CN111393483B - Tetravalent platinum naphthalimide complex, preparation method and application thereof - Google Patents

Tetravalent platinum naphthalimide complex, preparation method and application thereof Download PDF

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CN111393483B
CN111393483B CN202010369930.XA CN202010369930A CN111393483B CN 111393483 B CN111393483 B CN 111393483B CN 202010369930 A CN202010369930 A CN 202010369930A CN 111393483 B CN111393483 B CN 111393483B
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naphthalimide
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CN111393483A (en
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马静
王佳佳
方东
孙华
谢松强
李迎光
李林容
岳柯欣
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Henan University
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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a tetravalent platinum naphthalimide complex, and a preparation method and application thereof. The tetravalent platinum naphthalimide complex has good antitumor activity, the antitumor activity of the tetravalent platinum naphthalimide complex is better than that of cisplatin and oxaliplatin, and the stability of the tetravalent platinum naphthalimide complex is better than that of bivalent platinum such as cisplatin, carboplatin and oxaliplatin. The complex provided by the invention has a good targeting effect on tumor cells by using the tetravalent platinum modified by the naphthalimide, improves high selectivity on the tumor cells, is different from a classical divalent platinum drug, regulates subcellular organelles and nucleus function reversal drug resistance by targeting a tumor high polyamine microenvironment, and simultaneously relieves T cell immunosuppression around tumors. The complex also solves the problems of poor solubility, more complicated clinical compatibility, poor immunity of patients in clinical application of chemotherapeutic drugs and the like of the traditional bivalent platinum antitumor drugs, and has better lipid solubility and water solubility.

Description

Tetravalent platinum naphthalimide complex, preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a tetravalent platinum naphthalimide complex, and a preparation method and application thereof.
Background
The lack of targeting, drug resistance, weak anti-tumor metastasis activity and immunosuppression are the main reasons for the failure of platinum drugs such as cisplatin and oxaliplatin to treat cancers (including advanced cancers). In recent years, tetravalent platinum antineoplastic drugs as prodrugs of divalent platinum drugs have become the focus of research and development of platinum drugs. Tetravalent platinum central platinum ion belonging to d6Electronic configuration of d2sp3The stable internal-orbit complex formed by hybridization of orbital bonding not only retains broad spectrum and high-efficiency anti-tumor characteristics of bivalent platinum drugs, but also has the advantages of high stability, less accumulation in vivo, low toxic and side effects, strong targeting property, no cross drug resistance and the like, and simultaneously, the characteristic that tetravalent platinum axial ligands are easy to modify provides more possibility for the research diversity of tetravalent platinum compounds. At present, three medicaments of satraplatin (JM216), Ormaplatin (Ormaplatin) and iproplatin (JM9) enter clinical experiments successively, different platinum parent nucleus structures and different axial ligands have obvious influence on the properties of the platinum, and the key point of platinum medicament modification at present is mainly targeted modification of tetravalent platinum axial ligands.
Fig. 1 shows structural formulas of amonafide, mitonaphthylamine, cisplatin and oxaliplatin, and the current research shows that besides being used as a molecular probe to detect the distribution of drugs in subcellular organelles, various naphthalimide composite Polyamine analogs can simultaneously target tumor cells through Polyamine Transporters (PTs) highly expressed by the tumor cells, and show the anti-tumor growth and transfer activities by regulating and controlling the tumor Polyamine microenvironment and the subcellular organelle functions, reversing DNA damage repair and enhancing the T immunity around the tumor. Therefore, the regulation of subcellular organelles and nuclear functions by compounding various naphthalimide derivatives with a novel tetravalent platinum targeting tumor hyperaminoamine microenvironment becomes an effective means for reversing drug resistance and relieving T cell immunosuppression around tumors. Compared with a non-drug-resistant system, the cisplatin can obviously increase the contents of putrescine (Put), spermidine (Spd) and spermine (Spm) of various drug-resistant cell systems, and preliminarily shows that the tumor high polyamine microenvironment is closely related to drug resistance. In clinical experiments, it is found that amonafide can show good antitumor activity by targeting DNA damage, one of the reasons of cisplatin resistance is the repair effect after DNA damage, therefore, the naphthalimide compound tetravalent platinum can enhance DNA damage and improve DNA damage repair reversal drug resistance, and the synthesized part of the polyamine modified naphthalimide analogue can target subcellular organelles and cell nucleus by regulating and controlling polyamine steady state and shows good antitumor growth and metastasis activity.
Disclosure of Invention
In view of the above, the present invention aims to overcome the defects in the prior art, and provide a tetravalent platinum naphthalimide complex with high stability and high targeting property, to study whether the tetravalent platinum naphthalimide complex using oxaliplatin or cisplatin as a parent nucleus exerts dual inhibition effects on mitochondria and cell nucleus, and to study whether the tetravalent platinum naphthalimide complex can synergistically inhibit invasion and migration of tumor cells after entering the body.
The invention also provides a preparation method of the tetravalent platinum naphthalimide complex.
The invention further provides the application of the tetravalent platinum naphthalimide complex in preparing a tumor treatment medicament.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
a tetravalent platinum naphthalimide complex comprises 5 naphthalimide modified tetravalent platinum complexes with different structures shown in a formula 2:
Figure BDA0002477367610000021
wherein X, Y is single ligand or compound ligand, X, Y is the same or different and is NH3、R3-NH2、R3-NH-R4One of aromatic amine, alkyl substituted aromatic amine with 1-4 carbon atoms, aromatic heterocycle with 5-8 carbon atoms, chain alkyl substituted aromatic heterocycle with 1-4 carbon atoms and non-aromatic heterocycle;
R1and R2Is a leaving group, is a single ligand or a complex ligand, and R1、R2Identical or different, are chlorine atoms,
Figure BDA0002477367610000022
One of an aryl group, an alkyl-substituted aryl group having 1 to 4 carbon atoms, an aromatic heterocyclic ring having 5 to 8 carbon atoms, a chain alkyl-substituted aromatic heterocyclic ring having 1 to 4 carbon atoms, and a non-aromatic heterocyclic ring;
wherein R is3And R4The same or different, the carbon atom number is less than or equal to 8 chain or cyclic alkyl and derivatives thereof, the carbon atom number is 1-4 alkyl substituted aryl, aromatic heterocycle containing 5-8 carbon atoms, chain alkyl substituted aromatic heterocycle containing 1-4 carbon atoms, or non-aromatic heterocycle;
R5is one of chain alkyl with the carbon number less than or equal to 20 or cyclic alkyl with the carbon number of 4-8, aromatic heterocycle with the carbon number of 5-8, chain alkyl substituted aromatic heterocycle with the carbon number of 1-4 and non-aromatic heterocycle;
NA is naphthalimide or an analogue containing a 1, 8-naphthalimide structure;
the heteroatom in the heterocycle is a nitrogen, sulfur or phosphorus atom.
Further, X, Y are each independently selected from NH when they are separate ligands3One of isopropylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine, 2-methylpyridine and 2-aminomethylpyridine, and when X or Y is a complex ligand, X or Y is one of 1, 2-ethylenediamine, 1, 3-propylenediamine, 1, 2-cyclohexanediamine, 1, 2-cycloheptanediamine, 1-diaminomethylcyclohexane and 1, 2-diaminomethylcyclobutane; r1、R2When the ligand is a single ligand, the ligand is respectively and independently one selected from Cl, methyl methoxyacetate and methyl tetradecanoate, and when R is1Or R2When it is a complex ligand, R1Or R2One selected from the group consisting of diethyl cyclobutyl-1, 1-dicarboxylate, dimethyl oxalate and dimethyl malonate; r3And R4The same or different, is a chain or cyclic alkyl with the carbon number less than or equal to 8 and a derivative thereof; r5Is a chain alkyl with the carbon number less than or equal to 20; NA is
Figure BDA0002477367610000031
Figure BDA0002477367610000032
Figure BDA0002477367610000033
p is 0,1. 2, 3 or 5, wherein PA in the structural formula is
Figure BDA0002477367610000034
Figure BDA0002477367610000035
Figure BDA0002477367610000041
Specifically, the tetravalent platinum naphthalimide complex is a compound with the following structure:
Figure BDA0002477367610000042
wherein R is
Figure BDA0002477367610000043
Figure BDA0002477367610000044
Figure BDA0002477367610000045
m is 0, 5 or 14, n is 0-5 and n is an integer, p is 0, 1,2, 3 or 5, and PA in the structural formula is
Figure BDA0002477367610000046
Figure BDA0002477367610000051
The preparation method of the tetravalent platinum naphthalimide complex comprises the following steps: mixing and stirring a DMF solution of a compound shown as a formula 2 and a DMF solution of 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate for 10-20 minutes, then adding a DMF mixed solution of a compound shown as a formula 3 and N, N-diisopropylethylamine, reacting at room temperature in a dark place for 24-48 hours to obtain a compound with or without a Boc protective group, and removing the Boc protective group to obtain the compound shown as a formula 1, wherein the structural formula of the compound shown as the formula 2 is as follows:
Figure BDA0002477367610000052
the structural formula of the compound shown in the formula 3 is as follows:
Figure BDA0002477367610000053
wherein q is 0-5 and q is an integer, and NA is naphthalimide or an analogue containing a 1, 8-naphthalimide structure.
The tetravalent platinum naphthalimide complex is applied to the preparation of tumor treatment medicines.
Specifically, the tumors refer to human cervical cancer, human breast cancer, human lung adenocarcinoma, human liver cancer, human colon cancer cells and cisplatin-resistant human lung adenocarcinoma.
Specifically, the medicament comprises a tetravalent platinum naphthalimide complex and a pharmaceutically acceptable carrier.
According to the invention, the problems of poor solubility and the like of the conventional divalent platinum compounds are solved by utilizing the special stability of tetravalent platinum different from divalent platinum, utilizing the characteristic that tumor cells are different from normal cells and have more polyamine intake and utilizing more polyamine transport receptors on the surface of the tumor cells, and the tetravalent platinum naphthalimide complex is synthesized by utilizing an organic synthesis means for the first time.
The tetravalent platinum naphthalimide complex designed and synthesized by the invention can enhance the targeting property of platinum drugs, and simultaneously, the regulation and control of subcellular organelles and nuclear functions by targeting a tumor high polyamine microenvironment becomes an effective means for reversing drug resistance and relieving T cell immunosuppression around tumors, so that the poisoning effect of the platinum drugs by sulfur-containing protein GSH is reduced, the effective platinum content in tumor cells is further improved, the DNA repair proportion is reduced, and the effect of the platinum drugs on innate and acquired drug-resistant cells is enhanced.
Compared with the prior art, the invention has the beneficial effects that:
1. the polyamine transport protein with high expression on the surface of the tumor cells is utilized, so that the targeting property of the medicament to the tumor cells is improved, the bioavailability is improved, and the toxic and side effects to normal cells are reduced.
2. The double targeting effects of subcellular organelles and cell nucleuses are realized by modifying the naphthalimide structure.
3. Improves the water solubility and fat solubility of platinum drugs and increases the intake of tumor cells to the drugs.
4. The activity of the medicine is influenced by adjusting the length of the tetravalent platinum axial ligand chain and adjusting the reduction potential of the tetravalent platinum axial ligand chain.
5. Through the modification of tetravalent platinum axial ligand, the stability of the medicine is improved, the half-life period is prolonged, the dosage is reduced, and the maximum tolerance of an organism to the medicine is improved.
6. The effective combination of the medicament and the DNA of tumor cells is improved, and the oral antitumor medicament is obtained by utilizing the special stability that the structure of the tetravalent platinum medicament is superior to that of the divalent platinum medicaments.
Drawings
FIG. 1 shows the structural formulas of clinical naphthalimide (amonafide, mitonaphthylamine) and platinum drugs (cisplatin, oxaliplatin);
FIG. 2 is a graph showing the cellular uptake of tetravalent platinamide complex 6g (p ═ 0) and cisplatin in A549cisR and A549 cells and the platinum content bound to DNA;
FIG. 3 is a graph showing the difference between the uptake of tetravalent platinamide complex 6g (p ═ 0) in hepatoma cells SMMC-7721 and normal hepatoma cells HL-7702;
FIG. 4 is a graph showing the difference in the uptake of tetravalent platinum naphthalimide complex 6g (p ═ 0) in liver cancer cells (SMMC-7721), lung cancer cells (A549 and A549cisR) and breast cancer cells (MCF-7);
FIG. 5 is a graph showing the difference in the anti-migration ability of tetravalent platinum naphthalimide complex 6g (p ═ 0) in vitro;
FIG. 6 is a graph of the reduction studies of tetravalent platinum and the binding ability to nuclear target DNA assay, wherein a) is the reaction of oxaliplatin bound to 5' -dGMP in the presence of ascorbic acid incubated for 24h at 37 ℃; b) a reaction in which 6g of compound 6 (p ═ 0) which binds to 5' -dGMP in the presence of ascorbic acid was incubated at 37 ℃ for 24 h;
fig. 7 is a study of the binding effect of compound 6g (p ═ 0) with HSA over 0, 48, and 144h, respectively, a) is the reaction of compound 6g (p ═ 0) with HSA incubated at 37 ℃ for 0h, 24h, and 48 h; b) the reaction of oxaliplatin and HSA is incubated for 0h, 48h and 144h at 37 ℃;
FIG. 8 is a graph of the difference in lung cancer cell uptake and DNA-bound platinum content for tetravalent platinum naphthalimide complex 6g (p ═ 0) under the action of PTs inhibitor Spd;
FIG. 9 is a graph of the difference in uptake of tetravalent platinamide complex 6g (p ═ 0) in breast cancer cells and DNA-bound platinum content under the action of PTs inhibitor Spd;
FIG. 10 is a graph showing apoptosis of cisplatin-resistant lung cancer cells by tetravalent platinamide complex 6g (p ═ 0) and the positive drug cisplatin.
Detailed Description
The technical solution of the present invention is further described in detail by the following specific examples, but the scope of the present invention is not limited thereto.
Unless otherwise specified, each reagent referred to herein is derived from commercially available high purity reagents meeting experimental requirements; in the examples, the cis.
The invention realizes the connection of naphthalimide analogs with different structures and tetravalent platinum axial ligands by a chemical synthesis means, thereby synthesizing different series of tetravalent platinum naphthalimide complexes.
The tetravalent platinum naphthalimide complex can be reduced by reducing substances such as VC, NADPH and the like in vivo, and the reduced tetravalent platinum naphthalimide complex plays an anti-tumor role by combining with DNA of tumor cells.
The test results show that the tetravalent platinum naphthalimide complex has better activity on tumor growth and metastasis.
The different series of naphthalimide modified tetravalent platinum complexes are used as an antitumor compound, and the design, synthesis and anticancer activity test aims at preparing broad-spectrum, efficient and low-toxicity anticancer active molecules and providing novel candidate drugs for clinical cancer treatment.
Table 1 shows a typical tetravalent platinum naphthalimide complex skeleton
Figure BDA0002477367610000071
Middle group X, Y, R1、R2In different combinations, it will be appreciated by those skilled in the art that the group X, Y, R in the complexes of the invention1、R2The combination of (3) is not limited thereto.
Figure BDA0002477367610000072
Figure BDA0002477367610000081
On the basis, the invention introduces classical naphthalimide analogue fragments such as amonafide, mitotaneamine and the like which enter into clinical research stage into the mother nucleus of the existing classical platinum drug, designs and synthesizes a series of tetravalent platinum naphthalimide complexes for the first time, characterizes the structure of a target compound, tests the in vitro and in vivo antitumor activity of the target compound, and comprises the following aspects:
the series one is as follows: the structures of the monofunctional and bifunctional tetravalent platinum naphthalimide complexes 1(a-j), 2(a-j), 3(a-j) and 4(a-j) are as follows:
Figure BDA0002477367610000091
wherein p is 0, 1,2, 3 or 5.
The design idea of a series of compounds is as follows:
1) the polyamine transport Protein (PAT) is highly expressed on the surface of the tumor cell membrane, and the structure of polyamine analogues is introduced into target molecules, so that the targeting property can be enhanced. The structure of polyamine analogue is introduced into a tetravalent platinum system to design a tetravalent platinum complex a-d, so that the targeting property is enhanced, and simultaneously, the water solubility and stability of the compound are enhanced, thereby overcoming the defects of poor solubility, poor stability, low in-vivo utilization rate and the like of parent nucleus cisplatin.
2) In order to research the influence of different platinum drug parent nucleus structures on the activity, the invention designs and synthesizes compounds 1 and 3 taking the I-th generation cisplatin as the parent nucleus, designs compounds 2 and 4 taking the III-th generation platinum anti-tumor drug oxaliplatin as the parent nucleus structure, and compares the activity of the compounds with that of the cisplatin compounds 1 and 3 to search for the platinum drug parent nucleus more suitable for polyamine modification.
3) Clinical experimental studies have shown that small differences in polyamine structures of different chain lengths can have a significant impact on their biological function. Therefore, the invention introduces different kinds of clinical-stage-advanced naphthalimide analogue star molecules into a target molecular system to synthesize a-j respectively, aiming at researching the influence of different kinds of naphthalimide ligands on the activity of the tetravalent platinum compound.
4) The unilaterally axial ligand modified tetravalent platinum hydroxyl compound shows remarkable advantages in anti-tumor activity and reduction potential, and in order to better study the structure-activity relationship of the tetravalent platinum compound, the tetralin imide modified tetravalent platinum series compounds 3 and 4 are designed.
And a series II: the bifunctional targeting tetravalent platinum naphthalimide complexes 5(a-j) and 6(a-j) which have higher lipid solubility and can be combined with Human Serum Albumin (HSA) have the following structures:
Figure BDA0002477367610000101
wherein p is 0, 1,2, 3 or 5.
The design ideas of the series of two compounds are as follows:
the lipid-water partition coefficient is an extremely important chemical parameter for drugs. It is considered that the lower clogP value causes defects of poor compound absorption, difficult transmembrane and the like. Therefore, the invention introduces aliphatic chains with different lengths into tetravalent platinum axial ligands and designs a series of two compounds 5-6. Introduction of alkyl chains of different lengths in the target structure: a) the lipid-water distribution coefficient of the target molecule can be well adjusted; b) promoting the binding of the target molecule to HSA in blood, thereby promoting the transport of the compound in blood and tissues; c) the combination of the target molecule and HSA can effectively inhibit the degradation of platinum drugs, thereby improving the in vivo utilization rate and enhancing the activity of the platinum drugs.
And (3) a series of three: the structures of the monofunctional and bifunctional tetravalent platinum naphthalimide complexes 7(a-j), 8(a-j), 9(a-j) and 10(a-j) containing amido bonds are as follows:
Figure BDA0002477367610000111
wherein n is 0-5, and n is an integer, and p is 0, 1,2, 3 or 5.
The design idea of the series of three compounds is as follows:
the amido bond is a commonly-occurring structural segment in a drug molecule, and is easy to form a hydrogen bond with tissues, receptors and the like, so that the binding capacity of a target molecule and a target enzyme receptor is enhanced. The target structure is introduced into an amido bond, and the compounds 7-10 are designed, so that the target products with more excellent properties are obtained, and meanwhile, the target products 8 and 10 with unilateral modification are designed.
The synthesis of tetravalent oxaliplatin carboxylic acids according to the invention is well known to the person skilled in the art, see in particular: ma string, Wang Qingpeng, Yang Xiande, Hao Wenpei, Huang Zhonglv, Zhang Jianbao, Wang Xin, Wang Pen George.Glycosylated platinum (iv) pro drugs digested functionalized semiconducting cells and minimized side-effects [ J ]. Dalton transformations (Cambridge, England:2003),2016,45(29).
Specifically, the synthesis route of tetravalent oxaliplatin carboxylic acid of the invention is as follows:
Figure BDA0002477367610000121
Oxide-Oxp.HRMS：Calcd.for C8H16N2O6Pt(M+)(M+):431.06,found:431.0656.
Oxp(IV)-COOH HRMS：Calcd.for C12H20N2O9Pt(M+):531.08,found:531.0817.
the invention relates to a bifunctional targeting tetravalent platinum naphthalimide complex capable of being combined with HSA, which comprises the following specific components:
example 1: 6h (p is 0)
Figure BDA0002477367610000122
1H NMR(300MHz,Chloroform-d)δ8.45(s,1H),7.79(d,J＝8.5Hz,1H),7.71(s,1H),7.41(s,2H),6.43(s,2H),3.21(d,J＝6.7Hz,5H),2.44(s,2H),2.19(d,J＝18.3Hz,2H),1.56(d,J＝26.2Hz,3H),1.28(d,J＝19.4Hz,28H),0.85(s,3H).13C NMR(75MHz,Chloroform-d)δ184.11,181.13,175.16,166.47–163.55(m),138.96,128.45,127.35,126.40,123.36–121.12(m),118.26,116.21,111.78,62.92,47.03,36.27(d,J＝6.9Hz),31.89,29.26(d,J＝12.6Hz),26.88–21.83(m),14.08,8.76.
The preparation method comprises the following steps:
1) carrying out oxidation reaction on a bivalent platinum compound oxaliplatin on the OXP for 4 hours at the temperature of 60-70 ℃ by using hydrogen peroxide to prepare a tetravalent platinum compound OXIDE-OXP; dissolving a tetravalent oxaliplatin compound Oxide-Oxp (1equiv) and palmitic acid (4equiv) in DMF, reacting for one week at 70 ℃ under the protection of nitrogen, pumping out an oil pump, adding dichloromethane to precipitate a solid, and washing with trichloromethane and diethyl ether to prepare a compound Oxp (IV) -ZL;
2) mixing and stirring a DMF solution of Oxp (IV) -ZL and a DMF solution of 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) for 10 minutes, and then adding a compound
Figure BDA0002477367610000131
And N, N-Diisopropylethylamine (DIPEA) in DMF, and reacted at room temperature for 24 hours to obtain 6h (p ═ 0).
The molar ratio of Oxp (IV) -ZL to HATU in step 2) is 1: 1.5, Oxp (IV) -ZL and compounds
Figure BDA0002477367610000132
In a molar ratio of 1:1, compound
Figure BDA0002477367610000133
Molar ratio to DIPEA 1: 2.4.
the synthetic route is as follows:
the reaction formula of the synthetic route of the step 1) is as follows:
Figure BDA0002477367610000134
the reaction formula of the synthetic route of the step 2) is as follows:
Figure BDA0002477367610000141
the reaction reagent and the condition in the formula: (d) HATU, DIPEA, r.t.,24 h.
Wherein the content of the first and second substances,
Figure BDA0002477367610000142
the synthetic route of (A) is as follows:
Figure BDA0002477367610000143
the reaction reagent and the condition in the formula: (a) na (Na)2CrO3,CH3COOH,118℃,12h；(b)HNO3；Pd/C,H2(c)K2CO3,CH3CN,85℃,5h。
Example 2: 6g (p ═ 0)
Figure BDA0002477367610000144
1H NMR(300MHz,Chloroform-d)δ8.45(d,J＝7.3Hz,1H),8.22(dd,J＝15.6,8.3Hz,2H),7.52(t,J＝7.9Hz,1H),6.76(d,J＝8.3Hz,1H),4.13(t,J＝7.0Hz,2H),3.74(s,8H),2.37(t,J＝7.5Hz,2H),2.02–1.92(m,2H),1.17(s,16H),0.79(t,J＝6.5Hz,3H).13C NMR(75MHz,Methanol-d4)δ173.95,164.42,151.22,134.31,131.60,128.09,124.46,122.29,119.84,109.91,109.03,77.58,77.16,76.73,51.57,39.20,31.64,29.61,29.57,29.42,29.27,29.23,23.42,22.60,13.96.
The preparation method of example 2 differs from that of example 1 in that
Figure BDA0002477367610000151
Instead of in step 2)
Figure BDA0002477367610000152
The rest is the same as example 1.
Wherein the content of the first and second substances,
Figure BDA0002477367610000153
the synthetic route of (A) is as follows:
Figure BDA0002477367610000154
the reaction reagent and the condition in the formula: (a) na (Na)2CrO3,CH3COOH,118℃,12h；(b)HNO3；Pd/c,H2(c)K2CO3,CH3CN,85℃,5h。
Example 3: 6h (p 1)
Figure BDA0002477367610000155
1H NMR(300MHz,Chloroform-d)δ8.06–7.93(m,1H),7.83(dd,J＝6.3,2.8Hz,1H),7.76–7.71(m,1H),7.50–7.44(m,2H),4.10(s,6H),3.25–3.09(m,4H),2.66(s,2H),2.47–2.16(m,4H),1.52(d,J＝93.6Hz,6H),1.33(d,J＝7.3Hz,24H),0.88(t,J＝6.5Hz,3H).13C NMR(75MHz,Chloroform-d)δ172.38–165.15(m),154.93,144.21,138.17,132.29,131.63,130.69,120.79,114.96,50.80,46.05,43.80,42.41,35.82,33.60,33.44,33.26,33.08,29.69,26.57,17.94,12.59.
The preparation method of example 3 differs from that of example 1 in that
Figure BDA0002477367610000161
Instead of in step 2)
Figure BDA0002477367610000162
The rest is the same as example 1.
Wherein the content of the first and second substances,
Figure BDA0002477367610000163
the synthetic route of (A) is as follows:
Figure BDA0002477367610000164
the reaction reagent and the condition in the formula: (a) na (Na)2CrO3,CH3COOH,118℃,12h；(b)HNO3；Pd/c,H2(c)K2CO3,CH3CN,85℃,5h。
Example 4: 6g (p 1)
Figure BDA0002477367610000165
1H NMR(300MHz,Chloroform-d)δ7.99(dd,J＝16.5,6.6Hz,1H),7.82–7.78(m,1H),7.75–7.71(m,1H),7.46(d,J＝4.9Hz,2H),4.19(d,J＝53.7Hz,8H),3.21(q,J＝6.7,6.1Hz,2H),3.11(t,J＝5.8Hz,2H),2.69–2.56(m,2H),2.36(d,J＝33.8Hz,4H),1.58(d,J＝56.7Hz,6H),1.39–1.08(m,27H),0.87(q,J＝5.7Hz,3H).13C NMR(75MHz,Methanol-d4)δ176.30,173.90,164.82,164.22,141.29,134.11,126.95,125.89,117.18,110.08,108.24,39.05,33.40,32.97,31.68,29.41,25.60,22.35,7.85.
Example 4 was prepared in a manner different from that of example 1 in that
Figure BDA0002477367610000171
Instead of in step 2)
Figure BDA0002477367610000172
The rest is the same as example 1.
Wherein the content of the first and second substances,
Figure BDA0002477367610000173
the synthetic route of (A) is as follows:
Figure BDA0002477367610000174
the reaction reagent and the condition in the formula: (a) na (Na)2CrO3,CH3COOH,118℃,12h；(b)HNO3；Pd/c,H2(c)K2CO3,CH3CN,85℃,5h。
Example 5: 6h (p ═ 3)
Figure BDA0002477367610000175
1H NMR(300MHz,Methanol-d4)δ8.03–7.94(m,1H),7.83(dd,J＝8.4,6.3Hz,1H),7.79–7.73(m,1H),7.54–7.50(m,1H),4.28–3.95(m,2H),3.21(d,J＝7.3Hz,1H),3.13(d,J＝4.0Hz,2H),2.44–2.23(m,4H),1.62(d,J＝47.8Hz,6H),1.46–1.15(m,27H),0.88(t,J＝6.4Hz,3H).13C NMR(75MHz,Methanol-d4)δ184.40,183.95,164.92,164.34,134.31,128.28,126.71,116.93,110.89,108.98,61.98,41.89,39.84,35.97,31.83,29.44,29.27,29.08,26.39,25.65,25.12,23.84,22.59,13.96.
The preparation method of example 5 differs from that of example 1 in that
Figure BDA0002477367610000181
Instead of in step 2)
Figure BDA0002477367610000182
The rest is the same as example 1.
Wherein the content of the first and second substances,
Figure BDA0002477367610000183
the synthetic route of (A) is as follows:
Figure BDA0002477367610000184
the reaction reagent and the condition in the formula: (a) na (Na)2CrO3,CH3COOH,118℃,12h；(b)HNO3；Pd/c,H2(c)K2CO3,CH3CN,85℃,5h。
Example 6: 6g (p ═ 3)
Figure BDA0002477367610000185
1H NMR(300MHz,Methanol-d4)δ8.40(d,J＝8.4Hz,1H),8.09(d,J＝8.4Hz,1H),7.98(d,J＝7.7Hz,1H),7.84(d,J＝8.1Hz,1H),7.75(dd,J＝7.2,5.0Hz,1H),7.53–7.49(m,1H),4.13–4.01(m,1H),3.35(p,J＝1.6Hz,1H),3.13(d,J＝5.8Hz,4H),2.79–2.61(m,2H),2.47–2.24(m,4H),1.78–1.38(m,8H),1.37–1.11(m,22H),0.88(t,J＝6.4Hz,3H).13C NMR(75MHz,Methanol-d4)δ184.49,184.02,164.77,164.60,133.45,132.19,126.77,126.49,116.86,110.90,61.99,46.80,39.77,36.61,36.41,31.83,29.60,29.56,29.42,29.26,29.23,29.07,27.44,26.44,25.17,23.85,22.58,13.87,8.55.
The preparation method of example 6 differs from that of example 1 in that
Figure BDA0002477367610000191
Instead of in step 2)
Figure BDA0002477367610000192
The rest is the same as example 1.
Wherein the content of the first and second substances,
Figure BDA0002477367610000193
the synthetic route of (A) is as follows:
Figure BDA0002477367610000194
the reaction reagent and the condition in the formula: (a) na (Na)2CrO3,CH3COOH,118℃,12h；(b)HNO3；Pd/c,H2(c)K2CO3,CH3CN,85℃,5h。
Example 7: 6i (p ═ 0)
Figure BDA0002477367610000195
1H NMR(300MHz,Methanol-d4)δ8.57(s,1H),7.72(s,2H),7.38(s,2H),4.28(d,J＝6.4Hz,2H),2.81–2.46(m,3H),2.16(q,J＝7.2Hz,2H),1.90–1.40(m,4H),1.39–1.05(m,30H),0.88(dt,J＝28.1,7.2Hz,3H).13C NMR(75MHz,Methanol-d4)δ174.73,173.95,163.13,162.33,138.60,132.51,131.12–130.77(m),129.96,129.42,128.42,126.42,123.92,115.94,111.95,65.60,31.90,31.90,29.64,29.34,29.34,25.71(d,J＝7.7Hz),22.68,19.17,14.13,8.83.
The preparation method of example 7 differs from that of example 1 in that
Figure BDA0002477367610000201
Instead of in step 2)
Figure BDA0002477367610000202
The rest is the same as example 1.
Wherein the content of the first and second substances,
Figure BDA0002477367610000203
the synthetic route of (A) is as follows:
Figure BDA0002477367610000205
the reaction reagent and the condition in the formula: (a) na (Na)2CrO3,CH3COOH,118℃,12h；(b)HNO3；Pd/c,H2(c)K2CO3,CH3CN,85℃,5h。
Example 8: 5i (p ═ 0)
Figure BDA0002477367610000204
1H NMR(300MHz,Chloroform-d)δ8.80–8.52(m,1H),8.44–8.03(m,1H),7.79(s,3H),7.39(s,6H),3.23(dt,J＝11.1,5.6Hz,4H),2.88–2.46(m,2H),2.39–2.08(m,1H),1.47–1.01(m,22H),0.86(t,J＝6.5Hz,3H).13C NMR(75MHz,Chloroform-d)δ177.35,173.57,164.05,162.68,133.90,131.59,125.00,109.59,77.45,51.62,39.31,38.81,36.58,33.78,31.93,31.52,29.70,29.61,29.33,29.27,24.79,24.47,22.70,15.33,14.13.
The preparation method of example 8 differs from that of example 1 in that
Figure BDA0002477367610000211
Instead of in step 2)
Figure BDA0002477367610000212
The rest is the same as example 1.
Wherein the content of the first and second substances,
Figure BDA0002477367610000213
the synthetic route of (A) is as follows:
Figure BDA0002477367610000214
the reaction reagent and the condition in the formula: (a) na (Na)2CrO3,CH3COOH,118℃,12h；(b)HNO3；Pd/c,H2(c)K2CO3,CH3CN,85℃,5h。
The application also synthesizes a plurality of compounds, and the structural formula of the compounds can be obtained from a series I, II and III, which are not listed.
Test example 1: evaluation of target molecule biological Activity
(1) In vitro antitumor Activity test
The cancer cell lines selected for this test included: human cervical cancer cells (Hela), human breast cancer cells (MDA-MB-231), human breast cancer cells (Mcf-7), human lung adenocarcinoma cells (A549), human liver cancer cells (SMMC7721), human colon cancer cells (HCT-116) and cisplatin-resistant human lung adenocarcinoma cells (A549R).
The test method comprises the following steps: 100 μ L of cell suspension was added to a 96-well plate, the cell density was controlled at 3000-. After 24 hours of incubation in the 37 ℃ cell incubator, 100. mu.L of a compound medium solution having a gradient concentration (0.2, 0.6, 1.3, 3.2, 7.5, 17.8, 42.2, 100, unit. mu.M) was added to the 96-well plate, and the cell incubator was further incubated at 37 ℃ for 48 hours. 20. mu.L of 5mg/mL MTT solution was added to each well of a 96-well plate, and the plate was taken out after culturing in a 37 ℃ cell incubator for 4 hours, the medium was aspirated, and 150. mu.L DMSO was added thereto, and the plate was shaken in a shaker at 37 ℃ for 20min in the dark. The absorbance of each well was measured at 470nm with a microplate reader, and the IC thereof was calculated50Values, which were repeated at least three times for each set of experiments, were measured as shown in tables 2, 3 and 4. Four positive controls, cisplatin (Cis.), oxaliplatin (Oxp.), cisplatin Oxide (Oxide-Cis.), and oxaliplatin Oxide (Oxide-Oxp.), were added to the solution.
TABLE 2 platinum (IV) -naphthalimide complexes with HSA-binding Properties 5-6 (IC)50Unit: μ M) cytotoxicity profile (RF) in human tumor cell linesa:Resistant factor＝IC50(A549R)/IC50(A549))。
Figure BDA0002477367610000221
The results of the in vitro antitumor activity tests show that the tetravalent platinum naphthalimide complex shows antitumor activity obviously superior to tetravalent platinum parent nucleus, and naphthalimide ligands with different structures have obvious influence on the antitumor activity of the compound, and show better activity on various tested tumor cells. The activity of the product of cisplatin as a mother nucleus is obviously superior to that of oxaliplatin, and the complexes show better activity on cisplatin-resistant A549R cells, have no cross resistance with cisplatin, have RF value of 0.24-0.84, and have greater advantage compared with 3.02 of cisplatin. Wherein 6h-6g has better effect on SMMC7721, Hela, MDA-MB-231, MCF-7, HCT-116 and A549R than positive medicaments of cisplatin and oxaliplatin.
(2) In vitro normal cytotoxicity assay
Mouse embryonic fibroblasts (3T3) and human normal hepatocytes (HL-7702) required for the test were purchased externally, and the killing ability of the target compound against normal cells was measured by the above MTT method.
TABLE 3 Effect of platinum (IV) -naphthalimide complexes with HSA binding Properties on the viability of cancer cells and comparable normal cells (IC)50Unit: μ M).
Figure BDA0002477367610000222
Figure BDA0002477367610000231
As can be seen from the test results in Table 3 above, tetravalent platinum naphthalimide complexes differ greatly from normal hepatocytes and 3T3 cells in addition to their antitumor activities.
Test example 2: tetravalent platinum naphthalimide complex cell uptake and DNA binding capacity test
ICP-MS detects the medicine intake of cells and the content of platinum combined with the DNA of the cell nucleus target spot. Adding a mother solution of a compound to be detected into a 6-hole plate containing 100 ten thousand cells/hole to 10 mu M, culturing for 12h in a cell culture box at 37 ℃, collecting the cells, washing for three times by PBS, adding 1mL of concentrated nitric acid, nitrifying and cracking the cells, removing the nitric acid at 120 ℃, dissolving residues in a 2% dilute nitric acid solution, diluting by 10 times, quantitatively detecting the content of platinum element by utilizing ICP-MS, and further calculating the intake condition of the compound in the tumor cells. As shown in FIGS. 2 to 4, in which the platinum complex concentration was 10. mu.M, the detection time was 17 hours.
The experimental results of fig. 2-4 show that the uptake of lead compound 6g (p ═ 0) in SMMC-7721, MCF-7, MDA-MB-231 and a549R cells in the examples of the present invention is better than that of cisplatin and oxaliplatin, and the advantages are better, and the binding content of the lead compound to DNA is also obviously better than that of the positive control drugs cisplatin and oxaliplatin.
Test example 3: transwell migration experiment in vitro verification of anti-tumor migration capacity of tetravalent platinum naphthalimide complex
Selecting cultured cancer cells, inoculating the cancer cells to a Transwell upper chamber, incubating in an incubator for 8h, taking out a small chamber, wiping off the upper chamber cells, fixing the lower chamber cells by using ice methanol, air-drying, dyeing with 0.1% crystal violet for 0.5h, washing with PBS for 3 times, air-drying, observing under a mirror, photographing and counting and analyzing differences. The results are shown in FIG. 5.
From fig. 5, it can be seen that compound 6g (p ═ 0) has significantly better anti-tumor migration ability than the positive control drug cisplatin, and has concentration dependence.
Test example 4: the reduction research of the tetravalent platinum naphthalimide complex and the binding capacity with the nuclear target DNA.
The in vitro reduction test of tetravalent platinum is divided into a cis-platinum group and a target compound group, the reducibility of tetravalent platinum is researched by adding ascorbic acid, and the preposed test is to culture 5' -GMP at the constant temperature of 37 ℃ by shaking. In the test, the ratio of cis-platinum group is: cisplatin 1mM + GMP3 mM; the target compound comprises two groups, wherein one group is added with a reducing agent ascorbic acid in the following proportion: compound 1mM + GMP3mM + ascorbic acid 5mM, one group without ascorbic acid, in the following proportions: compound 1mM + GMP3 mM. The groups are respectively cultured in a constant-temperature shaking incubator at 37 ℃ for 24h, 48h and 72h, and then the combination condition of the medicine and the GMP is detected by HPLC. Wherein HPLC adopts the model of Waters E2695-2998, Venusil MP C18 col mu Mn chromatographic column, HRMS detects the product peak therein, and ESI ion source. The mobile phase conditions for the high performance liquid phase are shown in table 4.
Table 4 mobile phase conditions for the high performance liquid phase of tetravalent platinum reduction product.
Figure BDA0002477367610000241
The reduction studies of tetravalent platinum and the binding ability to the target DNA of the cell nucleus are shown in FIG. 6, wherein a) is a graph of the detection of the product after incubation of oxaliplatin in the presence of ascorbic acid with 5' -dGMP for 24h at 37 ℃; b) a detection profile of the product after incubation of 6g of compound 6 (p ═ 0) bound to 5' -dGMP in the presence of ascorbic acid at 37 ℃ for 24 h; the results of the experiment in fig. 6 show that the target compound binds to the target DNA in a manner similar to oxaliplatin, after being reduced by the reducing agent, and then binds to tumor cells.
Test example 5: binding Capacity test of target Compounds to HSA
The binding capacity of the target product to Human Serum Albumin (HSA) was investigated by fluorescence spectroscopy and HPLC. Dissolving a target compound and HSA in a culture medium according to a molar ratio of 1:5, placing the mixture into a shaking table at 37 ℃ for shaking, simulating a human blood environment, and detecting content changes of the target compound, the HSA and a binding product of the target compound and the HSA by HPLC (high performance liquid chromatography) and fluorescence spectrometry in 5min, 30min, 1h, 3h, 5h, 7h, 9h, 11h, 24h, 36h and 72h respectively.
Fig. 7 is a graph of the binding effect of compound 6g (p ═ 0) with HSA tested over 0, 48, and 144h, respectively, a) is a graph of the detection of the product of compound 6g (p ═ 0) with HSA after incubation at 37 ℃ for 0h, 24h, and 48 h; b) is the reaction of oxaliplatin with HSA at 37 ℃ for 0h, 48h and 144 h;
the test results show that the target compound 6g (p ═ 0) has a structure similar to a palmitate chain, and has better binding capacity with HSA, and the conclusion that the target compound has higher blood stability can be drawn.
Test example 6: targeted and targeting mechanism research of tetravalent platinum naphthalimide complex on tumor tissues
During the culture of tumor cells, a certain dosage of PAT transporter inhibitor is added to study cell IC50A change in value. And simultaneously separating the cytoplasmic matrix from the cell nucleus, extracting the DNA of the tumor cell by adopting a DNA small amount extraction kit, carrying out nitration treatment on the sample by adopting nitric acid, detecting the platinum content in the cytoplasmic matrix and the cell nucleus by adopting ICP-MS (inductively coupled plasma-mass spectrometry), and further confirming the relationship between the PAT protein on the surface of the tumor cell membrane and the target compound. The specific method comprises the following steps:
HeLa (5 x 10) to be assayed in logarithmic growth phase5Per well) and MCF-7(2 x 10)5/well) cells were plated in six-well plates and placed at 37 ℃ with 5% CO2Culturing in an incubator, enabling cells to grow in an adherent manner, adding 50 mu M of positive reference drugs cisplatin and oxaliplatin respectively and 50 mu M of target compounds into a six-well plate, continuously culturing for 10 hours, collecting the cells, washing with PBS (1mL multiplied by 3), centrifuging, nitrifying the cells with nitric acid (70%), putting into an oven, drying, taking out, re-dissolving the residues with nitric acid (2%), and detecting ICP-MS. Meanwhile, the HeLa cells in the six-hole plate are extracted by a DNA small amount extraction kit, and then nitrified by nitric acid and redissolved by 2% nitric acid, so that the DNA in the cells is used for ICP-MS detection.
Meanwhile, the spermidine group was added with the same dose of 50 μ M spermidine and aminoguanidine (1mM) to prevent interference of serum with the drug when the same dose of drug group (10 μ M) was added, and the platinum content was measured by ICP-MS after the same time as the drug group. The control was made by adding an equal amount of medium at the same time without spermidine addition.
As shown in FIGS. 8 to 9, FIGS. 8 to 9 are graphs showing the ability of Spermidine (SPD) to take up platinum from MCF-7 cells A549R cells using ICP-MS, respectively (in which spermidine concentration was 50. mu.M, platinum complex concentration was 10. mu.M, Aminoguanidine (AG) concentration was 1mM, non-toxic, aminoguanidine was incubated with the cells for 24h before administration, and detection time was 17 h). FIG. 8 is a graph of the difference in lung cancer cell uptake and DNA-bound platinum content for tetravalent platinum naphthalimide complex 6g (p ═ 0) under the action of PTs inhibitor Spd; fig. 9 is a graph of the difference in uptake of tetravalent platinamide complex 6g (p ═ 0) into breast cancer cells and DNA-bound platinum content under the action of the PTs inhibitor Spd. It can be seen from figures 8-9 that compound 6g (p ═ 0) targeted nuclear DNA in tumor tissues better than cisplatin and oxaliplatin.
Test example 7: tetravalent platinum naphthalimide complex and apoptosis condition of positive medicament cisplatin to cisplatin-resistant lung cancer cells
The apoptosis condition of the tetravalent platinum naphthalimide complex and the positive medicament cisplatin to cisplatin-resistant lung cancer cell is detected by adopting an apoptosis kit, the result is shown in figure 10 as a diagram of the apoptosis condition of the tetravalent platinum naphthalimide complex 6g (p ═ 0) and the positive medicament cisplatin to cisplatin-resistant lung cancer cell, and the experimental result shows that the apoptosis ratio of the tetravalent platinum naphthalimide complex is obviously higher than that of cisplatin.
The experimental results show that the polyamine-modified tetravalent platinum naphthalimide complex realizes targeting on tumor tissues, different naphthalimide complexes show larger difference on polyamine transporters on the surfaces of different tumor cell membranes, and products with different structures have selectivity on different tumor cells.
In conclusion, the compound synthesized by the invention has good antitumor activity, the antitumor activity of the compound is better than that of cisplatin and oxaliplatin, the stability of the compound is better than that of bivalent platinum such as cisplatin, carboplatin and oxaliplatin, in addition, the tetravalence platinum modified by naphthalimide has better targeting property on tumor cells, and the high selectivity on the tumor cells is improved. Because the complex is not easy to combine with protein and the like before being reduced in vivo, the tetravalent platinum naphthalimide complex can not only improve the in vivo utilization rate and enhance the curative effect, but also reduce the toxic and side effects of the traditional divalent platinum drugs on the kidney and the like.

Claims (2)

1. The application of the tetravalent platinum naphthalimide complex in preparing the medicine for improving the tumor treatment targeting is characterized in that when the tetravalent platinum naphthalimide complex is applied, the tetravalent platinum naphthalimide complex is used as a tumor treatment medicine and is added into tumor cells, spermidine is added, and the targeting on the tumor cells is improved; the tumor cell is human breast cancer cell MCF-7; the method comprises the following specific steps:
the MCF-7 cells in logarithmic growth phase were plated in six-well plates at 2 x 10 cells per well5Culturing in an incubator at 37 deg.C, charging 5% CO by volume2And (3) adding 50 mu M into a six-hole plate for adherent growth of cellsAdding 50 mu M spermidine into the tetravalent platinum naphthalimide complex, adding 1mM aminoguanidine, continuously culturing for 10h, collecting cells, washing the cells for 3 times by using 1mL of PBS, centrifuging, nitrifying the cells by using nitric acid with the mass fraction of 70%, drying, taking out the cells, and redissolving the residues by using nitric acid with the mass fraction of 2%, thereby realizing the improvement of the targeting property of the tetravalent platinum naphthalimide complex to tumor cells;
the tetravalent platinum naphthalimide complex is a compound 6hp-0 with the following structure:
Figure DEST_PATH_IMAGE001
6hp-0
the tetravalent platinum naphthalimide complex is prepared by the following steps:
1) carrying out oxidation reaction on a bivalent platinum compound oxaliplatin on the OXP for 4 hours at the temperature of 60-70 ℃ by using hydrogen peroxide to prepare a tetravalent platinum compound OXIDE-OXP; dissolving a tetravalent oxaliplatin compound Oxide-Oxp and palmitic acid in DMF, reacting for a week at 70 ℃ under the protection of nitrogen, pumping out an oil pump, adding dichloromethane to precipitate a solid, and washing with trichloromethane and diethyl ether to prepare a compound Oxp (IV) -ZL;
2) mixing and stirring a DMF solution of Oxp (IV) -ZL and a DMF solution of 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate for 10 minutes, then adding a DMF mixed solution of a compound 5 and N, N-diisopropylethylamine, and reacting at room temperature for 24 hours to obtain a compound 6 hp-0;
the compound 5 is
Figure 465893DEST_PATH_IMAGE002
；
In the step 2), the molar ratio of Oxp (IV) -ZL to 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate is 1: 1.5; the molar ratio of Oxp (IV) -ZL to compound 5 is 1: 1; molar ratio of compound 5 to N, N-diisopropylethylamine 1: 2.4.
2. use according to claim 1, characterized in that the mass ratio of tetravalent oxaliplatin compound Oxide-oxp. and palmitic acid in step 1) is 1: 4.
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