Zinc berberine complex and preparation method and application thereof

Abstract

The application discloses a berberine zinc complex and a preparation method and application thereof. The berberine-triphenylpyridine derivative BerT is reacted with a zinc salt ZnCl2 to obtain a berberine-triphenylpyridine zinc complex BerT1, then the BerT1 raw material is respectively reacted with auxiliary ligands 1,2-bis(diphenylphosphino)ethane, 2-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)quinolin-8-ol and 1,10-phenanthroline to synthesize the berberine zinc complexes BerT2-BerT4. The experimental results show that the berberine zinc complexes BerT1-BerT4 have good anticancer effect on human breast cancer MDA-MB-231 cells, and show superior in-vivo and in-vitro anti-tumor activity, have potential medicinal value, and can be more effective in treating human breast cancer in combination with the Bcl-2 selective inhibitor ABT-199, and are expected to be used in the preparation of various anti-tumor drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to berberine zinc complexes, their preparation methods, and applications. Background Technology

[0002] Zinc is closely related to life activities, participates in the synthesis of various important enzymes, and plays an important role in maintaining normal physiological functions. Zinc complexes have good anti-cancer activity and good selectivity in toxicity to normal cells. However, zinc complexes are still lacking in clinical treatment and need further research.

[0003] In addition, recent literature reports have highlighted the anticancer activity of berberine platinum and zinc complexes, with studies demonstrating their excellent anticancer properties. Specifically, the zinc complex exhibits a high inhibitory effect on the proliferation of human breast cancer MCF-7 cells, with an IC50 concentration of [missing information]. 50 The value was 0.21 ± 0.06 μM (Zhang SH, Wang ZF, Tan H. Novel zinc(II)-curcumin molecular probes bearing berberine and jatrorrhizine derivatives as potential mitochondria-targeting anti-neoplastic drugs[J]. European Journal of Medicinal Chemistry, 2022, 243: 114736.), but there have been no reports on zinc complexes of berberine-terpyridine derivative BerT. Summary of the Invention

[0004] One of the objectives of this invention is to provide berberine zinc complexes.

[0005] The berberine zinc complex of the present invention has the following chemical structural formula:

[0006] The second objective of this invention is to provide a method for preparing berberine zinc complexes.

[0007] The preparation method of berberine-zinc complex involves reacting berberine-terpyridine derivative BerT and ZnCl2 in anhydrous CH3OH at 68 °C for 3 days. After the reaction is completed, the mixture is cooled, filtered, and dried to obtain berberine-zinc complex BerT1.

[0008] In anhydrous CH3OH, berberine zinc complex BerT1 was reacted with 1,2-bis(diphenylphosphine)ethane (ppe) at 68 °C for 3 days. After cooling, the mixture was filtered and dried to obtain berberine zinc complex BerT2.

[0009] In anhydrous CH3OH, berberine zinc complex BerT1 was reacted with 2-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)quinoline-8-ol (ipq) at 68 °C for 3 days. After cooling, the mixture was filtered and dried to obtain berberine zinc complex BerT3.

[0010] In anhydrous CH3OH, berberine zinc complex BerT1 was reacted with 1,10-phenanthroline (phe) at 68 °C for 3 days. After cooling, the mixture was filtered and dried to obtain berberine zinc complex BerT4.

[0011] The synthesis of berberine-terpyridine derivative BerT involved mixing 0.1 mol of berberine (Ber), 0.1 mol of 4′-(4-bromomethylphenyl)-[2,2′:6′,2′′]terpyridine, and 0.1 mol of potassium carbonate with 1000 mL of N,N-dimethylformamide (DMF). The mixture was stirred at 80°C for 12 hours. The reaction solution was then poured into 1000 mL of ice water, cooled to room temperature, filtered, purified, concentrated under vacuum, and dried to obtain the final product.

[0012]

[0013] The synthetic route of this invention is as follows:

[0014] Another object of the present invention is to provide the application of berberine zinc complexes.

[0015] Specifically, this relates to the application of the aforementioned berberine zinc complex in the preparation of antitumor drugs. It also relates to the application of the aforementioned berberine zinc complex in the preparation of targeted therapy drugs for breast cancer.

[0016] Furthermore, the drug includes berberine zinc complex and Bcl-2 selective inhibitor ABT-199.

[0017] This invention uses a self-synthesized berberine-terpyridine derivative, BerT, reacted with zinc salt ZnCl2 to obtain the berberine-terpyridine zinc complex BerT1. Then, using BerT1 as a starting material, it was reacted with auxiliary ligands 1,2-bis(diphenylphosphine)ethane (ppe), 2-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)quinoline-8-ol (ipq), and 1,10-phenanthroline (phe) to synthesize novel zinc complexes BerT2-BerT4. Their anticancer activity and toxicity against human breast cancer MDA-MB-231 cells and normal human liver HL-7702 cells were investigated. Furthermore, the anticancer activity of the best-active zinc complex, BerT3, in combination with the Bcl-2 selective inhibitor ABT-199 in inhibiting human breast cancer was studied. Experimental results showed that the berberine zinc complex BerT1-BerT4 had a good anti-cancer effect on human breast cancer MDA-MB-231 cells, with an IC50 value of [missing information]. 50 The cyperamine concentrations (CCPs) were 1.97 ± 0.36, 0.60 ± 0.05, 0.52 ± 0.09, and 1.33 ± 0.18 μM, respectively, indicating that their activity was significantly greater than that of BerT, ZnCl2, PPE, IPQ, PHE, and the clinical drug cisplatin. Furthermore, they exhibited minimal toxicity to normal HL-7702 cells, suggesting that the berberine zinc complexes BerT1-BerT4 can target and inhibit the growth of human breast cancer MDA-MB-231 cells. In addition, when the most active complex, BerT3, was combined with ABT-199, the inhibitory effect on human breast cancer MDA-MB-231 cells was significantly enhanced, reaching 93.51%, significantly higher than that of BerT3 (51.02%) and ABT-199 (50.67%), demonstrating a synergistic effect. In vivo tumor suppression experiments showed that the berberine zinc complex BerT3 combined with ABT-199 exhibited good tumor-suppressing effects on a nude mouse model of MDA-MB-231 breast cancer cells, with an inhibition rate as high as 76.7%, significantly higher than that of BerT3 (59.8%) and ABT-199 (42.5%). In conclusion, the berberine zinc complexes BerT1-BerT4 demonstrated superior in vitro and in vivo antitumor activity, possessing potential pharmaceutical value. Furthermore, their combination with the Bcl-2 selective inhibitor ABT-199 showed even greater effectiveness in treating human breast cancer, and holds promise for the development of various antitumor drugs. Attached Figure Description

[0018] Figure 1 The mass spectra of BerT, the berberine-terpyridine derivative obtained in Example 1 of this invention; Figure 2 The 1H NMR spectrum of BerT, a berberine-terpyridine derivative prepared in Example 1 of this invention; Figure 3 The carbon NMR spectrum of BerT, a berberine-terpyridine derivative prepared in Example 1 of this invention; Figure 4 The 1H NMR spectrum of the complex BerT1 obtained in Example 1 of this invention; Figure 5 The carbon NMR spectrum of the complex BerT1 obtained in Example 1 of this invention; Figure 6 The infrared spectrum of the complex BerT1 obtained in Example 1 of this invention; Figure 7 The 1H NMR spectrum of the complex BerT2 obtained in Example 1 of this invention; Figure 8 The carbon NMR spectrum of the complex BerT2 obtained in Example 1 of this invention; Figure 9 The infrared spectrum of the complex BerT2 obtained in Example 1 of this invention; Figure 10 The 1H NMR spectrum of the complex BerT3 obtained in Example 1 of this invention; Figure 11 The infrared spectrum of the complex BerT3 obtained in Example 1 of this invention; Figure 12 The 1H NMR spectrum of the complex BerT4 obtained in Example 1 of this invention; Figure 13 The infrared spectrum of the complex BerT4 obtained in Example 1 of this invention. Detailed Implementation

[0019] The present invention will be further described below with reference to specific embodiments, but the present invention is not limited to these embodiments.

[0020] Example 1 I. Synthesis of the auxiliary ligand 2-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)quinoline-8-ol (ipq) Using 5,6-diamino-1,10-phenanthroline as a starting material, the auxiliary ligand 2-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)quinoline-8-ol (ipq) was synthesized according to the method reported in the literature (Xu X, Wang S, Mi Y, et al. A hydroxyquinoline-appended ruthenium(II)-polypyridyl complex that induces and stabilizes G-quadruplex DNA[J]. Journal of Coordination Chemistry, 2019, 72(2): 201-217.). In addition, 1,2-bis(diphenylphosphine)ethane (ppe) and 1,10-phenanthroline (phe) were purchased from Anaiji Chemical.

[0021] II. Synthesis of BerT, a Berberine-Tripyridine Derivative Berberine (Ber) (0.1 mol, 35.7 g), 4′-(4-bromomethylphenyl)-[2,2′:6′,2′′]terpyridine (0.1 mol, 40.1 g), and potassium carbonate (0.1 mol, 13.8 g) were added to a round-bottom flask, followed by the addition of 1000 mL of N,N-dimethylformamide (DMF). The mixture was stirred at 80°C for 12 hours. Subsequently, the reaction solution was poured into 1000 mL of ice water, cooled to room temperature, and filtered to obtain a light yellow powder. This powder was purified by neutral alumina chromatography (eluent: ethanol:dichloromethane = 1:10), concentrated under vacuum, and dried to obtain a bright yellow powder, the berberine-terpyridine derivative BerT, in 85.0% yield.

[0022] III. Synthesis of four novel berberine zinc complexes, BerT1-BerT4 In a thick-walled drug-resistant tube of approximately 15.0 cm, 0.1 mmol of berberine-terpyridine derivative BerT and 0.1 mmol of zinc salt ZnCl2 were added, followed by 3.0 mL of anhydrous CH3OH. After capping, the mixture was reacted at 68 °C for 3 days. After cooling, the mixture was filtered and dried to obtain a yellow solid complex BerT1 with a yield of 88.9%.

[0023] In addition, three thick-walled drug-resistant tubes, each approximately 15.0 cm in length, were used. 0.1 mmol of the complex BerT1 was weighed into each tube, and 0.1 mmol of 1,2-bis(diphenylphosphine)ethane (ppe), 2-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)quinoline-8-ol (ipq), and 1,10-phenanthroline (phe) were added to each tube, respectively. Then, 3.5 mL of anhydrous CH3OH was added dropwise to each tube. After capping, the mixture was reacted at 68 °C for 3 days. After cooling, the mixture was filtered and dried to obtain the reddish-brown compounds BerT2 (yield: 80.1%), BerT2 (yield: 90.5%), and BerT4 (yield: 84.6%).

[0024] The four novel berberine zinc complexes BerT1-BerT4 were identified as follows: (1) The mass spectrum of compound BerT is shown in the figure below. Figure 1 As shown.

[0025] ESI-MS: m / z 643.19 [M+H] + , and m / z 322.10 [(M+H) / 2] + , (calcd forC 41 H 31 N4O4, 643.19). (2) The proton NMR spectrum of compound BerT is shown in the figure below. Figure 2 As shown.

[0026] 1 H NMR (400 MHz, DMSO- d 6) δ 9.81 (s, 1H), 8.93 (s, 1H), 8.6 (dd, J = 4.6,0.7 Hz 2H), 8.71 (s, 2H), 8.67 (d, J = 7.9 Hz, 2H), 8.22 (d, J = 9.2 Hz, 1H),8.08 – 8.02 (m, 3H), 8.01 – 7.96 (m, 2H), 7.81 (d, J = 8.2 Hz, 2H), 7.77 (s,1H), 7.54 (ddd, J = 7.5, 4.8, 1.0 Hz, 2H), 7.06 (s, 1H), 6.16 (s, 2H), 5.46 (s,2H), 4.94 (t, J= 6.0 Hz, 2H), 4.11 (s, 3H), 3.19 (m, J = 6.0 Hz, 2H). (3) The carbon NMR spectrum of compound BerT is shown in the figure below. Figure 3 As shown.

[0027] 13 C NMR (101 MHz, DMSO- d 6) δ 155.73, 154.86, 150.65, 149.83, 149.36, 149.01, 147.68, 145.29, 141.97, 137.95, 137.53, 137.44, 137.35, 132.94, 130.64, 129.56, 126.95, 126.54, 124.62, 123.85, 121.77, 120.97, 120.38, 120.26, 117.86, 108.40, 105.43, 102.10, 74.91, 57.08, 55.36, 26.35. (4) Elemental analysis results are shown in Table 1.

[0028] Table 1. Elemental analysis results of the compounds in the examples.

[0029] (5) The proton NMR spectrum of compound BerT1 is shown in the figure below. Figure 4 As shown.

[0030] 1 H NMR (400 MHz, DMSO- d 6) δ 9.87 (s, 1H), 9.10 (s, 2H), 8.94 (s, 3H), 8.84 (s, 2H), 8.35 (s, 4H), 8.24 (s, 1H), 8.04 (s, 1H), 7.89 (s, 4H), 7.78(s, 1H), 7.08 (s, 1H), 6.17 (s, 2H), 5.51 (s, 2H), 4.95 (s, 2H), 4.13 (s,3H), 3.20 (s, 2H). (6) The carbon NMR spectrum of compound BerT1 is shown in the figure below. Figure 5 As shown.

[0031] 13C NMR (101 MHz, DMSO- d 6) δ 153.71, 150.62, 149.90, 149.11, 148.82, 147.73, 147.06, 141.94, 140.59, 139.43, 137.53, 132.99, 130.69, 129.29, 128.11, 127.35, 126.63, 123.89, 122.62, 121.77, 120.40, 120.29, 120.20, 120.12, 108.47, 105.44, 102.14, 74.79, 57.14, 55.37, 39.52, 26.37. (7) The infrared spectrum of compound BerT1 is shown in the figure below. Figure 6 As shown.

[0032] IR(KBr): 3505, 3387, 3054, 3006, 2894, 2844, 2056, 1615, 1602, 1565,1553, 1505, 1476, 1431, 1399, 1359, 1337, 1296, 1272, 1255, 1232, 1189, 1171,1141, 1114, 1100, 1062, 1039, 1015, 956, 912, 865, 830, 809, 793, 769, 749,731, 709, 692, 659, 638, 603, 551, 532, 503, 461 cm −1 . (8) The proton NMR spectrum of compound BerT2 is shown in the figure below. Figure 7 As shown.

[0033] 1 H NMR (400 MHz, DMSO- d 6): δ9.88 (s, 1H), 9.09 (s, 2H), 8.95 (s, 3H),8.84 (d, J = 4.2 Hz, 2H), 8.34 (d, J = 7.6 Hz, 4H), 8.25 (d, J = 9.1 Hz, 1H),8.03 (d, J = 9.0 Hz, 2H), 7.87 (d, J = 7.3 Hz, 3H), 7.76 (dd, J = 12.9, 7.4Hz, 7H), 7.53 (dt, J = 14.4, 7.5 Hz, 9H), 7.08 (s, 1H), 6.17 (s, 2H), 5.51 (s, 2H), 4.96 (s, 2H), 4.13 (s, 3H), 3.20 (s, 3H), 2.41 (s, 3H). (9) The carbon NMR spectrum of compound BerT2 is shown in the figure below. Figure 8 As shown.

[0034] 13 C NMR (101 MHz, DMSO- d 6): δ 153.66, 150.62, 149.87, 149.11, 148.83, 147.71, 147.05, 145.40, 141.94, 140.51, 139.40, 137.50, 137.47, 132.97, 132.54, 132.44, 131.88, 131.88, 130.63, 130.54, 130.54, 130.50, 130.50, 129.86, 129.28, 128.87, 128.87, 128.82, 128.81, 128.76, 128.76 128.09, 127.28, 126.60, 123.88, 122.57, 121.75, 120.39, 120.27, 120.05, 108.45, 105.44, 102.12, 74.75, 57.13, 55.38, 26.35. (10) The infrared spectrum of compound BerT2 is shown in the figure below. Figure 9 As shown.

[0035] IR(KBr): 3509, 3385, 3054, 3008, 2942, 2907, 1615, 1602, 1565, 1554,1506, 1476, 1438, 1400, 1359, 1337, 1295, 1272, 1256, 1233, 1187, 1175, 1141,1122, 1100, 1064, 1040, 1015, 997, 956, 912, 865, 830, 809, 793, 763, 754,741, 730, 694, 659, 638, 603, 533, 512, 479, 460 cm −1 . (11) The proton NMR spectrum of compound BerT3 is shown in the figure below. Figure 10 As shown.

[0036] 1 H NMR (400 MHz, DMSO- d 6): δ 9.83 (d, J = 19.6 Hz, 1H), 9.10 (s, 1H),8.99–8.90 (m, 2H), 8.85 (s, 1H), 8.70 (m, 4H), 8.50 (m, 2H), 8.34 (m, 2H),8.22 (d, J = 9.3 Hz, 2H), 8.00 (m, 5H), 7.88 (m, 4H), 7.79 (d, J = 7.5 Hz, 2H),7.76 (s, 1H), 7.52 (m, 4H), 7.05 (s, 1H), 6.15 (s, 2H), 5.47 (m, 2H), 4.95(m, 2H), 4.11 (s, 3H), 3.19 (m, 2H). (12) The infrared spectrum of compound BerT3 is shown in the figure below. Figure 11 As shown.

[0037] IR(KBr): 3506, 3384, 3052, 3022, 1615, 1602, 1586, 1567, 1554, 1505,1476, 1458, 1433, 1340, 1359, 1335, 1317, 1296, 1273, 1255, 1233, 1189, 1162,1141, 1114, 1100, 1078, 1038, 1015, 992, 957, 944, 912, 863, 853, 839, 827,810, 789, 748, 732, 708, 692, 660, 639, 624, 603, 575, 551, 503, 500 cm −1 . (13) The proton NMR spectrum of compound BerT4 is shown in the figure. Figure 12 As shown.

[0038] 1 H NMR (400 MHz, DMSO- d 6): δ 9.85 (d, J = 22.9 Hz, 1H), 9.11 (s, 1H), 8.94(s, 4H), 8.80 (m, 2H), 8.70 (m, 4H), 8.34 (m, 2H), 8.24 (d, J = 8.6 Hz, 1H),8.14 (s, 2H), 8.05–7.96 (m, 3H), 7.86 (m, 5H), 7.78 (s, 1H), 7.54 (s, 1H),7.07 (s, 1H), 6.17 (s, 2H), 5.49 (d, J = 16.2 Hz, 2H), 4.96 (brs, 2H), 4.12 (s, 3H), 3.20 (brs, 2H). (14) The infrared spectrum of compound BerT4 is shown in the figure below. Figure 13 As shown.

[0039] IR(KBr): 3495, 3383, 3051, 3009, 2895, 2844, 2058, 1810, 1615, 1602, 1585, 1566, 1554, 1506, 1476, 1427, 1399, 1359, 1336, 1296, 1273, 1256, 1233,1190, 1172, 1141, 1114, 1101, 1063, 1039, 1015, 992, 957, 912, 865, 853, 829,809, 791, 747, 730, 710, 692, 660, 639, 624, 603, 551, 533, 503, 461 cm −1 . Therefore, the structural formulas of the obtained berberine-terpyridine derivative BerT and four novel berberine zinc complexes BerT1-BerT4 can be determined as follows:

[0040] Example 2 To fully demonstrate the pharmaceutical applications of berberine-terpyridine derivative BerT and berberine zinc complexes BerT1-BerT4, the applicant conducted antitumor activity experiments on them.

[0041] I. Experiment on the inhibitory activity of berberine zinc complex BerT1-BerT4 on the proliferation of two human cell lines 1. Cell lines and cell culture This experiment used two human cell lines: human breast cancer MDA-MB-231 cells and human normal liver HL-7702 cells.

[0042] All human cell lines were cultured in RPMI-1640 medium containing 100 U / mL penicillin, 10 wt% fetal blood, and 100 U / mL streptomycin, and incubated at 37°C in an incubator containing 5% CO2 by volume.

[0043] 2. Preparation of the test compound All compounds used must have a purity of ≥95%. Their DMSO stock solutions were diluted with physiological buffer to a final solution of 20 µmol / L (final DMSO concentration ≤1%). The inhibitory effect of each compound on the growth of normal cells or selected tumor cells at this concentration was then tested.

[0044] 3. Cell growth inhibition experiment The specific steps are as follows: (1) Cells were digested, counted, and prepared to a concentration of 5×10⁻⁶.4 Add 100 μL of cell suspension per well to each well of a 96-well cell culture plate and incubate at 37°C in a 5.0% CO2 incubator for 24.0 h. (2) Dilute the drug to the required concentration with RPMI-1640 medium, add 100 μL of the corresponding drug-containing medium to each well of the 96-well plate, so that the final concentrations reach 0, 1.0, 2.5, 5.0, 10.0, 20.0 and 50.0 μM respectively. Set up 6 parallel experiments for each concentration. After adding the drug, place it in a 37℃, 5% CO2 incubator and continue to incubate for 48h. (3) Perform CCK-8 staining and measure the OD value at a wavelength of λ=450nm: Add 10μL of CCK-8 to each well, continue to incubate in an incubator for 2h, shake gently for 10min, and then measure the OD value of each well at a wavelength of λ=450nm using an ELISA reader. Calculate the inhibition rate of each compound on the growth of the selected cell lines, and then calculate the IC50 of each tested compound on the selected cell lines using the Bliss method. 50 Values. The results are shown in Table 2 below.

[0045] Table 2. IC50 of compounds against various cell lines 50 Value (µM)

[0046] Table 3. Inhibitory effect of the compound on MDA-MB-231 cells (%)

[0047] From IC 50 Based on the activity screening results, the berberine zinc complex BerT1-BerT4 showed good anti-cancer activity against human breast cancer MDA-MB-231 cells, with an IC50 value of [missing information]. 50 The concentrations were 1.97 ± 0.36, 0.60 ± 0.05, 0.52 ± 0.09, and 1.33 ± 0.18 μM, respectively, indicating that their activity was significantly greater than that of BerT, ZnCl2, PPE, IPQ, PHE, and the clinical drug cisplatin. Furthermore, they exhibited minimal toxicity to normal HL-7702 cells, suggesting that the berberine zinc complexes BerT1-BerT4 can target and inhibit the growth of human breast cancer MDA-MB-231 cells. In addition, when the most active complex, BerT3, was combined with ABT-199, the inhibitory effect on human breast cancer MDA-MB-231 cells was significantly enhanced, reaching 93.51%, significantly higher than that of BerT3 (51.02%) and ABT-199 (50.67%), demonstrating a synergistic effect.

[0048] II. In vivo tumor suppression experiment in tumor-bearing nude mice MDA-MB-231 breast cancer cells in logarithmic growth phase were collected and cultured in serum-free medium to form cells of 5.0 × 10⁻⁶. 7 A suspension with a live cell concentration of [number] cells / mL. 0.2 mL of the suspension is drawn using a 1.0 mL syringe, containing approximately 1 × 10 [cells / mL]. 7 A live cell was then inoculated subcutaneously into the right axilla of a nude mouse, and the subcutaneous tumor was allowed to grow to approximately 1 cm. 3 The tumor source, used as a subcutaneous xenograft tumor model, was passaged in nude mice. Human breast cancer MDA-MB-231 cells were passaged four times in nude mice until growth stabilized. Mice bearing tumors with vigorous growth and no ulceration were selected, euthanized by cervical dislocation, and the skin was disinfected with 75.0% medical alcohol. The tissue block was dissected, necrotic parts were removed, and the tumor tissue was cut into 1.5 mm pieces. 3 Small pieces were inoculated subcutaneously into the right axilla of nude mice using a cannula. The diameter of the transplanted tumor was measured with electronic calipers. The tumor volume was monitored until it reached 100-300 mm. 3 At that time, the animals were randomly grouped.

[0049] Nude mice bearing human breast cancer MDA-MB-231 tumors were randomly divided into a solvent group, a drug-treated group, and a cisplatin-positive control group, with 7 animals in each group. Intraperitoneal injection of the drug was initiated on the day of grouping, with the compound administered every two days and cisplatin administered every other day. Tumor diameter and body weight were measured every three days using electronic calipers. On day 21, the mice were euthanized by cervical dislocation, the tumors were dissected, weighed, photographed, and the tumor inhibition rate was calculated.

[0050] Tumor volume calculation formula: V = a × b 2 / 2, where a is the major axis and b is the minor axis; Relative tumor volume RTV=V t / V0, where V t V0 represents the volume at each measurement, and V0 represents the volume when grouping. Relative tumor proliferation rate T / C% = (T RTV / C RTV ) × 100%; Tumor growth inhibition rate (%) = (average tumor weight in the solvent group - average tumor weight in the treatment group) / average tumor weight in the solvent group × 100%.

[0051] Table 4. In vivo tumor inhibition results of complex BerT3 on nude mice bearing human breast cancer MDA-MB-231 tumors.

[0052] Table 4 shows that the in vivo tumor suppression experiments of the complex BerT3 combined with ABT-199 have a good tumor-suppressing effect on a nude mouse model of MDA-MB-231 breast cancer cells, with an inhibition rate as high as 76.7%, significantly higher than BerT3 (59.8%) and ABT-199 (42.5%). In summary, the four novel berberine zinc complexes BerT1-BerT4 exhibit superior in vitro and in vivo antitumor activity, have potential pharmaceutical value, and are even more effective in treating human breast cancer when combined with the Bcl-2 selective inhibitor ABT-199, showing promise for the preparation of various antitumor drugs.

[0053] In summary, the four novel berberine zinc complexes BerT1-BerT4 described in this invention exhibit excellent in vitro and in vivo antitumor activity and selectivity, as well as good cytotoxicity selectivity. Furthermore, their combination with the Bcl-2 selective inhibitor ABT-199 enhances their effectiveness in treating human breast cancer, demonstrating significant potential pharmaceutical value and promising applications in the preparation of various antitumor drugs.

Claims

1. Berberine zinc complex, characterized in that, The chemical structural formula is as follows: 。 2. A method for preparing berberine zinc complex, characterized in that, in Berberine-terpyridine derivative BerT and ZnCl2 were reacted in anhydrous CH3OH at 68 °C for 3 days. After the reaction was completed, the mixture was cooled, filtered, and dried to obtain the berberine zinc complex BerT1.

3. The method for preparing the berberine zinc complex according to claim 2, characterized in that, in In anhydrous CH3OH, the berberine zinc complex BerT1 was reacted with 1,2-bis(diphenylphosphine)ethane at 68 °C for 3 days. After cooling, the mixture was filtered and dried to obtain the berberine zinc complex BerT2.

4. The method for preparing the berberine zinc complex according to claim 2, characterized in that, in In anhydrous CH3OH, the berberine zinc complex BerT1 was reacted with 2-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)quinoline-8-ol at 68 °C for 3 days. After cooling, the mixture was filtered and dried to obtain the berberine zinc complex BerT3.

5. The method for preparing the berberine zinc complex according to claim 2, characterized in that, in In anhydrous CH3OH, the berberine zinc complex BerT1 was reacted with 1,10-phenanthroline at 68 °C for 3 days. After cooling, the mixture was filtered and dried to obtain the berberine zinc complex BerT4.

6. The method for preparing the berberine zinc complex according to any one of claims 2-5, characterized in that, The synthesis of the berberine-terpyridine derivative BerT involved taking 0.1 mol of berberine (Ber), 0.1 mol of 4′-(4-bromomethylphenyl)-[2,2′:6′,2′′]terpyridine and 0.1 mol of potassium carbonate, adding 1000 mL of N,N-dimethylformamide, stirring at 80°C for 12 hours, pouring the reaction solution into 1000 mL of ice water, cooling to room temperature, filtering, purifying, and vacuum concentrating and drying to obtain the product. The structural formula of the berberine-terpyridine derivative BerT is: 。 7. The use of the berberine zinc complex according to claim 1 in the preparation of antitumor drugs.

8. The use of the berberine zinc complex according to claim 1 in the preparation of targeted therapy drugs for breast cancer.

9. The application according to claim 8, characterized in that, The drug includes berberine zinc complex and Bcl-2 selective inhibitor ABT-199.

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