CN109251206B - Water-soluble platinum-porphyrin complex and preparation method thereof - Google Patents
Water-soluble platinum-porphyrin complex and preparation method thereof Download PDFInfo
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- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
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- A61K41/0076—PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
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Abstract
The invention relates to a water-soluble platinum-porphyrin complex and a preparation method thereof. The structural formula of the complex is as follows:
pharmacodynamic experiments prove that the compound has higher singlet oxygen yield and photo-cytotoxic activity when being used as a photosensitizer, and has obvious in vivo photodynamic treatment effect. After light irradiation, the IC50Can reach about 60nM, which is superior to positive control drug. The preparation method of the photosensitizer is reasonable in design, convenient to operate and suitable for industrial production.
Description
Technical Field
The invention relates to a water-soluble platinum-porphyrin complex and a preparation method thereof.
Background
Cancer, i.e., malignant tumor, is a disease caused by unlimited proliferation of cancer cells due to malfunction of mechanisms controlling cell division and proliferation. China is a cancer high-incidence area, and the number of people who die every year because of cancer reaches 250 ten thousand at present. Therefore, it is necessary to research cancer. There are generally three methods of treating cancer, including chemotherapy, surgical therapy, and radiation therapy. Chemotherapy uses chemical agents to inhibit the proliferation, infiltration, and metastasis of cancer cells, thereby treating cancer. Platinum anti-cancer drugs are widely applied to first-line clinical cancer therapy as important metal chemotherapy drugs, and are mainly used for ovarian cancer, prostatic cancer, testicular cancer, lung cancer, nasopharyngeal carcinoma, esophageal cancer, malignant lymphoma, head and neck cancer, thyroid cancer, osteogenic sarcoma and the like.
Photodynamic therapy (PDT) is an important new tumor treatment technology, has the characteristics of high efficiency, simplicity, convenience, no toxicity, targeting, safety and the like, and is clinically used for treating superficial bladder cancer, lung cancer, esophageal cancer, head and neck cancer, skin cancer and the like. PDT is gaining attention as a new and accurate therapy. The essential elements are oxygen, a photosensitizer and visible light (commonly used laser light). The method uses specific wavelength light to locally irradiate tumor part, so as to activate photosensitive drug, trigger photochemical reaction to generate singlet oxygen, destroy tumor, and further cause tumor cell necrosis or apoptosis. Photosensitizers are generally a class of porphyrin-like molecules with a cyclic planar two-dimensional structure, with a tetrapyrrole-based structure. Their water solubility is poor, often through central insertion of metals or modification of peripheral groups to improve their biocompatibility.
At present, many studies have been made to develop bifunctional antitumor drugs by combining photodynamic therapy with chemotherapy based on platinum drugs. The medicine can not only avoid the defects of single therapy, such as poor drug effect, normal cell injury, obvious nephrotoxicity and the like, but also retain or enhance the advantages of each therapy and obtain the maximized treatment benefit. Therefore, the development of the platinum-porphyrin and platinum-metalloporphyrin bifunctional antitumor photosensitizer is a work with great application prospect.
Disclosure of Invention
One of the purposes of the invention is to provide a water-soluble platinum-porphyrin complex.
The second purpose of the invention is to provide a preparation method of the complex.
The invention also aims to provide the application of the platinum-porphyrin complex in tumor photodynamic therapy.
In order to achieve the purpose, the invention adopts the following technical scheme:
a water-soluble platinum-porphyrin complex is characterized in that the structural formula of the compound is as follows:
wherein: m represents H or a metal element inserted into the center of porphyrin, wherein the metal element is independently selected from Ga (III), in (III), Zn (II), Cu (II), Co (II), Fe (II), Pt (II), Pd (II), Sn (IV) or Si (III)IV); a represents a nitrogen-containing heterocyclic compound independently selected from imidazole, thiazole, pyrrole, pyrazole, pyridine, pyrimidine, quinoline, pteridine or purine groups; n represents any number between 1 and 6; r1,R2,R3And R4Is a non-bridging cross-shaped platinum group and is independently selected from any one of the following structures
The complex is one of the following structures:
a method for preparing the complex, which is characterized by comprising the following steps: dissolving a chloric platinum complex in N, N-dimethylformamide, adding a one-time or four-time amount of silver nitrate, reacting at 20-60 ℃ for 12-36 hours, and filtering by using a sand core funnel to remove a precipitate; suspending porphyrin mother nucleus or metalloporphyrin mother nucleus in N, N-dimethyl formamide, dropping the reaction liquid into the suspension, and reacting for 12-36 hr under the protection of nitrogen. Precipitating with diethyl ether, filtering, and washing with cold methanol, chloroform and diethyl ether to obtain the target product.
The invention also includes pharmaceutically acceptable salts of compound (I) which are the nitrates, hydrochlorides, hydrobromides, phosphates, sulfates, fumarates, salicylates, benzenesulfonates, pyruvates, acetates or mandelates of the compounds of general formula (I).
The compound of the invention is used as a photosensitizer, has the functions of phototherapy and chemotherapy at the same time, and can be used as an anti-tumor medicament for application and photodynamic therapy. The compound has high singlet oxygen yield, high phototoxic activity and obvious in vivo photodynamic treatment effect. After light irradiation, the IC50Can reach about 60nM, which is superior to positive control drug. The preparation method of the photosensitizer is reasonable in design, convenient to operate and suitable for industrial production.
Drawings
FIG. 1 is a graph of in vivo PDT assessment in Colon26 tumor mice after administration of complex 2.
FIG. 2 is a graph showing the photodynamic therapy effect of tumors in a BALB/c mouse Colon26 model after PDT treatment of Complex 2.
Detailed description of the preferred embodiments
Example 1: structural formula, yield, ultraviolet, nuclear magnetic data and element analysis data of target compound 1
The oxaliplatin-containing prodrug ligand (C)6H14N2PtCl212.25mg,0.032mmol) is dissolved in 3mL of N, N-dimethylformamide, a time of silver nitrate (5.5mg,0.032mmol) is added, the reaction is carried out at 60 ℃ for 24 hours, and the sediment is removed by filtering through a sand core funnel; porphyrin mother nucleus (20mg,0.032mmol) was suspended in 3mL of N, N-dimethylformamide, and the above reaction mixture was added dropwise to the suspension and reacted under nitrogen atmosphere for 36 hours. Precipitating with diethyl ether, filtering, and washing with cold methanol, chloroform and diethyl ether to obtain the target product.
Yield: 72 percent; a purple solid; lambda [ alpha ]max(DMSO,nm)(ε,104M-1cm-1)415(29.6),515(1.68),549(0.57),588(0.54),and 643(0.22).1H NMR(400MHz；DMSO-d6):δ9.20(o-pyridyl,d,8H),8.83(β-pyrrole,s,8H),8.30(m-pyridyl,d,8H,J＝6.4Hz),6.65-5.72(NH2,m,4H),2.03(CH,m,2H),1.54-1.13(CH2,m,8H),7.95(CH,DMF),2.89(CH3,DMF),2.73(CH3,DMF).
Example 2: structural formula, yield, ultraviolet, nuclear magnetic data and mass spectrum data of target compound 2
The oxaliplatin-containing prodrug ligand (C)6H14N2PtCl249.02mg,0.129mmol) was dissolved in 3mL of N, N-dimethylAdding silver nitrate (22mg,0.129mmol) into formamide, reacting at 60 ℃ for 24 hours, and filtering by a sand core funnel to remove precipitates; porphyrin mother nucleus (20mg,0.032mmol) was suspended in 3mL of N, N-dimethylformamide, and the above reaction mixture was added dropwise to the suspension and reacted under nitrogen atmosphere for 36 hours. Precipitating with diethyl ether, filtering, and washing with cold methanol, chloroform and diethyl ether to obtain the target product.
Yield: 78 percent; a purple solid; lambda [ alpha ]max(DMSO,nm)(ε,104M-1cm-1)423(29.6),516(1.68),550(0.57),589(0.54),and 644(0.22).1H NMR(400MHz；DMSO-d6):δ9.23(o-pyridyl,d,8H),9.02(β-pyrrole,s,8H),8.51(m-pyridyl,d,8H,J＝6.4Hz),6.67-5.74(NH2,m,16H),2.04(CH,m,8H),1.59-1.16(CH2,m,32H),7.95(CH,DMF),2.89(CH3,DMF),2.73(CH3,DMF),2.09(CH3,CH3COCH3)；MS(ESI):m/z＝2115.0[M-NO3-2Cl+3H]+,1893.9[M-2NO3-2(dach)+H]+,1307.6[M-4NO3-2{Pt(dach)Cl}]+,963.5[M-4NO3-3{Pt(dach)Cl}]+,812.4[M-4NO3-3{Pt(dach)Cl}-{(dach)Cl}]+。
Example 3: structural formula, yield, ultraviolet, nuclear magnetic data and elemental analysis data of target compound 3
The oxaliplatin-containing prodrug ligand (C)6H14N2PtCl212.25mg,0.032mmol) in 3mL of N, N-dimethylformamide, adding silver nitrate (5.5mg,0.032mmol), reacting at 60 ℃ for 24 hours, and filtering with a sand core funnel to remove the precipitate; tin porphyrin (24.8mg,0.032mmol) was suspended in 3mL of N, N-dimethylformamide, and the above reaction mixture was added dropwise to the suspension and reacted under nitrogen atmosphere for 36 hours. Precipitating with diethyl ether, filtering, and washing with cold methanol, chloroform and diethyl ether to obtain the target product.
Yield: 68.6 percent; a purple solid; lambda [ alpha ]max(H2O,nm)(ε,104M-1cm-1)418(31.1),554(1.9),592(0.5)；1H NMR(400MHz；DMSO-d6):δ9.23(o-pyridyl andβ-pyrrole,m,16H),δ 8.31(m-pyridyl,d,8H),δ 6.24-5.76(NΗ2，m,4H)，δ2.06(CH,m,2H)，δ1.74-1.05(CH2,m,8H)；C46H40N11ClPtO5Sn·11H2O(M＝1175.5,M’＝1373.5),Calcd.C:41.41,H:4.76,N:11.33；Obsd.C:41.18,H:4.51,N:11.21.
Example 4: structural formula, yield, ultraviolet, nuclear magnetic data and elemental analysis data of target compound 4
The oxaliplatin-containing prodrug ligand (C)6H14N2PtCl249.02mg,0.129mmol) was dissolved in 3mL of N, N-dimethylformamide, silver nitrate (22mg,0.129mmol) was added, the reaction was carried out at 60 ℃ for 24 hours, and the precipitate was removed by filtration through a sand core funnel; tin porphyrin (24.8mg,0.032mmol) was suspended in 3mL of N, N-dimethylformamide, and the above reaction mixture was added dropwise to the suspension and reacted under nitrogen atmosphere for 36 hours. Precipitating with diethyl ether, filtering, and washing with cold methanol, chloroform and diethyl ether to obtain the target product.
Yield: 69.6 percent; a purple solid; lambda [ alpha ]max(H2O,nm)(ε,104M-1cm-1)426(35.2),555(2.8),593(0.7)；1H NMR(400MHz；DMSO-d6):δ9.26(o-pyridyl andβ-pyrrole,m,16H),δ8.51(m-pyridyl,d,8H),δ6.26-5.77(NΗ2，m,16H)，δ2.06(CH,m,8H)，δ1.82-1.04(CH2,m,32H)，δ 7.95(CH,DMF)，δ 2.89(CH3,DMF)，δ 2.73(CH3,DMF)；C64H82N20Cl4Pt4O14Sn·2DMF·15H2O(M＝2395,M’＝2811),Calcd.C:29.75,H:4.60,N:10.98；Obsd.C:29.88,H:4.48,N:10.96。
Example 5: structural formula, yield, ultraviolet, nuclear magnetic data and elemental analysis data of target compound 5
Will contain cisplatin prodrug ligand (PtH)6N2Cl238.7mg,0.129mmol) was dissolved in 3mL of N, N-dimethylformamide, silver nitrate (22mg,0.129mmol) was added, the reaction was carried out at 60 ℃ for 24 hours, and the precipitate was removed by filtration through a sand core funnel; tin porphyrin mother nucleus (24.8mg,0.032mmol) was suspended in 3mL of N, N-dimethylformamide, and the above reaction mixture was added dropwise to the suspension and reacted under nitrogen atmosphere for 36 hours. Precipitating with diethyl ether, filtering, and washing with cold methanol, chloroform and diethyl ether to obtain the target product.
Yield: 62.3 percent; a purple solid; lambda [ alpha ]max(H2O,nm)(ε,104M-1cm-1)421(38.3),554(2.2),592(0.5)；1H NMR(400MHz；DMSO-d6):δ9.23(o-pyridyl andβ-pyrrole,m,16H),δ8.45(m-pyridyl,d,8H),δ 4.97(NΗ3，s,12H)，δ4.51(NH3,s,12H)，δ7.95(CH,DMF)，δ 2.89(CH3,DMF)，δ2.73(CH3,DMF)；C40H50N20Pt4Cl4O14Sn·DMF·8H2O(M＝2075,M’＝2292),Calcd.C:22.15,H:3.15,N:12.94；Obsd.C:22.51,H:3.18,N:12.80.
Example 6: structural formula, yield, ultraviolet and nuclear magnetic data of target compound 6
Will contain a cisplatin prodrug ligand (PtC)6H10N2Cl243.9mg,0.129mmol) was dissolved in 3mL of N, N-dimethylformamide, silver nitrate (22mg,0.129mmol) was added, the reaction was carried out at 60 ℃ for 24 hours, and the precipitate was removed by filtration through a sand core funnel; indium porphyrin mother nucleus (24.5mg,0.032mmol) was suspended in 3mL of N, N-dimethylformamide, and the above reaction solution was added dropwise to the suspension and reacted for 36 hours under nitrogen protection. Precipitating with diethyl ether, filtering, cooling methanol, chloroform andwashing with ether to obtain the target product.
Yield: 68 percent; a purple solid; lambda [ alpha ]max(H2O,nm)(ε,104M-1cm-1)427(32.3),556(2.0),595(0.3)；1H NMR(400MHz；DMSO-d6):δ9.25(o-pyridyl andβ-pyrrole,m,16H),δ8.48(m-pyridyl,d,8H),δ8.37(Ar-H,d,4H),δ7.69(Ar-H,dd,4H),δ7.19(Ar-H,dd,4H),δ7.15(Ar-H,dd,4H),δ4.97(NΗ3，s,12H)，δ2.51(CH3,s,12H)。
Example 7: structural formula, yield, ultraviolet and nuclear magnetic data of target compound 7
Will contain a cisplatin prodrug ligand (PtC)6H14N2Cl244.4mg,0.129mmol) was dissolved in 3mL of N, N-dimethylformamide, silver nitrate (22mg,0.129mmol) was added, the reaction was carried out at 60 ℃ for 24 hours, and the precipitate was removed by filtration through a sand core funnel; gallium porphyrin mother nucleus (23mg,0.032mmol) was suspended in 3mL of N, N-dimethylformamide, and the above reaction solution was added dropwise to the suspension and reacted for 36 hours under nitrogen protection. Precipitating with diethyl ether, filtering, and washing with cold methanol, chloroform and diethyl ether to obtain the target product.
Yield: 60.5 percent; a purple solid; lambda [ alpha ]max(H2O,nm)(ε,104M-1cm-1)425(28.4),550(1.6),588(0.2)；1H NMR(400MHz；DMSO-d6):δ9.25(o-pyridyl andβ-pyrrole,m,16H),δ8.47(m-pyridyl,d,8H),δ4.97(NΗ3，s,12H)，δ4.51(NH3,s,12H)，δ2.67(CH2,d,16H),δ1.99(CH,m,8H),δ1.72(CH2,m,16H)。
Example 8: structural formula, yield, ultraviolet and nuclear magnetic data of target compound 8
The cisplatin-containing prodrug is preparedBody (PtC)8H18N2Cl256.8mg,0.129mmol) was dissolved in 3mL of N, N-dimethylformamide, silver nitrate (22mg,0.129mmol) was added, the reaction was carried out at 60 ℃ for 24 hours, and the precipitate was removed by filtration through a sand core funnel; cobalt porphyrin mother nucleus (21.6mg,0.032mmol) was suspended in 3mL of N, N-dimethylformamide, and the above reaction mixture was added dropwise to the suspension and reacted for 36 hours under nitrogen protection. Precipitating with diethyl ether, filtering, and washing with cold methanol, chloroform and diethyl ether to obtain the target product.
Yield: 71 percent; a purple solid; lambda [ alpha ]max(H2O,nm)(ε,104M-1cm-1)426(33.5),551(1.9),590(0.4)；1H NMR(400MHz；DMSO-d6):δ9.21(o-pyridyl andβ-pyrrole,m,16H),δ8.43(m-pyridyl,d,8H),δ5.33(CH,m,4H),δ 4.95(NΗ3，s,12H)，δ4.48(NH3,s,12H),δ3.57(CH,m,8H),δ2.72(CH2,m,16H),δ2.05(CH,m,4H),δ0.90(CH3,s,24H)。
Example 9: structural formula, yield, ultraviolet and nuclear magnetic data of target compound 9
Will contain a cisplatin prodrug ligand (PtC)6H14N2Cl273.5mg,0.192mmol) was dissolved in 3mL of N, N-dimethylformamide, silver nitrate (32.7mg,0.192mmol) was added and reacted at 60 ℃ for 24 hours, and the precipitate was removed by filtration with a sand core funnel; the silaporphyrin mother nucleus (21.7mg,0.032mmol) was suspended in 3mL of N, N-dimethylformamide, and the above reaction mixture was added dropwise to the suspension and reacted for 36 hours under nitrogen protection. Precipitating with diethyl ether, filtering, and washing with cold methanol, chloroform and diethyl ether to obtain the target product.
Yield: 65 percent; a purple solid; lambda [ alpha ]max(H2O,nm)(ε,104M-1cm-1)429(39.2),561(3.2),599(0.7)；1H NMR(400MHz；DMSO-d6):δ9.24(o-pyridyl,d,8H),9.06(β-pyrrole,s,8H),8.53(m-pyridyl,d,8H,J＝6.4Hz),6.69-5.77(NH2,m,24H),2.048(CH,m,12H),1.62-1.16(CH2,m,48H)。
The complex has physicochemical experiment and pharmacological experiment data, the numbers of various compounds in the experiment are consistent with those in the embodiment, and the corresponding structures and related analysis results are as follows:
table 1: structure, singlet oxygen yield and in vitro antitumor activity of complex
aSinglet oxygen yield in aqueous solution (mean ± SD of three replicates);
binhibition of Colon26 by drug at 100. mu.M concentration in mouse Colon cancer cells (mean. + -. SD of three replicates);
c'n.a.' means no activity, and the compound is defined as "no activity" means that the drug inhibits the enzyme less than 5% at a concentration of 100. mu.M.
Singlet oxygen yield: determination of singlet oxygen quantum yield (. PHI.) by photooxidation of steady-state photolysis of 9, 10-anthracenediyl-bis (methylene) dipropanedioic acid (ABDA)Δ). Rose Bengal (RB) is selected in the aqueous solution
As reference compound. ABDA solution (water, 2X 10) was placed in a 1cm quartz cuvette-4M) is mixed with a photosensitizer. An initial absorbance reading of the reaction mixture was taken at 380 nm. The kinetics of ABDA photooxidation was measured with the rate constant passing lnA0A linear least squares fit of the semi-logarithmic plot of/a to time. The singlet oxygen yield produced by the photosensitizer is calculated by the following equation:
wherein KRAnd KSThe kinetic slopes of the sample and reference compound ABDA, respectively. I isRAnd ISThe intensities of the absorbed light of the sample and the reference compound, respectively. The experiment was repeated three times.
Table 1 shows that the inventive complexes exhibit moderate to high levels of singlet oxygen quantum yield. The singlet oxygen quantum yield of the complex 4 is highest (phi)Δ0.82 ± 0.06), which means that 4 has considerable potential as a photosensitizer. Comparing 1, 2 and 3-9, it can be seen that the center insertion of metal can improve the singlet oxygen yield. Meanwhile, comparing 1, 3 and 2, 4 and 5-9, it is understood that the amount of peripheral platinum groups is increased, and the contribution to the singlet oxygen yield is large.
In vitro antitumor activity: colon26 cell line at 5X 103The density of each cell per well was seeded in 96-well plates. Cells were incubated with different concentrations of the complex and control drug for 24 hours. After a period of incubation, the complexes were removed by washing with PBS buffer and the medium was changed. The treatment was carried out with or without irradiation for 30 minutes using a red light lamp. Placing 96-well plates in CO2The culture was carried out in an incubator for 48 hours. Cell viability was determined by standard MTT assay with a microplate reader at absorbance 570 nm. All experiments were performed in dark and light conditions and repeated three times independently.
As shown in table 1, all complexes showed lower dark toxicity. After illumination, cell viability is greatly reduced, especially for complex 4, IC50The value was 0.06. mu.M. As can be seen from comparison of 1, 3 and 2, 4, 5-9, the antitumor activity was increased by the introduction of platinum group. Therefore, the coordination of the platinum group element to the porphyrin skeleton results in a large ΦΔAnd has great contribution to the cytotoxicity. Meanwhile, as can be seen from comparison of 1, 2 and 3, 4, the cytotoxic activity increased after the introduction of the metal element.
In vivo distribution experiments: three mice per group were dosed with complex 4. Major tissues and blood were collected at 2, 24 and 48 hours post-dose. The treated samples were analyzed for Pt content by ICP-AES monitoring.
As shown in fig. 1, after intravenous administration, the early stage is mainly distributed in spleen, kidney, liver and lung. After 24 hours, the platinum concentration in the blood decreased significantly. Since porphyrin-based photosensitizers can selectively accumulate in tumors, these porphyrins will be transported into tumor cells to play an important role because of the low density lipoprotein overexpression of cancer cells. Blood and muscle were chosen as references, and the tumor to blood and tumor to muscle ratios increased with time to reach 2.9 and 31.5, respectively, at 48 hours. While no significant accumulation was found compared to other organs.
Photodynamic therapy in animals: female BALB/c mice (5 weeks) were subcutaneously modeled with Colon26 tumor in the right and left shoulders, respectively. When the tumor volume reaches about 100mm3Mice were used for photodynamic therapy experiments. Group 1 mice were injected intravenously with complex 4 and group 2 mice served as controls. Each mouse in both groups was illuminated to tumors on the left shoulder and not the right shoulder. To assess toxic side effects, mouse body weights were measured.
As shown in fig. 2a, tumors on the shoulder of group 2 and the right shoulder of group 1 were not inhibited and showed similar growth rates. When the tumor volume in control group 2 was not significantly different between the left and right shoulders, indicating that illumination did not affect tumor growth only. There was no significant difference between the two groups of right tumors, so the cytotoxicity of complex 2 was not significant; however, the left tumors in group 4 disappeared on day 4 after complex 4-mediated PDT and remained without growth within 18 days (P < 0.05). Therefore, the complex can completely kill tumor cells. In the treatment group, mice did not have significant weight loss (less than 6%, fig. 2 b). All results show that the complex 2 can kill tumors in Colon26 tumor-bearing mice and is expected to become an effective medicament for future PDT clinical application.
Claims (2)
1. The water-soluble platinum-porphyrin complex is characterized in that the structural formula of the water-soluble platinum-porphyrin complex is as follows:
2. use of the complex according to claim 1 for the preparation of a medicament for photodynamic treatment of cancer.
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| Xiaojun Hu等，."Water-soluble metalloporphyrinates with excellent photo-induced anticancer activity resulting from high tumor accumulation".《Journal of Inorganic Biochemistry》.2017, * |
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