CN106543233B

CN106543233B - Chiral binuclear platinum complex containing unsaturated bond and preparation method and application thereof

Info

Publication number: CN106543233B
Application number: CN201610898197.4A
Authority: CN
Inventors: 高传柱; 余从涛; 陈骥
Original assignee: Kunming University of Science and Technology
Current assignee: Kunming University of Science and Technology
Priority date: 2016-10-14
Filing date: 2016-10-14
Publication date: 2021-04-09
Anticipated expiration: 2036-10-14
Also published as: CN106543233A

Abstract

The invention discloses a chiral binuclear platinum complex containing unsaturated bonds, which has the structural formula I or II, has antitumor activity, is simple and feasible in synthesis method, and is suitable for industrial production;

wherein R is selected from

n is 2-8; d is selected from

Z is selected from CH₃COO^‑、ClCH₂COO^‑、CH₃(CH₂)₆COO^‑、CH₃(CH₂)₈COO^‑、

Cl^‑。

Description

Chiral binuclear platinum complex containing unsaturated bond and preparation method and application thereof

Technical Field

The invention relates to an organic compound, in particular to a novel chiral binuclear platinum complex containing unsaturated bonds, a preparation method thereof and antitumor activity thereof.

Background

Cancer has been a serious threat to human health, and there are statistically 1000 million new cancer patients per year, of which approximately 600 million patients die from cancer. Since the discovery of anticancer activity of cisplatin by Rosenberg et al in 1967, cisplatin, as a highly potent anticancer drug, has been widely used for the treatment of various cancers, such as testicular cancer, ovarian cancer, cervical cancer, bladder cancer, lung cancer, head and neck cancer, and the like. Oxaliplatin, as a representative of third-generation platinum drugs, has made a significant breakthrough clinically. The research finds that the chiral ligand 1R, 2R-cyclohexanediamine is a core component of the medicine for treating the middle and late colorectal cancer.

Since the last 90 s, based on the continuous and intensive research on the action mechanism and the drug resistance mechanism of the platinum complex, scientists are no longer limited to the classical structure-activity relationship proposed by Cleare et al. Various platinum anti-tumor complexes different from the classical structure-activity relationship have been designed and have achieved good effects. The polynuclear platinum (II) complexes have attracted much interest among various non-classical platinum antineoplastic drugs. A large number of researches show that the binuclear and polynuclear platinum complex with a polyamine bridge chain shows good cytotoxic activity, and the bridged binuclear platinum complex and DNA form long-distance interchain cross connection, can span four or more base pairs to be subjected to multipoint bonding with the DNA, has strong bonding capability, can seriously damage the DNA structure, enables cancer cells to be difficult to self-repair, and does not generate drug resistance compared with other platinum drugs.

Curcumin is a yellow slightly acidic phenolic pigment with diketone extracted from plant curcuma longa, and is a main component of curcuma longa in curcuma genus for playing pharmacological action. Researches show that curcumin has pharmacological effects of oxidation resistance, tumor resistance, inflammation resistance, neuroprotection and the like, has low toxicity and has good clinical application value. Researches find that the unsaturated chain structure is one of the keys of curcumin for playing the role of antioxidation. In addition, the structure is also related to the anti-tumor effect, and the national tumor research institute of America has listed the structure as a third generation cancer chemopreventive medicine.

Therefore, the compound with the structure shown in the formula (I) is designed based on the chiral ligand 1R, 2R-cyclohexanediamine of oxaliplatin and the carbon chain with an unsaturated bond as a bridge, and the complex is expected to play the original anti-tumor effect of oxaliplatin and the advantages of a binuclear platinum anti-tumor drug in the subsequent platinum drug research, and simultaneously play the anti-oxidation effect of an unsaturated chain to assist in resisting cancer.

Disclosure of Invention

The invention aims to provide a chiral binuclear platinum complex containing unsaturated bonds, which has a structural formula shown as a formula I or a formula II;

wherein R is selected from

n＝2-8；

D is selected from

Z is selected from CH₃COO^-、ClCH₂COO^-、CH₃(CH₂)₆COO^-、CH₃(CH₂)₈COO^-、

Cl^-。

The synthesis path of the chiral binuclear platinum complex containing unsaturated bonds is as follows:

1. the 1-N-Boc-1R, 2R-cyclohexanediamine is a commercial product or is synthesized by adopting the following path:

2. synthesis of diethoxyketene reference is made to Enol ethers.II. Synthesis and reactions of 1,4-bis (ethoxy-methyl) -2, 3-butano, Chemische Berichte (1965),98, (7),2260-5. diethoxyketene is obtained

The synthesis route is as follows:

3. the diacid chloride is

Wherein n is 2-8, commercially available or synthesized as follows:

4. in the presence of a solvent, 1-N-Boc-1R, 2R-cyclohexanediamine is used as a raw material to perform substitution reaction with diethoxyketene or diacid chloride according to the molar ratio of 2:1 to prepare a polyamine ligand which takes an unsaturated chain as a bridge and contains a Boc protecting group, wherein when R is

When the solvent is diethyl ether, R is

When the solvent is the anhydrous dichloromethane,

5. adding the polyamine ligand containing the boc protecting group and taking the unsaturated chain as a bridge in the step 4 into 1-1.5mol/L ethyl acetate hydrochloride to remove the boc protecting group to prepare hydrochloride of the polyamine ligand, dissolving the hydrochloride of the polyamine ligand in water, adding saturated sodium carbonate solution, extracting with ethyl acetate, taking an organic phase, and drying to obtain the polyamine ligand taking the unsaturated chain as a bridge;

6. dissolving the polyamine ligand taking the unsaturated chain as the bridge in the step 5 in water, and then dropwise adding the solution to K₂PtI₄Reacting in water solution at 40-50 deg.C for 24 hr, filtering, sequentially adding ice water, diethyl ether and ethylWashing the solid with alcohol, vacuum drying to obtain amine platinum iodine, wherein the unsaturated chain is polyamine ligand and K of bridge₂PtI₄In a molar ratio of 1: 2;

7. dissolving amiplatin iodine in purified water, heating to 50-60 deg.C, and weighing AgZ or D (OAg)₂Adding the solution, stirring at 50-60 deg.C for 2h, filtering, and washing to obtain chiral binuclear platinum complex with unsaturated chain as bridge, wherein platinum iodide amine is mixed with D (OAg)₂The molar ratio of amine platinum iodide to AgZ is 1: 4; or adding a certain amount of silver nitrate into the platinum iodide amine solution, removing silver iodide precipitate, adding sodium chloride, filtering and washing to obtain a novel chiral binuclear platinum complex with an unsaturated chain as a bridge, wherein the molar ratio of the platinum iodide amine to AgNO3 to NaCl is 1:4: 4;

wherein D is selected from

Cl^-。

The other purpose of the invention is to apply the chiral binuclear platinum complex containing unsaturated bonds in the preparation of antitumor drugs, and the compound shown as the structural formula I or the structural formula II is an important component of the antitumor drug oxaliplatin because the compound has two chiral cyclohexanediamines, and the cyclohexanediamine is matched with the two platinum by the intermediate bridge chain. In addition, part of the bridge chain has a structure similar to that of curcumin, and research shows that the structure has a certain relation with tumor resistance and oxidation resistance. The coordination compound is expected to play the anti-tumor role of oxaliplatin in the subsequent platinum drug research, and also play the advantages of a binuclear platinum anti-tumor drug. In addition, compounds with partially unsaturated chains can also exert corresponding antitumor and antioxidant effects.

The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.

The main advantages of the invention are:

1. the complex provided by the invention has a pharmacological activity part chiral cyclohexanediamine of oxaliplatin, and simultaneously connects 2 platinum cores with an unsaturated chain part, so that the complex has the capacity of forming multipoint crosslinking with DNA, wherein the unsaturated chain has antioxidant potential, and in the embodiment, part of compounds preliminarily show cytotoxicity superior to the existing medicines oxaliplatin and carboplatin, so that the complex is expected to become a novel future binuclear platinum anti-tumor medicine;

2. the method has simple and easy operation in the synthetic process, simple and easy operation because the subsequent treatment is carried out by recrystallization, no high temperature and high pressure exist in the reaction process, no highly toxic substances are used, safety and environmental protection are realized, and the method is favorable for industrial production.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are only for illustrating the present invention and do not limit the scope of the present invention. Test methods without specific conditions noted in the following examples, generally according to conventional conditions or according to the conditions recommended by the manufacturer, all percentages and ratios are by weight unless otherwise indicated.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are exemplary only.

Example 1: preparation of the formula (R ═ R)₁，D＝D₁-D₄) The compounds shown, namely:

(1) preparation of 1-N-Boc-1R, 2R-cyclohexanediamine

Dissolving 22.4g (0.1mol) of 1R, 2R-cyclohexanediamine in 200mL of methanol solution, placing the solution in a 500mL single-neck bottle at normal temperature and continuously stirring; 19.4mL of 5.17mol/L hydrochloric acid methanol is measured by a measuring cylinder and is placed in a constant pressure funnel; slowly dripping hydrochloric acid methanol into a single-neck bottle under the ice bath condition; after the dripping, the ice bath was removed and the reaction was carried out at room temperature for 30 minutes. 38.28g (0.176mol) (Boc) were weighed out₂Dissolving O in 100mL of methanol, placing the mixture in a constant-pressure funnel, slowly dropwise adding the mixture into a single-neck bottle, reacting at normal temperature for 1 hour after dropwise adding, and spin-drying to obtain a white solid; dissolving the white solid in water, extracting with diethyl ether, and collecting water phase; adjusting the pH to 10, CH₂Cl₂Extracting, taking organic phase, spin-drying, and obtaining CH₂Cl₂Recrystallization from PE gave white crystals with a yield of 78%.¹H NMR(500MHz，CDCl₃)：δ7.28(s，1H，NH-Boc)，4.52(s，2H，NH₂)，2.33(m，1H)，1.98(m，1H)，1.69(m，4H)，1.46(s，9H，NH-Boc)，1.19-1.32(m,2H)，1.06-1.17(m，2H)。HR-MS(m/z):[C₁₁H₂₂N₂O₂+H]⁺＝215.1689。

(2) Preparation of

0.8816g (12mmol) of vinyl ether is dissolved in 10mL of anhydrous ether, placed in a double-necked bottle and condensed and refluxed at normal temperature; 0.621g (4.8mmol) of oxalyl chloride is dissolved in 3mL of diethyl ether and slowly added dropwise into a double-necked flask, and the color of the reaction solution is changed from zeroThe color gradually turns yellow and a large amount of heat is discharged; after the dropwise addition, the reaction was carried out for 3 hours, and then the reaction mixture was allowed to stand for 6 hours to obtain a yellow reaction solution. 2.5g (24.8mmol) of triethylamine is weighed and placed in a bottle shaped like a eggplant, the yellow reaction liquid is placed in a constant pressure funnel and slowly dripped into the triethylamine, a large amount of yellow solid is generated, and a large amount of white smoke and heat are accompanied, and N is dripped after the dripping is finished₂Stirred for 1 hour under protection and placed in a refrigerator for 12 hours. Taking out, washing yellow solid with diethyl ether, vacuum filtering to obtain purple solution, concentrating, and placing in refrigerator for 24 hr to obtain yellow needle or granule crystal

The yield was 69%.¹H NMR(500MHz,DMSO)：δ7.77(d，2H，CH＝CH-C＝O)，，6.01(d，2H，CH＝CH-C＝O)，4.11(dd，4H，CH₃CH₂)，1.28(t，6H，CH₃CH₂)。HR-MS(m/z):

[C₁₀H₁₄O₄+Na]⁺＝221.0785。

(3) Preparation of

(R＝R₁)

0.584g (3mmol) was weighed

Placing in a eggplant-shaped bottle and 20mL of ether solvent, dissolving 1.284g (6mmol) of the compound in the step (1) in 15mL of absolute ethyl alcohol, placing in a constant-pressure funnel, slowly dripping into the eggplant-shaped bottle at normal temperature, and stirring for 48 hours after dripping. Spin-drying to obtain yellow solid; recrystallization from ethanol gave regular yellow granular crystals with a yield of 92%.¹H NMR(500MHz,DMSO)：δ6.68(d，2H，CH＝CH-C＝O)，5.60(d，2H，CH＝CH-C＝O),1.90-1.96(m，2H)，1.76-1.80(m，4H)，1.69-1.72(m，6H)，1.30(s，18H，NH-Boc)，1.20-1.26(m,4H)，1.06-1.17(m，4H)。HR-MS(m/z):[C₂₈H₄₆N₄O₆+H]⁺＝535.3492。

(4) Preparation of

(R＝R₁)

Weighing

2.136g (4mmol) is dissolved in 50mL ethyl acetate, placed in an eggplant-shaped bottle, and added with 1.5mol/L ethyl acetate hydrochloride dropwise to make the reaction liquid have strong acidity (pH is 1-2), and after 12 hours of reaction at room temperature, the mixture is filtered by suction to obtain brown solid with the yield of 96 percent; dissolving the solid in distilled water, saturated with Na₂CO₃The hydrochloride was neutralized and extracted to give white crystals with a yield of 72%.¹H NMR(500MHz,DMSO)：δ4.56(d，2H，CH＝CH-C＝O),3.88-3.70(d,2H，CH＝CH-C＝O),2.58-2.61(m,4H),2.24-2.28(m,6H),193-2.01(m,4H),1.77-1.82(m，4H)，1.66-1.69(m，2H)。HR-MS(m/z):[C₁₈H₃₀N₄O₂+H]⁺＝533.2444。

(5) Preparation of Aminoplatinum iodide (R ═ R)₁)

Preparing an oil bath kettle at the temperature of 120 ℃ and an ice bath kettle at the temperature of 0 ℃; weighing the Compounds

0.835g (2.5mmol) was dissolved in 5mL of purified water; 20mL of purified water was placed in a two-necked flask and preheated to 80 ℃ in an oil bath pan. Weighing K₂PtCl₄2.08g (5mmol) of the total saponin is directly added into a double-necked bottle and stirred to be dissolved; KI 3.32g (20mmol) was weighed, a small amount of purified water was added and dissolved away from light and preheated to 80 ℃ which was quickly added to a two-necked flask and stirred continuously for 2.5 min. Quickly taking out the double-necked bottle, putting the double-necked bottle in an ice bath kettle, and continuously stirring to quickly reduce the temperature to 25 ℃; then the compound is mixed

Slowly dripping the solution into a double-neck bottle; after dropping, the reaction is placed at 45 ℃ and is kept away from light for reaction for 24 hours; filtering, washing with ice purified water, ether and ethanol for several times to obtain filter cake, i.e. R ═ R₁The yield of the amine platinum iodide compound was 91.44%.¹H NMR(500MHz,DMSO)：δ6.26(d，2H，CH＝CH-C＝O)，6.12(d，2H，NH)，5.68(d，2H，CH＝CH-C＝O),2.33(d，4H，NH₂)，1.88-2.05(m,6H)，1.43-1.54(m,4H)，1.24-1.37(m,6H)，0.97-1.10(m,4H)。IR(KBr，cm^-1)：v(NH)br 3418，v_s(CH),_Vas(CH)2943，2858，v_w(C＝C)1618，v_s(C＝O)1548，v(Pt＝N)488。HR-MS(m/z):[C₁₈H₃₀N₄O₂Pt₂I₄+Na]⁺＝1253.7720(100％，1254.7756(74％)，1255.7746(76％))，[C₁₈H₃₀N₄O₂Pt₂I₄+K]⁺＝1270.7496(30％)；

(6) Preparation of

(R＝R₁)

A. Preparation of platinum Complex (KM-1) (R ═ R₁，D＝D₁)

0.694g (0.55mmol) of the amiplatin iodide prepared in (5) was weighed out into a round-bottomed flask, and dissolved in 80mL of purified water. The mixture was stirred at 55 ℃ in the dark for 1h to obtain a suspension. 0.332g (1.1mmol) of silver oxalate was weighed into a reaction flask and reacted at 55 ℃ in the dark for 24 hours. And (3) carrying out suction filtration to remove AgI precipitate to obtain a yellow clear transparent solution, carrying out vacuum concentration to 5mL, placing the solution in a refrigerator at 0 ℃ for one night, and carrying out suction filtration to obtain a yellow solid with the yield of 35.76%.¹H NMR(500MHz,D₂O)：δ6.23(d，2H，CH＝CH-C＝O)，5.69(d，2H，CH＝CH-C＝O)，1.88-2.05(m,6H)，1.43-1.54(m,4H)，1.24-1.37(m,6H)，0.97-1.10(m,4H)。IR(KBr，cm^-1)：v(NH)br 3071，v_s(CH),_Vas(CH)2932，2889，v_sh(C＝O)1790，v_w(C＝C)1548，v(Pt＝O)780。v(Pt＝N)475。HR-MS(m/z):[C₂₂H₃₀N₄O₁₀Pt₂+Na]⁺＝922.1179(100％，923.1130(74％)，924.1148(76％))，[C₂₂H₃₀N₄O₁₀Pt₂+K]⁺＝939.0838(35％)

B. Preparation of platinum Complex (KM-2) (R ═ R₁，D＝D₂)：

The preparation method is the same as KM-1, and silver oxalate is replaced by 2-ethyl-1, 3-dicarboxylic acid silver, namely 0.694g (0.55mmol) of amine platinum iodine reacts with 0.381g (1.1mmol) of 2-ethyl-1, 3-dicarboxylic acid silver to replace silver oxalate, so that yellow solid is obtained, and the yield is 31.23%.¹H NMR(500MHz,D₂O)：δ6.19(d，2H，CH＝CH-C＝O)，5.65(d，2H，CH＝CH-C＝O)，3.27-3.31(t，2H)，2.42-2.49(m,3H)，2.24-2.34(m，4H)，1.89-1.96(m,4H)，1.71-1.78(m，1H)，0.99-1.48(m，12H)，0.76-.096(m，6H)。IR(KBr，cm^-1)：v(NH)br 3101，v_s(CH)，_Vas(CH)2937，2922，v_sh(C＝O)1608，v_w(C＝C)1568，v(Pt＝O)777，v(Pt＝N)463。HR-MS(m/z):[C₂₈H₄₂N₄O₁₀Pt₂+Na]⁺＝1006.2054(100％，1007.2079(86％)，1008.2063(63％))，[C₂₈H₄₂N₄O₁₀Pt₂+K]⁺＝1023.1838(42％)。

C. Preparation of platinum Complex (KM-3) (R ═ R₁，D＝D₃)：

The preparation method is the same as KM-1, silver oxalate is replaced by cyclobutyldicarboxylic acid silver, namely 0.694g (0.55mmol) of amine platinum iodide and 0.392g (1.1mmol) of 2-ethyl-1, 3-dicarboxylic acid silver are replaced by silver oxalate to react, yellow solid is obtained, and the yield is 36.68%.¹H NMR(500MHz,D₂O)：δ6.60(d，2H，CH＝CH-C＝O)，5.04(d，2H，CH＝CH-C＝O)，4.02-4.06(t，2H)，3.15-3.16(m,2H)，2.75-2.78(m，4H)，2.57-2.60(m,2H)，2.34-2.49(t，2H)，1.91-2.22(m，8H)，1.50-1.41(m，4H)。1.05-1.18(t，8H)。IR(KBr，cm^-1)：v(NH)br 3081，v_s(CH)，_Vas(CH)2943，2923，v_sh(C＝O)1627，v_w(C＝C)1571，v(Pt＝O)777，v(Pt＝N)481。HR-MS(m/z):[C₃₀H₄₂N₄O₁₀Pt₂+Na]⁺＝1031.2172(100％，1030.2089(52％)，1031.2065(76％))，[C₃₀H₄₂N₄O₁₀Pt₂+K]⁺＝1047.1838(44％)。

D. Preparation of platinum Complex (KM-4) (R ═ R₁，D＝D₄)：

The preparation method is the same as KM-1, and silver oxalate is replaced by 3-hydroxy-cyclobutane-1, 1-dicarboxylic acid silver, namely 0.694g (0.55mmol) of amine platinum iodine reacts with 0.442g (1.1mmol) of 3-hydroxy-cyclobutane-1, 1-dicarboxylic acid silver to obtain yellow solid with the yield of 36.68%.¹H NMR(500MHz,D₂O)：δ6.63(d，2H，CH＝CH-C＝O)，4.99(d，2H，CH＝CH-C＝O)，4.08-4.14(t，2H)，3.19-3.18(m,3H)，2.70-2.77(m,1H)，2.36-2.50(t，4H)，1.90-2.27(m，8H)，1.50-1.41(m，4H)。1.05-1.18(t，8H)。IR(KBr，cm^-1)：v(OH)br 3408，v(NH)br 3190，v_s(CH)，_Vas(CH)2943，2865，v_sh(C＝O)1578，v_w(C＝C)1501，v(Pt＝O)744，v(Pt＝N)440。HR-MS(m/z):[C₃₀H₄₂N₄O₁₂Pt₂+H]⁺＝1041.2089(100％，1040.2183(76％)，1042.2149(74％))，[C₃₀H₄₂N₄O₁₂Pt₂+Na]⁺＝1063.1989(27％)。

Example 2: preparation of the formula (R ═ R)₄N ═ 3), i.e.:

z is

R₄＝

n＝3:

Wherein the preparation method of the 1-N-Boc-1R, 2R-cyclohexanediamine is the same as that of the step (1) in the example 1;

(1) preparation of

(R＝R₄，n＝3)

Dissolving 0.15mol of glutaric acid in 10mL of thionyl chloride, slowly raising the temperature to 80 ℃, reacting for 3.5 hours under the condition of condensation reflux to obtain a brown solution, and distilling under reduced pressure to obtain glutaryl chloride.

0.2mol of 1-N-Boc-1R, 2R-cyclohexanediamine is dissolved in anhydrous dichloromethane, excessive triethylamine is dripped to be used as an acid-binding agent (about 0.4mol), and 0.1mol of glutaryl chloride is dripped slowly. After the addition, the reaction was carried out for 1 hour. Spin-drying to obtain white solid. Adding excessive dichloromethane to dissolve, adding a small amount of ethanol under heating to dissolve, cooling for crystallization, and filtering to obtain pure product with yield of 86%.¹H NMR(500MHz,CDCl₃)：δ2.33(d，2H，CH₂of C2)，1.99(t，4H，CH₂of C1and C1’)，1.71(dd，4H)，1.53-1.59(m，6H)，1.46(s，18H，CH₃of Boc)，1.23-1.33(m，4H)，1.05-1.20(m，6H)。HR-MS(m/z):[C₂₇H₄₈N₄O₆+Na]⁺＝547.3470。

(2) Preparation of

(R＝R₄，n＝3)

1.068g (2mmol) of the compound (1) is dissolved in 50mL of ethyl acetate, placed in an eggplant-shaped bottle, dropwise added with ethyl acetate hydrochloride to enable the reaction solution to be strongly acidic (pH is 1-2), reacted at room temperature for 12 hours, and then filtered by suction to obtain light brown solid with the yield of 96%. Dissolving the solid in distilled water, saturated with Na₂CO₃The hydrochloride was neutralized and extracted to give white crystals with a yield of 72%.¹H NMR(500MHz,CDCl₃)：δ2.39(d，2H，CH₂of C2)，2.08(t，4H，CH₂of C1and C1’)，1.75(dd，4H)，1.59-1.66(m，6H)，1.33-1.43(m，4H)，1.05-1.28(m，6H)。HR-MS(m/z):[C₁₇H₃₂N₄O₂+Na]⁺＝347.2529。

(3) Preparation of amiplatin iodine (R ═ R)₄，n＝3)

Preparing oil bath pan at 120 deg.C and ice bath pan at 0 deg.C, weighing

0.81g (2.5mmol) was dissolved in 5mL of purified water. 20mL of purified waterPlaced in a double-necked flask and preheated to 80 ℃ in an oil bath pan. Weighing K₂PtCl₄2.08g (5mmol) was added directly to the flask and dissolved by stirring. Weighing KI 3.32g (50mmol), adding a small amount of purified water, dissolving in dark place, preheating to 80 ℃, and quickly adding into a double-necked flask and continuously stirring for 2.5 min. The double-necked bottle is quickly taken out and placed in an ice bath kettle, and the mixture is continuously stirred, so that the temperature is quickly reduced to 25 ℃. And (3) slowly dropwise adding the compound solution obtained in the step (2) into a double-neck bottle. After dropping, the reaction was left at 45 ℃ for 24 hours in the dark. Filtering, washing with ice purified water, diethyl ether and ethanol respectively for several times to obtain filter cake, wherein R is R₄The yield of the amine platinum iodide compound was 91.78%.¹H NMR(500MHz,DMSO)：δ2.32(d，2H，CH₂of C2)，2.14(t，4H，CH₂of C1and C1’)，1.74(dd，4H)，1.50-1.63(m，6H)，1.29-138(m，4H)，1.10-1.24(m，6H)。IR(KBr，cm^-1)：v(NH)br 3407，v_s(CH),_Vas(CH)2936，2847，v_s(C＝O)1567，v(Pt＝N)478。HR-MS(m/z):[C₁₇H₃₂N₄O₂Pt₂I₄-I]⁺＝1094.8955(100％，1093.8945(31％)，1095.8951(48％))，[C₁₇H₃₂N₄O₂Pt₂I₄+Na⁺＝1117.8850(30％)。

(4)

Preparation of (R ═ R)₄，n＝3)

A. Preparation of platinum Complex (KM-5(R ═ R)₄，n＝3，Z＝Z₁)：

0.672g (0.55mmol) of the platinum iodide amine obtained in the step (3) is weighed out and placed in a round-bottom flask, and 80mL of purified water is added for dissolution. The mixture was stirred at 55 ℃ in the dark for 1h to obtain a suspension. 0.367g (2.2mmol) of silver acetate was weighed into a reaction flask and reacted at 55 ℃ for 24 hours in the dark. And (3) carrying out suction filtration to remove AgI precipitate to obtain a yellow clear transparent solution, carrying out vacuum concentration to 5mL, placing the solution in a refrigerator at 0 ℃ for one night, and carrying out suction filtration to obtain a yellow solid with the yield of 35.76%.¹H NMR(500MHz,H₂O)：2.56-2.78(m,12H of4CH₃)，δ2.31(d，2H，CH₂of C2)，2.02(t，4H，CH₂of C1and C1’)，1.64(dd，4H)，1.49-1.54(m，6H)，1.18-1.30(m，4H)，1.02-1.18(m，6H)。IR(KBr，cm^-1)：v(NH)br 3044，v_s(CH),_Vas(CH)2937，2868，v_sh(C＝O)1677，v(Pt＝N)472。HR-MS(m/z):[C₂₁H₃₂N₄O₁₀Pt₂+H]⁺＝965.2645(100％，965.2632(56％)，966.2703(76％))，[C₂₁H₃₂N₄O₁₀Pt₂+Na]⁺＝987.2470(41％)。

B. Preparation of platinum Complex (KM-6) (R ═ R₄，n＝3，Z＝Z₂)：

The preparation method is the same as KM-5, silver monochloroacetate is used for replacing silver acetate, namely 0.672g (0.55mmol) of amine platinum iodide and 0.442g (2.2mmol) of silver monochloroacetate are used for replacing silver acetate to react, yellow solid is obtained, and the yield is 32.12%.¹H NMR(500MHz,H₂O)：δ,4.36-4.51(m,8H of 4ClCH2)，δ2.36(d，2H，CH₂of C2)，1.96-2.04(t，4H，CH₂of C1and C1’)，1.48-1.64(dd，4H)，1.39-1.46(m，6H)，1.20-1.27(m，4H)，0.97-1.12(m，6H)。IR(KBr，cm^-1)：v(NH)br 3044，v_s(CH),_Vas(CH)2937，2868，v_sh(C＝O)1677，v(Pt＝N)472。HR-MS(m/z):[C₂₇H₄₄N₄O₁₀Pt₂+H]⁺＝1103.1055(100％，1102.1052(78％)，1103.1101(36％))，[C₂₇H₄₄N₄O₁₀Pt₂+Na]⁺＝1125.0867(32％)。

C. Preparation of platinum Complex (KM-7) (R ═ R₄，n＝3，Z＝Z₃)：

The preparation method is the same as KM-1, silver heptanoate is used for replacing silver acetate, namely, 0.672(0.55mmol) amine platinum iodine reacts with 0.552g (2.2mmol) silver heptanoate for replacing silver acetate, yellow solid is obtained, and the yield is 35.87%.¹H NMR(500MHz,H₂O)：0.89-2.93(m,60H of 4COO(CH₂)₆CH₃)，δ2.31(d，2H，CH₂of C2)，2.02(t，4H，CH₂of C1and C1’)，1.64(dd，4H)，1.49-1.54(m，6H)，1.18-1.30(m，4H)，1.02-1.18(m，6H)。IR(KBr，cm^-1)：v(NH)br 3030，v_s(CH),_Vas(CH)2989，2878，v_sh(C＝O)1659，v(Pt＝N)485。HR-MS(m/z):[C₂₉H₄₄N₄O₁₀Pt₂+H]⁺＝1301.6411(100％，1300.6453(38％)，1301.6423(74％))，[C₂₉H₄₄N₄O₁₀Pt₂+Na]⁺＝1324.6248(36％)。

D. Preparation of platinum Complex (KM-8) (R ═ R₄，n＝3，Z＝Z₄)：

0.672g (0.55mmol) of the platinum iodide amine obtained in the step (3) is weighed out and placed in a round-bottom flask, and 80mL of purified water is added for dissolution. The mixture was stirred at 55 ℃ in the dark for 1h to obtain a suspension. And adding 22mL of newly prepared silver nitrate solution with the concentration of 0.1mol/L into the solution, reacting for 24 hours at 50 ℃ in a dark place, and removing silver iodide precipitate. After 0.145g (2.5mmol) of sodium chloride was added to the filtrate, the mixture was reacted at 50 ℃ for 24 hours under dark conditions to obtain a yellow solid with a yield of 36.14%.¹H NMR(500MHz,H₂O)：δ2.31(d，2H，CH₂of C2)，2.02(t，4H，CH₂of C1and C1’)，1.64(dd，4H)，1.49-1.54(m，6H)，1.18-1.30(m，4H)，1.02-1.18(m，6H)。IR(KBr，cm^-1)：v(NH)br 3084，v_s(CH),_Vas(CH)2960，2868，v_sh(C＝O)1676，v(Pt＝N)479。HR-MS(m/z):[C₂₉H₄₄N₄O₁₂Pt₂+H]⁺＝869.0859(100％，868.0869(84％)，869.0903(37％))，[C₂₉H₄₄N₄O₁₂Pt₂+Na]⁺＝893.0676(42％)。

While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.

The MTT method is used for testing the in-vitro inhibition effect of the novel binuclear platinum complex on human colon cancer cells HCT-116, human liver cancer cells HEPG-2, human lung adenocarcinoma cells A549 and human breast cancer cells MCF-7, and cisplatin, carboplatin and/or oxaliplatin are respectively used as positive controls. The tumor cell line culture and test method is as follows:

the colon cancer cell line HCT-116 was cultured in mcCoy's 5A containing 10% fetal bovine serum, and MCF-7 and HEPG-2 were cultured in 10% calf serum in RPM I1640 medium at 37 deg.C under saturated humidity and 5% CO₂The culture environment of (2).

The cell culture conditions were counted in logarithmic phase and cell density was adjusted to 4000-. Three groups of dosing, control, i.e., cell only without dosing, and zero, i.e., cell-free culture medium only, were set in the well plate. After 24 hours incubation, the compounds were dissolved in DMSO or glucose in advance and diluted to the desired concentration with complete medium at the time of the assay, noting that the final DMSO concentration cannot exceed 0.1%. Each concentration was set with 6 multiple wells. After addition of the reagent, the mixture was incubated for 48 hours, 20. mu.l of MTT at a concentration of 5mg/mL was added thereto, and the mixture was incubated for 4 hours, and then the solution was aspirated, and 150. mu.l of DMSO was added thereto to completely dissolve formazan. Within 30min, the OD value is measured by the enzyme-labeling instrument 490 wavelength, and the inhibition rate is calculated. The test was conducted 3 times in parallel, and the half inhibition IC50 value was calculated from the inhibition, and the results are shown in table 1.

TABLE 1 in vitro inhibition of HCT-116, A549, HEPG-2 and MCF-7 by dinuclear platinum complexes

The experimental result shows that 8 tested compounds have certain cytotoxicity on 4 selected cancer cells, and the cytotoxicity of part of the compounds is higher than that of the existing medicines of carboplatin and oxaliplatin, so that the compounds have the potential of becoming a new generation of anti-cancer medicines.

Claims

1. The structural formula is a chiral binuclear platinum complex containing unsaturated bonds shown in formula I or formula II:

；

wherein R is selected from

，n=2-8；

D is selected from

；

Z is selected from

、Cl^-。

2. The method for preparing a chiral binuclear platinum complex containing unsaturated bonds as claimed in claim 1, which is characterized by comprising the following steps:

(1) in the presence of a solvent, 1-N-Boc-1R, 2R-cyclohexanediamine is used as a raw material to perform substitution reaction with diethoxyketene or diacid chloride according to the molar ratio of 2:1 to prepare a polyamine ligand which takes an unsaturated chain as a bridge and contains a Boc protecting group, wherein when R is

When the solvent is diethyl ether, R is

When the solvent is the anhydrous dichloromethane,

；

(2) adding the polyamine ligand containing the boc protecting group and taking the unsaturated chain as a bridge in the step (1) into 1-1.5mol/L ethyl acetate hydrochloride to remove the boc protecting group to prepare hydrochloride of the polyamine ligand, dissolving the hydrochloride of the polyamine ligand in water, adding saturated sodium carbonate solution, extracting with ethyl acetate, taking an organic phase, and drying to obtain the polyamine ligand taking the unsaturated chain as a bridge;

；

(3) dissolving the polyamine ligand taking the unsaturated chain as the bridge in the step (2) in water, and then dropwise adding the solution to K₂PtI₄Reacting in water solution at 40-50 deg.C for 24 hr, filtering, sequentially washing the solid with ice water, diethyl ether and ethanol, and vacuum drying to obtain amine platinum iodine, wherein the unsaturated chain is polyamine ligand and K of bridge₂PtI₄In a molar ratio of 1: 2;

，

；

(4) dissolving amiplatin iodine in purified water, heating to 50-60 deg.C, and weighing AgZ or D (OAg)₂Adding into the solution, stirring at 50-60 deg.C for 2h, filtering, and washing to obtain chiral binuclear platinum complex with unsaturated chain as bridge, wherein platinum iodide amine is mixed with D (OAg)₂The molar ratio of amine platinum iodide to AgZ is 1: 4; or adding silver nitrate into the platinum iodide solution, removing silver iodide precipitate, adding sodium chloride, filtering, and washing to obtain chiral binuclear platinum complex with unsaturated chain as bridge, wherein the platinum iodide and AgNO are₃The mol ratio of NaCl is 1:4: 4;

，

wherein R is selected from

，n=2-8；

D is selected from

；

Z is selected from

、Cl^-。

3. The use of the chiral binuclear platinum complex containing unsaturated bonds as claimed in claim 1 for preparing an antitumor drug.