A five- and six-membered ring metal platinum complex with high anti-tumor activity, its preparation method and its application

Abstract

The present invention discloses a five-membered and six-membered ring metal platinum complex with high anti-tumor activity, a preparation method thereof and an application thereof. The structure of the five-membered and six-membered ring metal platinum complex is as follows: The present invention uses a pinene-functionalized cyclometalated main ligand and a phenyl isocyanate derivative as an auxiliary ligand to coordinate with platinum metal ions. After the reaction, a five-membered and six-membered metal heterocycle is formed, and 8 pairs of cyclometalated platinum complexes are obtained respectively. These compounds show high anti-tumor activity against K562 leukemia cells, BEL-7402 liver cancer cells, SGC-7901 gastric cancer cells, A549 lung cancer cells and Hela cervical cancer cells. The IC50 value is far lower than that of the traditional platinum drug cisplatin, greatly improving the anti-tumor activity and universality of the platinum complex, and will play an important role in the field of anti-tumor.

Description

Technical Field

[0001] The present invention relates to a five - six - membered ring metal platinum complex with high anti - tumor activity, its preparation method and its application, belonging to the field of novel metal anti - tumor drugs. Background Art

[0002] Cisplatin is a platinum - based complex and one of the most successful anti - cancer drugs. Since Rosenberg discovered cisplatin in 1965 and it was approved by the FDA in 1978, cisplatin has been widely used in the treatment of various cancers, including all common cancers: breast cancer, colon / rectal cancer, lung cancer, prostate cancer and skin cancer. However, the anti - tumor activity of cisplatin against some tumor cells is not significant enough.

[0003] Cyclometalated complexes are an important class of organometallic compounds with different coordination modes and geometric structures. In recent years, cyclometalated platinum complexes have attracted extensive attention due to their rich photophysical and photochemical properties. Recently, platinum complexes based on carbon ligands and cyclometalated ligands have been reported to show high anti - tumor activity and can interact significantly with DNA. Chi - Ming Che et al. initially studied the cytotoxicity of cyclometalated platinum complexes, especially a series of platinum complexes based on C^N^N ligands. Although platinum complexes based on 6 - phenyl - 2,2'-bipyridine and chloro ligands did not show obvious cytotoxicity to many cancer cells; however, when chlorine is replaced by other ligands such as 2,4 - diamino - 6-(4 - pyridyl)-1,3,5 - triazine and carbene base ligands, the cytotoxicity of the modified platinum complexes is significantly improved. In addition, the significant difference in cytotoxicity between N^C^N - and C^N^N - coordinated platinum complexes is related to the trans - effect of carbon donors in cyclometalated platinum complexes, which plays a crucial role in promoting ligand dissociation to produce active binding sites. Despite the rapid development of the preparation of anti - tumor platinum drugs in recent years, there are still many challenges in significantly improving the anti - tumor activity and universality of platinum complexes by changing the coordination mode of the main ligand. Currently, the research on the anti - tumor activity of five - six - membered ring metal platinum complexes is relatively lacking and urgently needs to be further developed and explored. Summary of the Invention

[0004] The present invention provides a five - six - membered ring metal platinum complex with high anti - tumor activity, its preparation method and its application.

[0005] To solve the above - mentioned technical problems, the technical solutions adopted by the present invention are as follows:

[0006] A five - six - membered ring metal platinum complex with high anti - tumor activity has the following structure:

[0007]

[0008] The above five- and six-membered ring metal platinum complexes solve the problems of drug resistance and universality of anti-tumor platinum drugs, and show high anti-tumor activity against K562 leukemia cells, BEL-7402 liver cancer cells, SGC-7901 gastric cancer cells, A549 lung cancer cells, and Hela cervical cancer cells. The IC 50 value is much higher than that of the traditional platinum drug cisplatin and will play an important role in the field of anti-tumor.

[0009] The above five- and six-membered ring metal platinum complexes with high anti-tumor activity are preferably

[0010] More preferably Most preferably

[0011] The above five- and six-membered ring metal platinum complexes with high anti-tumor activity are formed by coordinating a cyclometalated main ligand modified with pinene and a phenyl isocyanide derivative as an auxiliary ligand with platinum metal ions, and then reacting with a silver salt.

[0012] The structure of the cyclometalated main ligand modified with pinene is

[0013] To improve the anti-tumor activity, the phenyl isocyanide derivative auxiliary ligand is 2,6-dimethylphenyl isocyanide; the silver salt is at least one of silver nitrate, silver perchlorate, silver hexafluorophosphate, or silver trifluoromethanesulfonate.

[0014] This application includes the following preferred embodiments:

[0015] Complex (-)-Pt1: The cyclometalated main ligand is selected from The auxiliary ligand is selected from 2,6-dimethylphenyl isocyanide, and the anion is selected from nitrate.

[0016] Complex (-)-Pt2: The cyclometalated main ligand is selected from The auxiliary ligand is selected from 2,6-dimethylphenyl isocyanide, and the anion is selected from perchlorate.

[0017] Complex (-)-Pt3: The cyclometalated main ligand is selected from The auxiliary ligand is selected from 2,6-dimethylphenyl isocyanide, and the anion is selected from trifluoromethanesulfonate.

[0018] Complex (-)-Pt4: The cyclometalated main ligand is selected from The auxiliary ligand is selected from 2,6-dimethylphenyl isocyanide, and the anion is selected from hexafluorophosphate.

[0019] Complex (-)-Pt5: The cyclometalated main ligand is selected from The auxiliary ligand is selected from 2,6-dimethylphenyl isocyanide, and the anion is selected from nitrate.

[0020] The complex (-)-Pt6: The cyclometalated main ligand is selected from The auxiliary ligand is selected from 2,6-dimethylphenyl isocyanide, and the anion is selected from perchlorate.

[0021] The complex (-)-Pt7: The cyclometalated main ligand is selected from The auxiliary ligand is selected from 2,6-dimethylphenyl isocyanide, and the anion is selected from trifluoromethanesulfonate.

[0022] The complex (-)-Pt8: The cyclometalated main ligand is selected from The auxiliary ligand is selected from 2,6-dimethylphenyl isocyanide, and the anion is selected from hexafluorophosphate.

[0023] As one of the preferred specific embodiments, the preparation method of the above five-membered and six-membered cyclometalated platinum complex with high anti-tumor activity includes the following steps:

[0024] 1) Dissolve the pinene-modified cyclometalated platinum chloride complex precursor in dichloromethane to obtain Solution 1;

[0025] 2) Dissolve 2,6-dimethylphenyl isocyanide in dichloromethane to obtain Solution 2;

[0026] 3) Dissolve the silver salt in distilled water to obtain Solution 3;

[0027] 4) Under the protection of argon, stir and mix Solution 1 and Solution 2, react at room temperature for 1 - 12 h, then slowly add dropwise Solution 3. After the addition is complete, continue to stir at room temperature for 5 - 24 h. Wash the obtained mixture successively with distilled water and brine in a separatory funnel, collect the dichloromethane solution, dry by centrifugation, evaporate the solvent by rotary evaporation, and dry under vacuum to obtain the target five-membered and six-membered cyclometalated platinum complex.

[0028] The above slow dropping rate is preferably 0.8 - 1.2 mL / min.

[0029] To improve the product yield, the molar amount of the above silver salt is 1 - 5 times the molar amount of the pinene-modified cyclometalated platinum chloride complex precursor; the molar amount of 2,6-dimethylphenyl isocyanide is 1 - 3 times the molar amount of the pinene-modified cyclometalated platinum chloride complex precursor.

[0030] All operations not specifically stated in this application are carried out at room temperature.

[0031] To improve the sufficiency of the material reaction, in step 1), the concentration of Solution 1 is 0.0075 - 0.015 mol / L; in step 2), the concentration of Solution 2 is 0.015 - 0.045 mol / L; in step 3), the concentration of Solution 3 is 0.015 - 0.075 mol / L.

[0032] In step 3) above, the silver salt is silver nitrate, silver perchlorate, silver hexafluorophosphate or silver trifluoromethanesulfonate.

[0033] The above five - and six - membered ring metal platinum complexes with high anti - tumor activity can be used in the preparation of anti - tumor drugs.

[0034] The above five - and six - membered ring metal platinum complexes with anti - tumor activity have high anti - tumor activity against K562 leukemia cells, BEL - 7402 liver cancer cells, SGC - 7901 gastric cancer cells, A549 lung cancer cells and Hela cervical cancer cells. The IC 50 value is much higher than that of the traditional platinum drug cisplatin.

[0035] Preferably, the above five - and six - membered ring metal platinum complexes with anti - tumor activity are used in the preparation of drugs against K562 leukemia cells, BEL - 7402 liver cancer cells, SGC - 7901 gastric cancer cells, A549 lung cancer cells and Hela cervical cancer cells.

[0036] The above five - and six - membered ring metal platinum complexes with anti - tumor activity can be distributed on the cell membrane to quickly stain K562 leukemia cells, BEL - 7402 liver cancer cells, SGC - 7901 gastric cancer cells, A549 lung cancer cells and Hela cervical cancer cells.

[0037] Advantages of the present invention:

[0038] 1. The five - and six - membered ring metal platinum complexes of the present invention show obvious anti - tumor activity against K562 leukemia cells, BEL - 7402 liver cancer cells, SGC - 7901 gastric cancer cells, A549 lung cancer cells and Hela cervical cancer cells, and can be used in the preparation of related anti - tumor drugs.

[0039] 2. The five - and six - membered ring metal platinum complexes of the present invention have a lower IC 50 value compared with the traditional platinum drug cisplatin, and have better anti - tumor activity.

[0040] 3. The preparation process of the five - and six - membered ring metal platinum complexes of the present invention is simple, the yield can reach 97%, and it is easy to be prepared and popularized on a large scale. Description of the Drawings

[0041] Figure 1 1H NMR spectrum of the isocyanide - coordinated five - and six - membered ring metal platinum complex prepared in Example 3; 1

[0042] Figure 2 13C NMR spectrum of the isocyanide - coordinated five - and six - membered ring metal platinum complex prepared in Example 3; 13

[0043] Figure 3 ​​Crystal structure diagram of the isocyanide-coordinated five-six-membered ring metal platinum complex prepared in Example 3;

[0044] Figure 4 For the isocyanide-coordinated five-six-membered ring metal platinum complex prepared in Example 7 1 1H NMR spectrum;

[0045] Figure 5 For the isocyanide-coordinated five-six-membered ring metal platinum complex prepared in Example 7 13 13C NMR spectrum;

[0046] Figure 6 Crystal structure diagram of the isocyanide-coordinated five-six-membered ring metal platinum complex prepared in Example 7;

[0047] Figure 7 Confocal images of HeLa cells stained with the isocyanide-coordinated five-six-membered ring metal platinum complexes prepared in Example 3 and Example 7. Detailed implementation manners

[0048] To better understand the present invention, the content of the present invention will be further clarified below in conjunction with examples, but the content of the present invention is not limited to the following examples only.

[0049] In each example, the preparation of the pinene-modified cyclometalated platinum chloride complex precursors (-)-(N^C*N)PtCl and (-)-(N^N*C)PtCl was referred to Zhang H.-H., Wu, S.-X., and Wang, Y.-Q. et al., Mechanochromicluminescent property and anti-counterfeiting application of AIE-active cyclometalated platinum(II) complexes featuring a fused five-six-membered metallacycle [J]. Dyes and Pigments, 2022, 197: 109857.

[0050] In each example, the room temperature was 15 - 25 °C.

[0051] Synthesis of Complex Pt1 in Example 1

[0052] Synthesis of the isocyanide-coordinated five-six-membered ring metal platinum complex (-)-(N ^ N * C)PtCN:

[0053] 97 mg (0.15 mmol) of the pinene-modified cyclometalated platinum chloride complex precursor (-)-(N^ N * C)PtCl was dissolved in 10 mL of dichloromethane to obtain Solution 1 (concentration: 0.015 mol / L); 20 mg (0.15 mmol) of 2,6-dimethylphenyl isocyanate was dissolved in 10 mL of dichloromethane to obtain Solution 2 (concentration: 0.015 mol / L); subsequently, 26 mg (0.15 mmol) of silver nitrate was dissolved in 10 mL of distilled water to obtain Solution 3 (concentration: 0.015 mol / L); under argon protection, Solution 1 and Solution 2 were stirred and mixed, and after reacting at room temperature for 1 h, Solution 3 was slowly added dropwise (dropwise rate: 1 mL / min). After the addition was complete, stirring was continued at room temperature for 5 h. The resulting mixture was successively washed with distilled water and brine in a separatory funnel. The dichloromethane solution was collected, dried by centrifugation, the solvent was rotary evaporated, and then dried under vacuum to obtain the target product, an isocyanide-coordinated five-six-membered ring platinum metal complex, an orange-yellow solid (yield: 83%), with the structure [(-)-(N ^ N * C)PtCN]NO3.

[0054] Example 2 Synthesis of Complex Pt2

[0055] Synthesis of isocyanide-coordinated five-six-membered ring platinum metal complex (-)-(N ^ N * C)PtCN:

[0056] 49 mg (0.075 mmol) of the pinene-modified cyclometalated platinum chloride complex precursor (-)-(N ^ N * C)PtCl was dissolved in 10 mL of dichloromethane to obtain Solution 1 (concentration: 0.0075 mol / L); 20 mg (0.015 mmol) of 2,6-dimethylphenyl isocyanate was dissolved in 10 mL of dichloromethane to obtain Solution 2 (concentration: 0.015 mol / L); subsequently, 47 mg (0.225 mmol) of silver perchlorate was dissolved in 10 mL of distilled water to obtain Solution 3 (concentration: 0.0225 mol / L); under argon protection, Solution 1 and Solution 2 were stirred and mixed, and after reacting at room temperature for 6 h, Solution 3 was slowly added dropwise (dropwise rate: 1 mL / min). After the addition was complete, stirring was continued at room temperature for 12 h. The resulting mixture was successively washed with distilled water and brine in a separatory funnel. The dichloromethane solution was collected, dried by centrifugation, the solvent was rotary evaporated, and then dried under vacuum to obtain the target product, an isocyanide-coordinated five-six-membered ring platinum metal complex, an orange-yellow solid (yield: 88%), with the structure [(-)-(N ^ N * C)PtCN]ClO4.

[0057] Example 3 Synthesis of Complex Pt3

[0058] Isocyanide-coordinated five- and six-membered ring platinum metal complex (-)-(N ^ N * C)PtCN synthesis:

[0059] Dissolve 97 mg (0.15 mmol) of the pinene-modified cyclometalated platinum chloride complex precursor (-)-(N ^ N * C)PtCl in 10 mL of dichloromethane to obtain Solution 1 (concentration: 0.015 mol / L); dissolve 40 mg (0.3 mmol) of 2,6-dimethylphenyl isocyanide in 10 mL of dichloromethane to obtain Solution 2 (concentration: 0.03 mol / L); then dissolve 116 mg (0.45 mmol) of silver trifluoromethanesulfonate in 10 mL of distilled water to obtain Solution 3 (concentration: 0.045 mol / L); under argon protection, stir and mix Solution 1 and Solution 2, react at room temperature for 9 h, then slowly add dropwise Solution 3 (dropwise rate: 1 mL / min), after the addition is complete, continue to stir at room temperature for 18 h, wash the resulting mixture successively with distilled water and brine in a separatory funnel, collect the dichloromethane solution, dry by centrifugation, then rotary evaporate the solvent, and dry under vacuum to obtain the target product isocyanide-coordinated five- and six-membered ring platinum metal complex, an orange-yellow solid (yield: 97%), 1 1H NMR spectrum and 13 13C NMR spectrum are as Figure 1-2 shown. It can be seen from the figure that the target structure [(-)-(N ^ N * C)PtCN]OTf is obtained, and the crystal structure is as Figure 3 shown.

[0060] Synthesis of Complex Pt4 in Example 4

[0061] Isocyanide-coordinated five- and six-membered ring platinum metal complex (-)-(N ^ N * C)PtCN synthesis:

[0062] Dissolve 97 mg (0.15 mmol) of the pinene-modified cyclometalated platinum chloride complex precursor (-)-(N ^ N *C) PtCl was dissolved in 10 mL of dichloromethane to obtain Solution 1 (concentration: 0.015 mol / L); 60 mg (0.45 mmol) of 2,6-dimethylphenyl isocyanide was dissolved in 10 mL of dichloromethane to obtain Solution 2 (concentration: 0.045 mol / L); subsequently, 190 mg (0.75 mmol) of silver hexafluorophosphate was dissolved in 10 mL of distilled water to obtain Solution 3 (concentration: 0.075 mol / L); under argon protection, Solution 1 and Solution 2 were stirred and mixed, and after reacting at room temperature for 12 h, Solution 3 was slowly added dropwise (dropwise rate: 1 mL / min). After the addition was complete, stirring was continued at room temperature for 24 h. The resulting mixture was washed successively with distilled water and brine in a separatory funnel, the dichloromethane solution was collected, dried by centrifugation, the solvent was evaporated, and then dried under vacuum to obtain the target product, an isocyanide-coordinated five- and six-membered ring metal platinum complex, an orange-yellow solid (yield: 91%), with the structure [(-)-(N ^ N * C)PtCN]PF6.

[0063] Example 5 Synthesis of Complex Pt5

[0064] Synthesis of isocyanide-coordinated five- and six-membered ring metal platinum complex (-)-(N ^ C * N)PtCN:

[0065] 97 mg (0.15 mmol) of the terpene-modified cyclometalated platinum chloride complex precursor (-)-(N ^ C * N)PtCl was dissolved in 10 mL of dichloromethane to obtain Solution 1 (concentration: 0.015 mol / L); 20 mg (0.15 mmol) of 2,6-dimethylphenyl isocyanide was dissolved in 10 mL of dichloromethane to obtain Solution 2 (concentration: 0.015 mol / L); subsequently, 26 mg (0.15 mmol) of silver nitrate was dissolved in 10 mL of distilled water to obtain Solution 3 (concentration: 0.015 mol / L); under argon protection, Solution 1 and Solution 2 were stirred and mixed, and after reacting at room temperature for 1 h, Solution 3 was slowly added dropwise (dropwise rate: 1 mL / min). After the addition was complete, stirring was continued at room temperature for 5 h. The resulting mixture was washed successively with distilled water and brine in a separatory funnel, the dichloromethane solution was collected, dried by centrifugation, the solvent was evaporated, and then dried under vacuum to obtain the target product, an isocyanide-coordinated five- and six-membered ring metal platinum complex, a yellow-green solid (yield: 80%), with the structure [(-)-(N ^ C * N)PtCN]NO3.

[0066] Example 6 Synthesis of Complex Pt6

[0067] Synthesis of isocyanide-coordinated five- and six-membered ring platinum metal complex (-)-(N ^ C * N)PtCN:

[0068] Dissolve 49 mg (0.075 mmol) of the pinene-modified cyclometalated platinum chloride complex precursor (-)-(N ^ C * N)PtCl in 10 mL of dichloromethane to obtain Solution 1 (concentration: 0.0075 mol / L); dissolve 20 mg (0.015 mmol) of 2,6-dimethylphenyl isocyanide in 10 mL of dichloromethane to obtain Solution 2 (concentration: 0.015 mol / L); then dissolve 47 mg (0.225 mmol) of silver perchlorate in 10 mL of distilled water to obtain Solution 3 (concentration: 0.0225 mol / L); under argon protection, stir and mix Solution 1 and Solution 2, react at room temperature for 6 h, then slowly add Solution 3 dropwise (dropwise rate: 1 mL / min). After the addition is complete, continue to stir at room temperature for 12 h. Wash the resulting mixture successively with distilled water and brine in a separatory funnel, collect the dichloromethane solution, dry by centrifugation, rotary evaporate the solvent, and dry under vacuum to obtain the target product isocyanide-coordinated five- and six-membered ring platinum metal complex, a yellow-green solid (yield: 87%), with the structure [(-)-(N ^ C * N)PtCN]ClO4.

[0069] Synthesis of Complex Pt7 in Example 7

[0070] Synthesis of isocyanide-coordinated five- and six-membered ring platinum metal complex (-)-(N ^ C * N)PtCN:

[0071] Dissolve 97 mg (0.15 mmol) of the pinene-modified cyclometalated platinum chloride complex precursor (-)-(N ^ C *(N)PtCl was dissolved in 10 mL of dichloromethane to obtain Solution 1 (concentration: 0.015 mol / L); 40 mg (0.3 mmol) of 2,6-dimethylphenyl isocyanate was dissolved in 10 mL of dichloromethane to obtain Solution 2 (concentration: 0.03 mol / L); subsequently, 116 mg (0.45 mmol) of silver trifluoromethanesulfonate was dissolved in 10 mL of distilled water to obtain Solution 3 (concentration: 0.045 mol / L); under argon protection, Solution 1 and Solution 2 were stirred and mixed, and after reacting at room temperature for 9 h, Solution 3 was slowly added dropwise (dropwise rate: 1 mL / min). After the addition was complete, stirring was continued at room temperature for 18 h. The resulting mixture was washed successively with distilled water and brine in a separatory funnel, the dichloromethane solution was collected, dried by centrifugation, the solvent was evaporated, and then dried in vacuo to obtain the target product, an isocyanide-coordinated five- and six-membered ring platinum metal complex, a yellow-green solid (yield: 95%). 1 1H NMR spectrum and 13 13C NMR spectrum are as Figure 4-5 shown. It can be seen from the figure that the target structure: [(-)-(N ^ C * N)PtCN]OTf was obtained. The crystal structure is as Figure 6 shown.

[0072] Synthesis of Complex Pt8 in Example 8

[0073] Synthesis of isocyanide-coordinated five- and six-membered ring platinum metal complex (-)-(N ^ C * N)PtCN:

[0074] 97 mg (0.15 mmol) of the terpene-modified cyclometalated platinum chloride complex precursor (-)-(N ^ C * N)PtCl was dissolved in 10 mL of dichloromethane to obtain Solution 1 (concentration: 0.015 mol / L); 60 mg (0.45 mmol) of 2,6-dimethylphenyl isocyanate was dissolved in 10 mL of dichloromethane to obtain Solution 2 (concentration: 0.045 mol / L); subsequently, 190 mg (0.75 mmol) of silver hexafluorophosphate was dissolved in 10 mL of distilled water to obtain Solution 3 (concentration: 0.075 mol / L); under argon protection, Solution 1 and Solution 2 were stirred and mixed, and after reacting at room temperature for 12 h, Solution 3 was slowly added dropwise (dropwise rate: 1 mL / min). After the addition was complete, stirring was continued at room temperature for 24 h. The resulting mixture was washed successively with distilled water and brine in a separatory funnel, the dichloromethane solution was collected, dried by centrifugation, the solvent was evaporated, and then dried in vacuo to obtain the target product, an isocyanide-coordinated five- and six-membered ring platinum metal complex, a yellow-green solid (yield: 90%), with the structure of [(-)-(N ^ C *N)PtCN]PF6。

[0075] Comparative Example 1 Synthesis of Ionic Cyclometalated Chiral N^C^N Platinum Complex (from Patent Application No.: 202210166254.5)

[0076] Dissolve the pinene-modified N^C^N coordinated platinum complex precursor (100 mg, 0.18 mmol) in 10 mL of dichloromethane to obtain Solution 1 (concentration: 0.018 mol / L); subsequently, dissolve silver trifluoromethanesulfonate (141 mg, 0.55 mmol) in 10 mL of distilled water to obtain Solution 2 (concentration: 0.055 mol / L); after stirring and mixing Solution 1 and Solution 2, under argon protection, slowly add dropwise (dropwise rate: 1 mL / min) a 10 mL dichloromethane solution (concentration: 0.018 mol / L) of 1,2,3-tris(dodecyloxy)-5-isocyanobenzene (118 mg, 0.18 mmol). After the addition is complete, continue to stir at room temperature for 12 h; wash the resulting mixture successively with distilled water and brine, collect the dichloromethane solution, dry by centrifugation, evaporate the solvent by rotary evaporation, and dry under vacuum to obtain the target product, a red solid (yield: 93%).

[0077] Comparative Example 2 Synthesis of Cationic Platinum Complex (from Patent Application No.: 202211618129.X)

[0078] Dissolve the N^C^N coordinated platinum chloride complex precursor (100 mg, 0.17 mmol) in 15 mL of dichloromethane solution. Subsequently, dissolve (132 mg, 0.51 mmol) silver trifluoromethanesulfonate in 15 mL of distilled water. After mixing the above two solutions and stirring, under argon protection, slowly add dropwise a 10 mL dichloromethane solution of 2,6-dimethylphenyl isocyanide (22 mg, 0.17 mmol). After the addition is complete, stir at room temperature for 10 hours. Wash the mixture with distilled water, collect the organic phase, dry by centrifugation, evaporate the solvent by rotary evaporation, and dry under vacuum to obtain the target product, the N^C^N coordinated cationic platinum complex, a red solid (yield 99%).

[0079] Comparative Example 3 Synthesis of Molecular Platinum Complex (from Patent Application No.: 202211618129.X)

[0080] Dissolve the N^C^N coordinated platinum chloride complex precursor (100 mg, 0.17 mmol) in 15 mL of dichloromethane solution. Under argon protection, slowly dropwise add 15 mL of dichloromethane solution containing 2,6-dimethylphenyl isocyanide (22 mg, 0.17 mmol). After the addition is complete, stir at room temperature for 1 hour, add (141 mg, 0.51 mmol) tetrabutylammonium chloride, continue to stir at room temperature for 10 hours, rotary evaporate the solvent, wash with methanol, and dry under vacuum to obtain the target product, the C^N coordinated molecular platinum complex, a green solid (yield: 99%).

[0081] Table 1

[0082]

[0083] Table 1 shows the anti-tumor effects of the isocyanide coordinated five- and six-membered ring metal platinum complexes prepared in each example. It can be found that the platinum complex obtained in Example 3 shows high anti-tumor activity against K562 leukemia cells, BEL-7402 liver cancer cells, SGC-7901 gastric cancer cells, A549 lung cancer cells, and Hela cervical cancer cells. The IC 50 value is much lower than that of the traditional platinum drug cisplatin and will play an important role in the field of anti-tumor.

[0084] Figure 7 Figure 15 is a confocal image of the isocyanide coordinated five- and six-membered ring metal platinum complexes prepared in Example 3 and Example 7 staining HeLa cells. As Figure 7 can be seen, the isocyanide coordinated five- and six-membered ring metal platinum complexes prepared in Example 3 and Example 7 can quickly stain HeLa cells, and the luminescent five- and six-membered heterocyclic platinum complexes are mainly distributed on the cell membrane.

Claims

1. A five - membered and six - membered ring metal platinum complex with anti - tumor activity, characterized in that: Its structure is as follows:

2. The five- and six-membered ring metal platinum complex with anti-tumor activity according to claim 1, characterized in that: Its structure is as follows:

3. The preparation method of the five- or six-membered ring metal platinum complex with anti-tumor activity according to claim 1 or 2, characterized in that: It is formed by the coordination of a cyclometalated main ligand modified with pinene and a phenyl isocyanide derivative auxiliary ligand with a platinum metal ion, and then reacting with a silver salt; The structure of the pinene-modified cyclometalated main ligand is The phenyl isocyanate derivative auxiliary ligand is 2,6-dimethylphenyl isocyanate.

4. The preparation method according to claim 3, characterized in that: The silver salt is at least one of silver nitrate, silver perchlorate, silver hexafluorophosphate or silver trifluoromethanesulfonate.

5. The preparation method according to claim 3 or 4, characterized in that: It includes the following steps: 1) Dissolve the cyclometalated platinum chloride complex precursor modified with pinene in dichloromethane to obtain Solution 1; 2) Dissolve 2,6-dimethylphenyl isocyanide in dichloromethane to obtain Solution 2; 3) Dissolve the silver salt in distilled water to obtain Solution 3; 4) Under argon protection, stir and mix Solution 1 and Solution 2, react at room temperature for 1 - 12 h, then slowly add dropwise Solution 3. After the addition is complete, continue to stir at room temperature for 5 - 24 h. Wash the obtained mixture successively with distilled water and brine in a separatory funnel, collect the dichloromethane solution, dry by centrifugation, rotary evaporate the solvent, and dry in vacuo to obtain the target product, the five-membered and six-membered cyclometalated platinum complex.

6. The preparation method according to claim 5, characterized in that: The molar amount of the silver salt used is 1 - 5 times the molar amount of the cyclometalated platinum chloride complex precursor modified with pinene; the molar amount of 2,6-dimethylphenyl isocyanide used is 1 - 3 times the molar amount of the cyclometalated platinum chloride complex precursor modified with pinene.

7. The preparation method according to claim 5, characterized in that: In Step 1), the concentration of Solution 1 is 0.0075 - 0.015 mol / L; in Step 2), the concentration of Solution 2 is 0.015 - 0.045 mol / L; in Step 3), the concentration of Solution 3 is 0.015 - 0.075 mol / L.

8. Use of the five- or six-membered ring metal platinum complex with anti-tumor activity according to claim 1 or 2, characterized in that, It is used for the preparation of anti-tumor drugs.

9. The use according to claim 8, characterized in that: It is used for the preparation of drugs against K562 leukemia cells, BEL-7402 liver cancer cells, SGC-7901 gastric cancer cells, A549 lung cancer cells and Hela cervical cancer cells.

10. The use according to claim 8, characterized in that: It is used for the rapid staining of K562 leukemia cells, BEL-7402 liver cancer cells, SGC-7901 gastric cancer cells, A549 lung cancer cells and Hela cervical cancer cells distributed on the cell membrane.

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