,1H),2.38(t, J＝7.4Hz,2H),2.17–2.04(m,2H),1.93–1.84(m,2H),1.64–1.36(m,5H), 1.14(dt,J＝13.9,10.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ180.77, 163.55,163.35,162.88,146.23,136.72,134.33,131.26,130.05,129.66,124.47, 123.31,123.06,61.84,31.27,31.12–30.99,23.99.
1-5: a yellow solid;1H NMR(400MHz,DMSO-d6)δ8.11–7.85(m,3H),7.58 –7.50(m,1H),7.21(s,1H),5.91(s,1H),3.99(t,J＝6.9Hz,2H),2.73–2.53(m, 2H),2.25(dt,J＝14.9,7.1Hz,2H),1.90(ddd,J＝24.2,23.1,10.8Hz,4H),1.61 –1.25(m,4H),1.23–0.96(m,3H).13C NMR(101MHz,DMSO-d6)δ180.74, 174.37,164.35,164.11,163.59,148.27,133.97,131.95,127.35,125.83,122.98, 122.24,122.16,121.04,112.12,62.40,61.92,46.17,34.28,31.80,31.00,24.35, 24.07,23.51.
the asymmetric mono-substituted naphthalimide tetravalent platinum compound can be used independently or combined with platinum compounds, 5-fluorouracil compounds, taxol compounds and the like which are already on the market to prepare a pharmaceutical composition with anti-tumor activity. The pharmaceutical composition can be tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, capsules, hard capsules, soft capsules, sustained-release capsules, oral liquid, mixtures, buccal agents, granules, medicinal granules, pills, powder, ointment, suspensions, solutions, injections, powder injections, freeze-dried powder injections, suppositories, liniments, ointments, plasters, creams, sprays, aerosols, drops, patches and the like.
The pharmaceutical composition of this embodiment comprises the following ingredients: 1-10.07 g of the asymmetric mono-substituted naphthalimide tetravalent platinum compound prepared in example 1, 0.02g of microcrystalline cellulose, 0.05g of starch, 0.03g of lactose, 0.01g of povidone, 0.02g of sodium carboxymethyl starch and 0.02g of aerosil.
As an alternative implementation, the pharmaceutically acceptable excipients described in the present invention include, but are not limited to, liquid or solid fillers, diluents, excipients (such as cocoa butter and suppository waxes), solvents or packaging materials. The pharmaceutically acceptable excipients may be aqueous or non-aqueous. Conventional adjuvants include gums, such as gelatin; starches, such as corn starch, potato starch; sugars such as lactose, glucose and sucrose; cellulosic materials and mixtures thereof, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate. Pharmaceutically acceptable excipients that may be used include, but are not limited to, powdered tragacanth, malt, talc, oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, and the like), alcohols (e.g., propylene glycol, ethanol, glycerol, sorbitol, mannitol, polyethylene glycol, and the like), esters (e.g., ethyl oleate, ethyl laurate, agar), buffers (e.g., magnesium hydroxide, aluminum hydroxide, boric acid and sodium borate, and phosphate buffer), alginic acid, pyrogen-free water, isotonic saline, ringer's solution.
In order to better understand the essence of the invention, the following pharmacological experiment results of the inhibition effect of the compounds on the growth of five cancer cells illustrate the potential application of the compounds in the pharmaceutical field. The pharmacological examples give partial activity data for a portion of the compounds. It must be noted that the pharmacological examples of the invention are intended to illustrate the invention and not to limit it. The simple modification of the present invention according to the essence of the present invention falls within the scope of the present invention.
(ii) antitumor Activity test
The test method comprises the following steps:
the viability of the cells was determined by the MTT method in this experiment based on the semi-Inhibitory Concentration (IC) of each test sample on cell growth50) Value, measure the anticancer activity of the complex.
100uL of the cells in the logarithmic growth phase were seeded into a 96-well plate at a cell density of 3000-. The cells were incubated in a 37 ℃ cell incubator for 24 hours, then 100uL of the compound medium solution with gradient concentration was added to a 96-well plate, and the cells were further incubated in a 37 ℃ cell incubator for 48 hours. 20uL of MTT solution of 5mg/mL is added into each well of a 96-well plate, the plate is taken out after being cultured in a cell culture box at 37 ℃ for 4 hours, the culture medium is sucked out, and DMSO 150uL is added, and the plate is shaken for 20min in a shaking table at 37 ℃ in a dark place. Determining absorbance OD value of each well by enzyme-linked immunosorbent assay at 570nm, and calculating IC50The value is obtained. Each set of experiments was repeated at least three times.
The cancer cell lines selected for the experiment include: human ovarian carcinoma cell SKOV-3, human cervical carcinoma cell Hela, human lung adenocarcinoma cell A549, cisplatin-resistant lung adenocarcinoma cell A549R, human kidney epithelial cell 293T and mouse colon carcinoma cell CT 26.
The test results are shown in table 2 below:
TABLE 2 antitumor Activity data for Compound 1
aRF drug resistance factor RF IC50(A549R)/IC50(A549).
Discussion of antitumor Activity:
from table 2 it can be found that: all target compounds showed moderate to potent antitumor activity against all cell lines tested. IC (integrated circuit)50The results show that the target compounds have better activity than tetravalent platinum parent nucleus 4 c-1. Compounds with different carbon linkage lengths and substituents exhibit different anti-tumor properties. Complex 1-1 with two carbon linkers was more potent and showed significant activity against all tumor cell lines tested than compounds 1-2 and 1-3 with three and four carbon linkers, while the platinum naphthalimide compound 1-5 with an amino group was superior to the platinum naphthalimide compound 1-4 containing a nitro group. Meanwhile, the platinum (IV) naphthalimide compound has great potential in overcoming cisplatin resistance. Particularly, the compound 1-1 has better drug resistance overcoming performance, and the drug Resistance Factor (RF) of A549R is reduced to 0.7, which is lower than cisplatin and oxaliplatin.
Conclusion on antitumor activity:
the activity of the asymmetric mono-substituted naphthalimide tetravalent platinum compound is obviously superior to that of an intermediate tetravalent platinum; and the oxaliplatin has better antitumor activity, is better than the reference medicament oxaliplatin, and has better application prospect compared with cisplatin.
(II) cell uptake and DNA uptake assay
The test method comprises the following steps:
the cellular intake and DNA intake of the medicine are measured by ICP-MS method for quantitative determination of platinum element content. SKOV-3 cells in log phase in good condition were taken in six well plates (10)6Perwell), cultured in a 5% carbon dioxide incubator at 37 ℃ for 3 hours to adhere to the wall, 100. mu.M of the compound was added, culture was continued for 10 hours, and the cells were collected, washed three times with PBS (1 mL. times.3), and centrifuged to collect the cells. The cells were nitrified by adding concentrated nitric acid (LC) at a concentration of 70% to prepare a sample, which was then tested by ICP-MS.
Determination of drug content in DNA: after the cells are collected by the above treatment, DNA is extracted by using a DNA extraction kit, and concentrated nitric acid (LC) with the concentration of 70% is added for nitration to prepare a sample, and the sample is tested by ICP-MS.
Cell uptake and DNA uptake assay results analysis:
the results of cellular uptake are shown in fig. 1, and the results of DNA uptake are shown in fig. 2, and the results in fig. 1 show that the cellular uptake of compound 1-1 is significantly higher than that of oxaliplatin, a bivalent platinum drug. Proved that the capability of the asymmetric mono-substituted naphthalimide tetravalent platinum compound entering cancer cells is stronger than that of oxaliplatin which is a clinical bivalent platinum medicament.
In addition, the results in FIG. 2 show that the test of the compound 1-1 also finds that the capability of the asymmetric mono-substituted naphthalimide quadrivalent platinum compound on DNA after entering cancer cells is stronger than that of a clinical bivalent platinum drug.
(III) in vivo Activity test
The test method comprises the following steps:
in order to further determine the potential of the asymmetric mono-substituted naphthalimide tetravalent platinum complex as an anti-tumor drug, the biological activity of the asymmetric mono-substituted naphthalimide tetravalent platinum complex is evaluated. In the part, an oxaliplatin framework tetravalent platinum compound 1-1 with high activity is selected as a typical compound, and oxaliplatin is used as a positive reference drug for testing. Literature work demonstrates that the presence of the immune system is very important for the exertion of the anti-cancer activity of oxaliplatin and oxaliplatin analogues. Therefore, partial immunodeficiency Balb/c mice are selected in the part, and a CT26 tumor-bearing mouse model is constructed.
BALB/c mice (18-20g) were purchased from the animal center of Shandong university (Shandong, China). All animals were fed according to the guidelines of the national institutes of health for laboratory animal care and use.
Mouse source 5 × 105Individual CT26 cells were injected subcutaneously into the right axilla of male BALB/c mice and treatment was initiated when tumor nodules were palpable (day 6). Mice were randomly divided into three groups, the NaCl group; oxaliplatin group (5mg Pt/kg); compound 1-1 group (5mg Pt/kg). The drug was injected intraperitoneally on days 6, 9, 12, 15 and 18 for a total of 5 doses, and the mice were sacrificed 24 hours after the last dose (day 19). Tumor growth rate was assessed by measuring the diameter of the tumor. Serum, tumor tissue and organ tissue of the mouse, heart, lung, liver, spleen and kidney were collected. Tissue samples were evaluated by formalin fixation and paraffin embedding, by Hematoxylin and Eosin (HE) staining.
The in vivo antitumor results show (as shown in figures 3-7), that compound 1-1 can effectively inhibit the volume growth of tumors compared with the NaCl control group, and the inhibition ability is comparable to that of oxaliplatin (as shown in figure 3). After the experiment, tumor tissues are weighed, and the tumor volume of the compound 1-1 administration group is found to be significantly smaller than that of the NaCl group and slightly smaller than that of the oxaliplatin administration group (as shown in figures 5 and 8). This demonstrates that compound 1-1 has significant in vivo anti-tumor capacity, even stronger than the bivalent platinum clinical drug oxaliplatin.
Analysis of body weight changes in mice revealed that compound 1-1 had less effect on body weight, was relatively superior to oxaliplatin, and had lower toxicity (as shown in figure 4).
The HE staining results of normal tissue sections showed (as shown in fig. 6) that both compound 1-1 and oxaliplatin produced significant toxic effects on normal tissues heart, lung, liver, spleen, and kidney during the 12 day dosing period, indicating that compound 1-1 had low in vivo toxicity.
HE staining results of normal tissue sections showed (as shown in fig. 7) that tumor tissue cell density became sparse in tumor-bearing mice treated with compound 1-1, which is comparable to the positive reference drug oxaliplatin. This again confirms the in vivo activity of compound 1-1.
In a word, the in vivo experiment result of the compound shows that the compound 1-1 can effectively inhibit the growth of tumors, has obvious in vivo anti-tumor activity, slightly superior to the reference medicament oxaliplatin in activity and does not generate obvious systemic toxicity or tissue toxicity. The asymmetric monosubstituted naphthalimide tetravalent platinum compound is an anti-tumor lead compound with development potential.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. A compound having the structural formula (1):
wherein,is cisplatin, carboplatin, heptaplatin, nedaplatin, oxaliplatin, lobaplatin, miboplatin, picoplatin, NDDP or
R3Is methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene or hexadecylene;
R4is Cl, Br or OH;
R5in the 2, 3 or 4 position of the naphthalimide structure, amino, nitryl, hydrogen, bromine, dimethylamino, methoxyl or acetamido is adopted.
2. A process for the preparation of a compound according to claim 1, characterized in that: the preparation method comprises the following steps:
the asymmetric mono-substituted naphthalimide tetravalent platinum compound with the general formula 1 has the following reaction formula:
wherein the feeding mol ratio of the compound 4 to the compound 5 to the TBTU to the triethylamine is 1: (1.0-1.3): (1.0-1.3): (1.0-1.3), the feeding relationship of the compound 4 and DMF is 1 g: (30-80 mL).
3. The method of claim 2, wherein: the preparation method of the asymmetric mono-substituted naphthalimide modified tetravalent platinum compound with the general formula 1 comprises the following steps: adding TBTU and naphthalimide derivative 5 into a reaction vessel, replacing air in a system with nitrogen, adding dry DMF, stirring and reacting for about 10min at room temperature, adding dried triethylamine into the reaction system, stirring and reacting for about 10min at room temperature, finally adding tetravalent platinum compound 4 into the reaction system, replacing air in a flask with nitrogen again, placing the reaction system at 25-120 ℃ for light-shielding reaction for 12-72h, removing the solvent under reduced pressure, and carrying out column chromatography to obtain the asymmetric mono-substituted naphthalimide modified tetravalent platinum compound with the general formula 1.
4. The method of claim 2, wherein: r in said Compound 44Is Cl, Br or OH, and has the general formula:
5. the production method according to claim 3, characterized in that: the reaction formula for compound 4a is as follows:
the preparation method of the tetravalent platinum compound with the general formula 4a comprises the following steps: adding a compound with a general formula 3 into a reaction vessel, adding 30mL of distilled water into every 1.0g of the compound with the general formula 3, stirring to disperse the compound, slowly dropwise adding 50mL of 30% hydrogen peroxide into the reaction system, raising the temperature to 60 ℃, stirring to react for 4h, stopping the reaction, standing at-4 ℃ for crystallization for 12 h, filtering and separating to obtain a yellow solid, adding a proper amount of distilled water, heating to 80 ℃ to dissolve and clear, standing at 4 ℃ for crystallization for 12 h, and filtering to obtain a compound with a general formula 4 a.
6. The production method according to claim 3, characterized in that: the reaction formula of compound 4b is as follows:
the preparation method of the tetravalent platinum compound with the general formula 4b comprises the following steps: adding the compound with the general formula 3 into a reaction container, adding 150mL of distilled water into every 1.0g of the compound with the general formula 3, stirring to disperse the compound, adding 0.46g of N-bromosuccinimide into the reaction system, stirring the system overnight in a dark place, filtering out solids, and performing reduced pressure spin drying on the solution to obtain a yellow solid. Washing the solid with ethanol and ether, drying and filtering to obtain the compound with the general formula 4 b.
7. The production method according to claim 3, characterized in that: the reaction formula for compound 4c is as follows:
the preparation method of the tetravalent platinum compound with the general formula 4c comprises the following steps: adding the compound with the general formula 3 into a reaction vessel, adding 150mL of distilled water into every 1.0g of the compound with the general formula 3, stirring to disperse the compound, adding 0.34g of N-chlorosuccinimide into the reaction system, stirring the system overnight in a dark place, filtering out a solid, and performing reduced pressure spin drying on the solution to obtain a yellow solid. Washing the solid with ethanol and ether, drying and filtering to obtain the compound with the general formula 4 c.
8. The compound of claim 1 for use in the preparation of an anti-tumor medicament against human ovarian cancer, human cervical cancer, human lung adenocarcinoma, cisplatin-resistant human lung adenocarcinoma, and mouse colon cancer.
9. A pharmaceutical composition characterized by: which comprises a therapeutically effective amount of a compound of formula (1) as defined in claim 1, together with pharmaceutically acceptable adjuvants.
10. A therapeutic agent for tumor, characterized by: which comprises a therapeutically effective amount of a compound of formula (1) as defined in claim 1, together with pharmaceutically acceptable excipients.
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