CN112442091B - Replication protein A targeted platinum compound - Google Patents
Replication protein A targeted platinum compound Download PDFInfo
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- CN112442091B CN112442091B CN201910831956.9A CN201910831956A CN112442091B CN 112442091 B CN112442091 B CN 112442091B CN 201910831956 A CN201910831956 A CN 201910831956A CN 112442091 B CN112442091 B CN 112442091B
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a replication protein A targeted platinum compound, which is a series of platinum anti-tumor compounds synthesized by combining tetravalent cisplatin with an RPA (replication protein A) small molecule inhibitor through an axial hydroxyl position and introducing an aliphatic hydrocarbon chain. The platinum anti-tumor compound has the advantages of inhibiting RPA activity and tumor specificity selection, thereby showing anti-tumor activity superior to that of the classical platinum drugs and potential for overcoming clinical platinum drug resistance.
Description
Technical Field
The invention belongs to the technical field of platinum compounds, and particularly relates to research on anti-tumor activity, toxic and side effect reduction and clinical platinum drug resistance of platinum compounds based on DNA damage repair.
Background
The malignant tumor threatens the health and life safety of human beings all the time, and has very important value and significance for the treatment and research of the malignant tumor. The development trend of the current novel antitumor drugs is to improve the targeting property, selectivity and safety of the chemotherapeutic drugs. Platinum drugs represented by Cisplatin (CDDP) play a crucial role in clinical tumor therapy (such as ovarian cancer and non-small cell lung cancer), and more than 50% of tumor chemotherapy requires the participation of platinum drugs. However, tumor resistance has greatly limited the development of this class of drugs. Over 80% of patients with epithelial ovarian cancer have tumor recurrence and failure due to platinum drug resistance.
As known from the molecular mechanism of action of platinum drugs, the action target of the platinum drugs is DNA, and the platinum drugs can be subjected to interchain or intrachain crosslinking with the DNA to form a DNA adduct, so that the DNA is damaged, the DNA replication and transcription are hindered, and finally the apoptosis is caused. Therefore, DNA damage repair is closely related to the chemotherapy effect and tumor resistance of platinum drugs. Research shows that the chemotherapy effect of platinum drugs can be greatly reduced by Nucleoside Excision Repair (NER) and homologous recombination repair (HR), so that the chemotherapy sensitivity of tumor cells to the platinum drugs can be further enhanced by selectively inhibiting the NER and the HR.
Replication Protein A (RPA) is a major single-stranded binding protein in eukaryotic cells, and comprises three subunits, namely RPA1, RPA2 and RPA3, and plays an important role in DNA replication and damage repair. When the DNA is replicated, the RPA has the functions of melting, combining a single-stranded template and maintaining continuous replication of the DNA; in the case of DNA damage, RPA plays an important role as an important DNA damage repair protein in repair processes such as Nucleotide Excision Repair (NER), DNA mismatch repair (MMR), and homologous recombination repair (HR). Meanwhile, RPA and protein with functions of maintaining, protecting and repairing chromosome structure are gathered at DNA damage sites, and detection and repair of DNA damage are completed together. Meanwhile, DNA damage homologous repair proteins Rad51 and Rad52 and RPA-ssDNA are cooperated to complete DNA damage repair. The effect of RPA on the repair mechanisms such as NER and HR, which results in decreased efficacy of platinum chemotherapeutic drugs and increased resistance of tumor cells (Shuck S C, turchi J. Targeted inhibition of RPA regenerative cytoxic activity, therapy with chemotherapeutic DNA damagings and infection in cellular function [ J ]. Cancer Research,2010,70 (8): 3189.). Recent findings of RPA inhibitors have led to the re-visualization of eosin in patients with malignant tumors. The combination of the RPA inhibitor and the platinum drugs has very important significance for improving the antitumor activity and the antitumor drug resistance.
Disclosure of Invention
Compared with clinical medicine cisplatin, the platinum antitumor compound (namely the novel platinum (IV) RPA inhibitor prodrug) of the invention shows in-vivo and in-vitro antitumor activity which is obviously superior to that of cisplatin, and has the advantages of reducing systemic toxicity and overcoming cisplatin resistance.
Combining RPA small molecule inhibitors with platinum drugs to form novel platinum (IV) RPA small molecule inhibitor prodrugs has the following advantages: (1) From the chemical structure, the novel platinum compound changes the polarity, log P, transmembrane transport rate and other physical and chemical properties of the prior compound, and further changes the uptake mode of a platinum drug to increase the platinum content in cells; meanwhile, the chemical inertness of Pt (IV) octahedron chemical configuration is used, so that the reactivity and toxicity of the platinum drugs are reduced, and synergistic molecules are reduced and released in cells, so that the curative effect of platinum chemotherapy is improved. (2) From the point of view of the target of action, RPA inhibitors block RPA-DNA interactions. In DNA replication, RPA inhibitors exploit the highly proliferative nature of cancer cells to arrest cells in S phase, thereby causing apoptosis. Therefore, the characteristics of targeting and cooperativity of the small-molecule inhibitor of the replication protein A are utilized, so that the repair of the platinum drug by a DNA repair mechanism is reduced, and the drug resistance of tumor cells to the platinum drugs is overcome.
The technical purpose of the invention is realized by the following technical scheme:
the platinum compound based on the RPA inhibitor (namely, the platinum compound targeted by the replication protein A) has the following chemical formula:
wherein R is 1 Is I or Br; r 2 Hydrogen atom, butyryl, hexanoyl, octanoyl, dodecanoyl, hexadecanoyl; n is 2 or 3. Preferably R 1 Is I; r is 2 Is a hydrogen atom or a hexanoyl group; n is 2 or 3.
For the purposes of this application, the target compound is synthesized from a tetravalent cisplatin prodrug as the parent, in combination with a small molecule inhibitor of RPA followed by an aliphatic chain at an axial position.
TDRL-505：R＝Br，n＝2；TDRL-550：R＝I，n＝2
TDRL-543：R＝Br，n＝3；TDRL-551：R＝I，n＝3
The preparation method of the platinum compound is carried out according to the following conditions: 1. preparation of substance 3 is obtained by reacting substance 2 with substance TDRL (e.g., TDRL-551, TDRL-550, TDRL-505, and TDRL-543), wherein TDRL is in excess relative to substance 2, substance TDRL and substance2 in a molar ratio of (1.1-1.2): 1, the reaction temperature is 50-60 ℃, preferably 55-60 ℃, the reaction time is 12-36h, preferably 18-24 h, the reaction process is carried out under the protection of inert protective gas (such as argon, nitrogen and helium) and a light-tight environment, magnetic stirring is selected, 200-300 revolutions per minute is carried out, an organic solvent is selected to provide a reaction environment for the substance 2 and the substance TDRL, and the solubility and the dispersibility of the substance 2 and the substance TDRL in the organic solvent are required to be considered, such as dimethyl sulfoxide, N' -dimethylformamide and tetrahydrofuran; after the reaction is finished, extracting to obtain a product in the reaction liquid, and removing the solvent, unreacted raw materials, the catalyst and impurities. Collecting dichloromethane layer, drying with anhydrous sodium sulfate, filtering, rotary evaporating, and performing thin layer chromatography (developing agent [ CH ] 2 Cl 2 :CH 3 OH]1) purification to give material 3
2. Preparation of substances 3a-3e are obtained by reacting substance 3 with a series of corresponding fatty acid anhydrides in a molar ratio of substance 3 to fatty acid anhydride of 1: (2-2.5). The reaction temperature is 45-55 ℃, preferably 50-55 ℃, the reaction time is 4-8h, preferably 6-8 h, the reaction is protected from light under the protection of inert protective gas (such as argon, nitrogen and helium), magnetic stirring is selected, 200-300 revolutions per minute is selected, an organic solvent is selected to provide a reaction environment for the substance 3 and a series of corresponding fatty acid anhydrides, and the solubility and the dispersibility of the substance 3 and the series of corresponding fatty acid anhydrides in the organic solvent need to be considered, such as dimethyl sulfoxide, N' -dimethylformamide, tetrahydrofuran (Muhammad N, sadia N, zhu C, et al, biotin-labeled platinum (IV) complex as target cytotoxic peptide antibody peptide nucleic acid molecules [ J ] of the reaction system]Chem.commu.2017: 10.1039.c7 cc05311h.). After the reaction is finished, removing DMF solvent by rotary evaporation, and performing thin layer chromatography (developing agent [ CH ] 2 Cl 2 :CH 3 OH]= 20) purification to give final product 3a-3e.
In the reaction, catalysts O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) and Triethylamine (TEA) can be selected and used, and the molar ratio of the substances TDRL to TBTU is 1:2, molar ratio of substance TDRL to triethylamine 1:4.
in the above technical solution, substance 2 is composed of cisplatin and 30% by volume 2 O 2 The aqueous solution is returned to 70-80 ℃ in the darkFlow stirring reaction generation, reaction time: 4-6h. The material TDRL is generated by refluxing and stirring an intermediate and glutaric anhydride in a chloroform solution at 60-70 ℃, and the reaction time is as follows: 3-4h. (Mishra AK, dormi S, turchi A M, et al chemical inhibitor targeting the replication protein A-DNA interactions inhibitors of the efficacy of Pt-based chemistry in lung and ovarian cancer [ J].Biochemical Pharmacology,2015,93(1):25-33.)。
The application of the platinum compound in preparing antitumor drugs. Compared with the prior art, the platinum compound has antitumor activity in cell lines such as HeLa, A549, NCI-H460 and the like which is obviously superior to that of classical platinum drugs such as cisplatin and the like. The platinum compound of the invention still maintains excellent antitumor activity in the NCI-H460/cis cisplatin-resistant cell line. The novel platinum (IV) RPA small-molecule inhibitor prodrug can inhibit DNA repair by two repair modes, namely NER (nucleotide excision repair) and HRR (homologous recombination repair) while causing DNA damage. In an in-vivo antitumor experiment, the invention has good antitumor activity and antitumor drug resistance, and simultaneously reduces the toxicity of platinum drugs.
Drawings
FIG. 1 is a NMR spectrum of substance 3 prepared in the example of the present invention.
FIG. 2 is a NMR carbon spectrum of substance 3 prepared in example of the present invention.
FIG. 3 is a liquid phase purity detection profile of substance 3 prepared in the example of the present invention.
FIG. 4 is a high resolution mass spectrum of substance 3 prepared in the example of the present invention.
FIG. 5 is a NMR spectrum of substance 3a prepared in example of the present invention.
FIG. 6 is a NMR carbon spectrum of substance 3a prepared in example of the present invention.
FIG. 7 is a liquid phase purity measurement chart of substance 3a prepared in the example of the present invention.
FIG. 8 is a NMR spectrum of substance 3b prepared in example of the present invention.
FIG. 9 is a NMR carbon spectrum of substance 3b prepared in example of the present invention.
FIG. 10 is a high-resolution mass spectrum of substance 3b prepared in the example of the present invention.
FIG. 11 is a liquid phase purity detection spectrum of substance 3b prepared in the example of the present invention.
FIG. 12 is a NMR spectrum of substance 3c prepared in example of the present invention.
FIG. 13 is a NMR carbon spectrum of substance 3c prepared in example of the present invention.
FIG. 14 is a liquid phase purity detection spectrum of substance 3c prepared in the example of the present invention.
FIG. 15 is a high resolution mass spectrum of substance 3c prepared in the example of the present invention.
FIG. 16 is a NMR spectrum of 3d substance prepared in example of the present invention.
FIG. 17 is a NMR carbon spectrum of material 3d prepared in an example of the invention.
FIG. 18 is a liquid phase purity detection profile of substance 3d prepared in the example of the present invention.
FIG. 19 is a NMR spectrum of substance 3e prepared in example of the present invention.
FIG. 20 is a NMR carbon spectrum of substance 3e prepared in example of the present invention.
FIG. 21 is a liquid phase purity detection profile of substance 3e prepared in the example of the present invention.
FIG. 22 is a NMR spectrum of substance 4 prepared in example of the present invention.
FIG. 23 is a NMR carbon spectrum of substance 4 prepared in example of the present invention.
FIG. 24 is a high resolution mass spectrum of substance 4 prepared in the example of the present invention.
FIG. 25 is a NMR spectrum of substance 5 prepared in example of the present invention.
FIG. 26 is a NMR carbon spectrum of substance 5 prepared in example of the present invention.
FIG. 27 is a high resolution mass spectrum of substance 5 prepared in the example of the present invention.
FIG. 28 is a NMR spectrum of substance 6 prepared in example of the present invention.
FIG. 29 is a NMR carbon spectrum of substance 6 prepared in example of the present invention.
FIG. 30 is a high resolution mass spectrum of substance 6 prepared in the example of the present invention.
FIG. 31 is a graphical representation of the results of 3b vs. cell cycle and apoptosis prepared in the examples of the invention.
FIG. 32 is a graph showing the results of in vivo antitumor experiments with 3b prepared in the examples of the present invention.
Detailed Description
The technical scheme of the invention is further explained by combining specific examples. The experimental apparatus was as follows: nuclear magnetic resonance analyzer, AVANCE III 400MHz, bruker, switzerland; high resolution mass spectrometry, agilent 6520Q-TOF LC/MS, agilent USA; high performance liquid chromatograph, SPD-20A, shimadzu corporation, japan; confocal laser microscopy, olympus FV-1000, japan; electronic analytical balance, sartorius BP211D, germany; a rotary evaporator, shanghai Shensheng science and technology, inc. R204; constant temperature magnetic stirrer, henan consolidated to Waals Instrument Co., ltd 85-2. The raw materials and reagents were as follows: cisplatin, shandong platinum source pharmaceutical Co., ltd, chemically pure; TBTU, tianjin sienss biochemical technologies ltd, chemically pure; 30% of H 2 O 2 Tianjin North-coupled chemical Co., ltd, chemically pure; ultra-dry N, N '-dimethylformamide and ultra-dry N, N' -dimethyl sulfoxide, welibos technologies ltd, chemically pure; dichloromethane, jindongtianzheng fine chemical reagent factory, tianjin, analytically pure; anhydrous ether, analytical pure, kang ke science and technology ltd, tianjin; methanol, kang ke de science co ltd, tianjin, pure in chromatography; human non-small cell lung cancer cell line a549, human non-small cell lung cancer cell line NCI-H460 and human cervical cancer cell line HeLa, ATCC, usa; human non-small cell lung cancer cell line NCI-H460cisR, beijing synergetics cell resource center; DMEM medium and RPMI 1640 medium, gibco, usa; fetal bovine serum, hyclone, USA.
Example 1 Synthesis and characterization of prodrugs based on a novel platinum class of Pt (IV) RPA Small molecule inhibitors, as shown in FIGS. 1-30
Accurately weighing cisplatin (100mg, 0.34mmol) in a 10mL round-bottomed flask, slowly adding 2mL dropwise and 30% H 2 O 2 The reaction solution was refluxed at 75 ℃ in the dark for 5 hours, and then left to stand in the dark at 4 ℃ overnight. After standing, the suspension was centrifuged to give a yellow solid precipitate, which was washed with distilled water, ethanol and ether and then dried under vacuum to give material 2 as 89mg of a yellow solid powder with a yield of 88.28%.
Accurately weighing the substance 2 (50.11mg, 0.15mmol) in a 25mL round-bottom flask, adding DMSO to dissolve, and stirring the reaction solution at 60 ℃ for 30min in the dark under the protection of argon until the solution is clear. Substances TDRL-551 (0.15 mmol) and TBTU (0.30 mmol) are accurately weighed, DMSO is added for dissolution, 70 mu L of triethylamine (0.6 mmol) is added into the reaction solution, ultrasonic reaction is carried out for 30min at room temperature, and the reaction solution is added into a substance 2 round-bottom flask for reaction. The reaction solution is stirred for 12 hours at 60 ℃ in the dark under the protection of argon gas to obtain a reddish brown clear liquid. Washing the reaction solution with water, and performing centrifugal separation to obtain a light yellow solid precipitate. The precipitate was purified by thin layer chromatography using dichloromethane-methanol (15). Yield: 45.5mg, yield: 33.4%, purity: 97.16 percent. 1 H NMR(400MHz,DMSO-d 6 ,ppm),δ7.96(d,J＝8.9Hz,1H),7.83(d,J＝8.4Hz,1H),7.59(d,J＝8.4Hz,1H),7.33(d,J＝2.1Hz,1H),7.25(dd,J＝9.0,2.3Hz,1H),6.29-5.75(m,4H),4.19(q,J＝6.9Hz,1H),3.97(dd,J＝18.0,12.1Hz,1H),3.21(dd,J＝28.3,5.2Hz,1H),2.86(dtd,J＝30.5,15.4,7.5Hz,1H),2.26(t,J＝7.3Hz,1H),1.91-1.71(m,1H),1.39(t,J＝6.9Hz,1H)； 13 C NMR(101MHz,DMSO-d 6 ,ppm):δppm 181.21,170.98,160.97,154.22,148.77,138.18,131.13,130.58,129.97,129.24,122.66,120.86,107.24,97.89,64.30,41.06,36.46,33.58,21.63,15.02.HR-MS(ESI,positive-ion mode)，m/z:calcd for C 25 H 29 Cl 3 IN 5 O 5 Pt[M+H] + :905.9927；found:905.9911.
Accurately weighing substance 3 (30mg, 0.033mmol) and placing in a 25mL round-bottom flask, adding DMF to dissolve until the solution is clear, adding butyric anhydride (10.80 mu L,0.066 mmol) into the solution, and reacting for 24h at 45 ℃ in the dark under the protection of argon to obtain a light yellow solution. After the reaction is finished, DMF is removed by rotary evaporation, and the product is purified by thin-layer chromatography to obtain a light yellow solid powder of the substance 3 a. Yield: 20.10mg, yield: 59.11%, purity: 96.14 percent. 1 H NMR(400MHz,DMSO-d 6 ,ppm)δ7.95(d,J＝9.0Hz,1H),7.84(d,J＝8.3Hz,1H),7.59(d,J＝8.3Hz,1H),7.34(d,J＝1.9Hz,1H),7.25(dd,J＝9.0,2.2Hz,1H),6.56(s,3H),5.83(dd,J＝12.0,5.2Hz,1H),4.18(q,J＝6.8Hz,1H),3.97(dd,J＝18.1,12.2Hz,1H),3.36-3.18(m,3H),3.03-2.66(m,2H),2.33(t,J＝7.3Hz,1H),2.20(t,J＝7.3Hz,1H),1.89-1.70(m,1H),1.47(dd,J＝14.7,7.3Hz,1H),1.39(t,J＝6.9Hz,2H),0.87(t,J＝7.4Hz,2H). 13 C NMR(101MHz,DMSO-d 6 ,ppm)δ180.76,180.36,170.20,160.33,153.68,148.13,137.54,130.45,129.94,129.31,128.60,122.02,120.25,106.57,97.38,63.66,62.05,40.41,37.61,35.00,32.74,20.73,18.83,14.39,13.66.
Accurately weighing substance 3 (30mg, 0.033mmol) and placing in a 25mL round bottom flask, adding DMF to dissolve, stirring to be clear, adding hexanoic anhydride (15.20 μ L,0.066 mmol) into the solution, and stirring under argon protection at 45 ℃ for 24h in dark to obtain a light yellow solution. After the reaction is finished, DMF is removed by rotary evaporation, and the product is purified by thin-layer chromatography to obtain the substance 3b light yellow solid powder with the yield: 23.30mg, yield: 63.96%, purity: 98.68 percent. 1 H NMR(400MHz,DMSO-d 6 ,ppm)δ7.95(d,J＝9.1Hz,1H),7.84(d,J＝8.5Hz,1H),7.59(d,J＝8.5Hz,1H),7.34(d,J＝2.3Hz,1H),7.25(dd,J＝9.0,2.4Hz,1H),6.88-6.33(m,3H),5.83(dd,J＝12.0,5.3Hz,1H),4.18(q,J＝6.9Hz,1H),4.04-3.85(m,1H),3.28(dd,J＝18.1,5.2Hz,1H),2.88(tdd,J＝23.4,15.6,7.5Hz,1H),2.33(t,J＝7.4Hz,1H),2.21(t,J＝7.5Hz,1H),1.90-1.70(m,1H),1.56-1.43(m,1H),1.39(d,J＝7.0Hz,1H),1.26(dd,J＝7.1,3.9Hz,2H),0.86(t,J＝6.9Hz,1H). 13 C NMR(101MHz,DMSO-d 6 ,ppm)δ180.87,180.37,170.32,170.20,160.23,153.60,148.02,137.54,130.63,129.93,129.21,128.55,121.91,120.55,106.92,97.59,63.66,35.94,35.65,32.85,31.12,24.80,22.00,20.65,14.39,13.74.HR-MS(ESI)m/z calcd for C 31 H 40 Cl 3 IN 5 O 6 Pt[M+H] + :1006.07156,found:1006.07227.
Accurately weighing substance 3 (30mg, 0.033mmol), placing in a 25mL round bottom flask, adding DMF to dissolve, stirring to clarify, adding caprylic anhydride (19.61 μ L,0.066 mmol) to the solution, stirring under argon protection at 45 deg.C in the dark for 24h, and turning the solution into light yellow solution. After the reaction is finished, DMF in the reaction solution is removed by rotary evaporation, and the mixture is purified by thin-layer chromatography to obtain a substance 3c light yellow solid powder, wherein the yield is as follows: 20.5mg, yield: 61.75%, purity: 97.96 percent. 1 H NMR(400MHz,DMSO-d 6 ,ppm)δ7.95(d,J＝9.0Hz,1H),7.84(d,J＝8.3Hz,1H),7.59(d,J＝8.3Hz,1H),7.34(s,1H),7.26(d,J＝8.9Hz,1H),6.56(s,2H),5.95-5.76(m,1H),4.35-4.07(m,1H),3.97(dd,J＝18.0,12.1Hz,1H),3.28(dd,J＝18.2,5.1Hz,1H),3.07-2.75(m,1H),2.33(t,J＝7.1Hz,1H),2.21(t,J＝7.4Hz,1H),1.89-1.70(m,1H),1.44(d,J＝6.9Hz,1H),1.39(t,J＝6.9Hz,1H),1.24(s,3H),0.86(t,J＝6.5Hz,1H). 13 C NMR(101MHz,DMSO-d 6 ,ppm)δ180.86,170.20,160.33,153.68,148.13,137.54,130.44,128.61,122.02,106.57,97.39,63.65,40.08,39.87,39.66,39.45,39.25,39.04,38.83,35.65,32.74,31.18,28.56,25.42,22.07,20.72,14.39,13.96.HR-MS(ESI)m/z calcd for C 33 H 44 Cl 3 IN 5 O 6 Pt[M+H] + :1034.10293,found:1034.10339.
Accurately weighing substance 3 (30mg, 0.033mmol) and placing in a 25mL round-bottom flask, adding DMF to dissolve, stirring until the solution is clear, adding dodecanoic anhydride (25.25mg, 0.066 mmol) into the solution, and stirring for 24h at 45 ℃ in the dark under the protection of argon to obtain a light yellow solution. And (3) after the reaction is finished, performing rotary evaporation to remove DMF in the reaction solution, and purifying by using a thin-layer chromatography to obtain a substance 3d light yellow solid powder, wherein the yield is as follows: 20.5mg, yield: 63.94%, purity: 96.54 percent. 1 H NMR(400MHz,DMSO-d 6 ,ppm)δ7.95(d,J＝9.0Hz,1H),7.84(d,J＝8.4Hz,1H),7.59(d,J＝8.4Hz,1H),7.34(d,J＝2.1Hz,1H),7.25(dd,J＝9.0,2.3Hz,1H),6.56(s,3H),5.83(dd,J＝12.0,5.2Hz,1H),4.18(q,J＝6.8Hz,1H),3.97(dd,J＝18.0,12.1Hz,1H),3.28(dd,J＝18.1,5.1Hz,1H),3.01-2.74(m,1H),2.33(t,J＝7.3Hz,1H),2.21(t,J＝7.4Hz,1H),1.94-1.74(m,1H),1.45(s,1H),1.40(dd,J＝13.5,6.6Hz,2H),1.23(s,8H),0.85(t,J＝6.7Hz,2H). 13 CNMR(101MHz,DMSO-d 6 ,ppm)δ180.87,180.36,170.19,160.33,153.66,148.13,137.54,130.44,129.92,129.30,128.59,122.01,120.24,106.56,97.37,63.65,35.67,35.01,32.75,31.28,29.04,29.02,28.97,28.92,28.71,28.61,25.43,22.08,20.73,14.39,13.95.
Accurately weighing substance 3 (30mg, 0.033mmol) and placing in a 25mL round-bottom flask, adding DMF to dissolve, stirring to be clear, adding palmitic anhydride (32.65mg, 0.066 mmol) into the solution, and stirring for 24h at 45 ℃ in the dark under the protection of argon to obtain a light yellow solution. And (3) after the reaction is finished, performing rotary evaporation to remove DMF in the reaction solution, and purifying by using a thin-layer chromatography to obtain a substance 3e light yellow solid powder, wherein the yield is as follows: 26.0mg, yield: 68.73%, purity: 98.84 percent. 1 H NMR(400MHz,DMSO-d 6 ,ppm)δ7.96(d,J＝8.8Hz,1H),7.84(d,J＝8.1Hz,1H),7.59(d,J＝8.2Hz,1H),7.34(s,1H),7.26(d,J＝9.0Hz,1H),6.63(d,J＝61.2Hz,3H),5.83(dd,J＝12.0,5.0Hz,1H),4.19(d,J＝6.9Hz,1H),3.97(dd,J＝17.7,12.1Hz,1H),3.45(s,1H),3.28(dd,J＝18.1,5.0Hz,1H),3.06-2.72(m,1H),2.33(t,J＝7.0Hz,1H),2.21(t,J＝7.3Hz,1H),1.89-1.75(m,1H),1.45(s,1H),1.41(dd,J＝16.5,9.7Hz,2H),1.23(s,11H),0.85(t,J＝6.3Hz,1H). 13 CNMR(101MHz,DMSO-d 6 ,ppm)δ181.37,180.87,170.70,160.83,154.16,148.64,138.04,130.95,129.09,122.51,120.74,107.06,97.87,64.15,58.05,42.75,36.17,33.24,31.77,29.54,29.49,29.19,25.94,22.58,21.23,14.89,14.45.
Accurately weighing substance 2 (50.11mg, 0.15mmol) in a 25mL round-bottom flask, adding DMSO to dissolve, stirring the reaction solution at 60 ℃ under the protection of argon in the dark for 30min, and enabling the solution to become colorless and clear. And accurately weighing substances TDRL-543 (0.15 mmol) and TBTU (0.30 mmol), adding DMSO for dissolving, adding 70 mu L of triethylamine into the reaction solution, carrying out ultrasonic oscillation reaction for 30min at room temperature, adding the reaction solution into the substance 2 solution, and stirring the reaction bottle for 12h at 60 ℃ in a dark place under the protection of argon to obtain a reddish brown clear liquid. Washing the reaction solution with water, and performing centrifugal separation to obtain a light yellow solid precipitate. Thin layer chromatography purification using dichloromethane-methanol (15. Yield: 38.3mg, yield: 29.7 percent. 1 H NMR(400MHz,DMSO-d 6 ,ppm)δ7.96(d,J＝8.5Hz,1H),7.75(d,J＝8.3Hz,1H),7.66(d,J＝8.4Hz,1H),7.33(s,1H),7.25(d,J＝8.9Hz,1H),6.21-5.77(m,4H),4.19(dd,J＝13.8,6.8Hz,1H),3.98(dd,J＝18.0,12.1Hz,1H),3.22(dd,J＝36.5,4.9Hz,1H),2.98-2.73(m,1H),2.27(t,J＝7.2Hz,1H),1.82(dd,J＝14.8,7.5Hz,1H),1.39(t,J＝6.9Hz,2H)； 13 C NMR(101MHz,DMSO-d 6 ，ppm)δ180.81,170.58,160.55,160.16,153.59,148.35,131.93,130.45,129.55,128.93,123.90,122.24,120.44,106.83,63.87,48.78,40.71,36.05,33.16,21.22,14.59；HR-MS(ESI,positive-ion mode)m/z:calcd for C 25 H 29 BrCl 3 N 5 O 5 Pt[M+H] + :858.0065；found:858.0107.
Accurately weighing substance 2 (50.11mg, 0.15mmol) in a 25mL round-bottom flask, adding DMSO to dissolve, stirring the reaction solution at 60 ℃ under the protection of argon in the dark for 30min, and enabling the solution to become colorless and clear. And accurately weighing substances TDRL-505 (0.15 mmol) and TBTU (0.30 mmol), adding DMSO to dissolve, adding 70 mu L of triethylamine into the reaction solution, performing ultrasonic oscillation reaction for 30min at room temperature, adding the reaction solution into the substance 2 solution, and stirring the reaction bottle for 12h at 60 ℃ in a dark place under the protection of argon to obtain a reddish brown clear liquid. Washing the reaction solution with water, and performing centrifugal separation to obtain a light yellow solid precipitate. Purification by thin layer chromatography using dichloromethane-methanol (13. Yield: 35.2mg, yield: 27.7 percent. 1 H NMR(400MHz,DMSO-d 6 ,ppm)δ8.02(s,1H),7.91(d,J＝8.9Hz,1H),7.73(d,J＝8.3Hz,2H),7.66(d,J＝8.2Hz,2H),7.33(s,1H),7.25(d,J＝8.9Hz,1H),6.27-5.67(m,7H),4.18(d,J＝6.9Hz,2H),3.99(dd,J＝17.8,12.2Hz,1H),3.27(s,1H),3.03(d,J＝44.8Hz,2H),2.55(d,J＝7.1Hz,1H),1.39(t,J＝6.8Hz,3H)； 13 C NMR(101MHz,DMSO-d 6 ,ppm)δ180.12,170.06,160.32,153.47,148.14,134.96,133.29,131.74,130.24,129.87,129.26,128.65,123.70,122.07,120.22,106.71,63.67,57.50,40.60,31.19,29.90,14.37；HR-MS(ESI,positive-ion mode)m/z:calcd for C 24 H 27 BrCl 3 N 5 O 5 Pt[M+H] + :843.9099；found:843.9970.
Accurately weighing substance 2 (50.11mg, 0.15mmol) in a 25mL round-bottom flask, adding DMSO to dissolve, stirring the reaction solution at 60 ℃ for 30min in the dark under the protection of argon, and enabling the solution to become colorless and clear. And accurately weighing substances TDRL-550 (0.15 mmol) and TBTU (0.30 mmol), adding DMSO to dissolve, adding 70 μ L triethylamine into the reaction solution, ultrasonically shaking at room temperature for 30min, adding the reaction solution into the substance 2 solution, and stirring the reaction bottle at 60 ℃ under the protection of argon in the dark for 12h to obtain a red brown clear liquid. Washing the reaction solution with water, and performing centrifugal separation to obtain a light yellow solid precipitate. With dichloromethane-methanol (1)3) as a developing solvent, and purifying by thin-layer chromatography to obtain a substance 6 which is light yellow solid powder. Yield: 34.8mg, yield: 25.9 percent. 1 H NMR(400MHz,DMSO-d 6 ,ppm)δ8.01(s,1H),7.91(d,J＝9.0Hz,1H),7.83(d,J＝8.3Hz,2H),7.57(d,J＝8.3Hz,2H),7.33(s,1H),7.26(d,J＝8.9，2.2Hz,1H),6.32-5.70(m,7H),4.18(d,J＝6.9Hz,2H),3.98(dd,J＝17.9,12.1Hz,1H),3.27(dd,J＝18.1,5.2Hz,1H),3.15-2.87(m,2H),2.62-2.52(m,1H),1.39(t,J＝6.9Hz,3H)； 13 C NMR(101MHz,DMSO-d 6 ,ppm)δ180.34,170.27,160.56,153.97,148.38,137.83,130.71,130.09,129.52,128.80,122.30,120.52,106.86,97.58,63.92,57.66,40.74,36.03,31.35,30.08,14.65；HR-MS(ESI,positive-ion mode)m/z:calcd for C 24 H 27 Cl 3 IN 5 O 5 Pt[M+H] + :891.9770；found:891.9813.
Example 2 evaluation of antitumor Activity of Compound (3 a-3 e) and cisplatin
The MTT colorimetric method is one of the methods for detecting the growth and survival of cells in experimental research. In mitochondria of living cells, exogenous MTT can be reduced to formazan, a crystal substance which is purple blue and difficult to dissolve in water, by succinate dehydrogenase in cells, and formazan is deposited in cytoplasm of cells, but dead cells do not have the phenomenon. When formazan encounters DMSO, formazan deposited in cells will be dissolved by DMSO. Detecting formazan optical density (OD value) at 570nm wavelength with enzyme labeling instrument to indirectly reflect the number of living cells, positively correlating the amount of MTT crystal with the number of living cells, and processing data with Graphpad Prism 6 software to calculate IC 50 Value and plot, IC 50 Values refer to the half inhibitory concentration of the drug being measured on cell growth. The experimental result shows that the antitumor activity of the novel platinum (IV) RPA small-molecule inhibitor prodrug is obviously superior to that of classical platinum drugs such as cisplatin in cell lines such as HeLa, A549, NCI-H460 and the like as shown in the following table. The novel platinum (IV) RPA small molecule inhibitor prodrug still maintains excellent antitumor activity in cis-platinum resistant cell lines such as NCI-H460cisR and the like. The series of prodrugs and cisplatin of the invention acted on IC for 72h in different cell lines 50 Value of a
a IC 50 Values ± standard deviation (μ M) were obtained from a fitted dose-response curve by a one-half dilution method with triplicate wells per group, repeated 1 time, dosed incubation for 72 h. b FI (multiple of growth) is IC 50 (CDDP) and IC 50 (substance 3 b). c RF (chemical resistance coefficient) IC 50 (NCI-H460 cisR) and IC 50 (NCI-H460). b FI (multiple of growth) is IC 50 (CDDP) and IC 50 (substance 3). e ND, not determined.
Example 3
We use cell cycle, apoptosis experiments to verify the antitumor activity of the novel platinum (IV) RPA small molecule inhibitor prodrug of the invention. The cell cycle refers to the process from the completion of one mitosis to the end of the next mitosis for a cell. It can be divided into three phases: G0/G1 phase, S phase, G2/M phase. The G0/G1 phase is the preparation phase of mitosis, and the synthesis of RNA and related proteins is doubled, thus preparing for the synthesis of genetic material DNA; the S phase is a DNA synthesis phase, and all DNA synthesis is completed in the S phase; the G2/M phase is a protein synthesis and mitosis phase, and the synthesized chromosome and other components are evenly distributed into two newly formed daughter cells, and the processes are repeated to realize the proliferation of the cells. The cell cycle has very important significance in the regulation and control of cell proliferation and apoptosis.
As shown in FIGS. 31 and 32, the results of cell cycle experiments show that the number of cells distributed in G2 and S phases of the novel platinum (IV) RPA small molecule inhibitor prodrug of the invention shows an increasing trend along with the increasing concentration of the substance 3b (0.1-10 μ M); meanwhile, the proportion of cells in the G1 phase gradually decreases. This shows that after the drug action, in the cell cycle process, the cells are gathered in the G2 phase and the S phase, the substance 3b can block the HeLa cells in the G2 phase and the S phase, the substance 3b mainly blocks the S phase of the tumor cells under the concentration of 1 μ M in the treatment group, and the substance is converted into the G2 phase block under the concentration of 10 μ M. Cycle arrest was more pronounced for HeLa cells with 3b compared to the control. The apoptosis experimental result shows that compared with cisplatin as a control group, and mono-substitution (3) and combined medication (551 + Pt), the apoptosis rate of the substance 3b in the treatment group is obviously increased, the apoptosis rate of the treatment group is obviously increased along with the increase of the administration concentration, and the apoptosis area is mainly concentrated in the late withering area. This shows that the novel platinum (IV) RPA small molecule inhibitor prodrug 3b can effectively induce apoptosis of HeLa cells.
Example 4
The evaluation of the in vivo antitumor activity and the anti-drug resistance activity of the novel platinum (IV) RPA small molecule inhibitor prodrug is further researched through an in vivo antitumor experiment. The method comprises the following steps of taking 4-year nude mice as experimental animals, constructing nude mice subcutaneous transplantation tumor models by using human tumor cell strains (HeLa) with relatively sensitive in vitro activity, randomly grouping the nude mice with tumors after the models are successfully constructed, carrying out tail vein injection administration, observing and recording animal weight and tumor volume, maintaining the experiment for 4 weeks, killing the experimental animals by adopting a cervical vertebra dislocation method after the experiment is finished, collecting tumor tissues and main organs, and using the tumor tissues and the main organs for HE staining and action mechanism analysis. The experimental result shows that in six experimental models of PBS, CDDP,551+ Pt, TDRL-551, substance 3 and substance 3b, through a 24-day experimental period, compared with other groups, the substance 3b treatment group has an obvious tumor inhibition effect, and the tumor volumes of four groups of nude mice of PBS, TDRL-551,551+ Pt and substance 3 are in an overall ascending trend. Although the CDDP administration group also has obvious tumor inhibiting effect, the weight loss of nude mice in the CDDP group is too obvious. Therefore, the CDDP compound generates large toxic and side effects on the nude mice.
The preparation of the platinum compound can be realized by adjusting the process parameters according to the content of the invention, and the platinum compound has anticancer performance basically consistent with the embodiment. The invention being thus described by way of example, it should be understood that any simple alterations, modifications or other equivalent alterations as would be within the skill of the art without the exercise of inventive faculty, are within the scope of the invention.
Claims (10)
1. The replication protein A targeted platinum compound is characterized by having a structure shown as the following chemical formula:
wherein R is 1 Is I or Br; r is 2 Is hydrogen atom, butyryl, hexanoyl, octanoyl, dodecanoyl or hexadecanoyl; n is 2 or 3.
2. The replication protein a-targeted platinum-based compound of claim 1, wherein R is 1 Is I; r is 2 Is a hydrogen atom, a hexanoyl group; n is 2 or 3.
3. The preparation method of the platinum compound with the replication protein A targeting is characterized in that a tetravalent cisplatin prodrug is used as a matrix, an RPA small molecular inhibitor and an aliphatic chain are combined successively at an axial position to synthesize a target compound, and the preparation method is carried out according to the following conditions:
substance 3
(1) Preparation of substance 3 is obtained by reacting substance 2 with substance TDRL, wherein substance TDRL is in excess with respect to substance 2 and the molar ratio of substance TDRL to substance 2 is (1.1-1.2): 1, the reaction temperature is 50-60 ℃, the reaction time is 12-36h, the reaction process is carried out under the protection of inert protective gas and in a dark environment, and n is 2 or 3;
substance 2
(2) Preparation of substances 3a-3 e: obtained by reacting substance 3 with a series of corresponding fatty acid anhydrides in a molar ratio of substance 3 to fatty acid anhydrides of 1: (2-2.5), reacting for 4-8h at the reaction temperature of 45-55 ℃ in the dark under the protection of inert protective gas;
4. the method for preparing the replication protein A-targeted platinum compound as claimed in claim 3, wherein in the preparation of the substance 3, the reaction temperature is 55-60 ℃, the reaction time is 18-24 h, and the inert protective gas is argon, nitrogen or helium; magnetic stirring is selected, 200-300 revolutions per minute.
5. The method of claim 3, wherein the organic solvent used in the preparation of substance 3 is dimethylsulfoxide, N' -dimethylformamide, or tetrahydrofuran.
6. The method for preparing replication protein A targeted platinum compound according to claim 3, wherein in the preparation of the substance 3, catalysts O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate and triethylamine are used, and the molar ratio of the substances TDRL and O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate is 1:2, the molar ratio of substances TDRL and triethylamine is 1:4.
7. the method of claim 3, wherein substance 2 is prepared from cisplatin and 30% by volume H 2 O 2 The aqueous solution is generated by refluxing and stirring reaction at 70-80 ℃ in the dark for 4-6h.
8. The method for preparing the replication protein A targeted platinum compound as claimed in claim 3, wherein in the preparation of the substances 3a to 3e, the reaction temperature is 50 to 55 ℃, the reaction time is 6 to 8 hours, and the inert protective gas is argon, nitrogen or helium; magnetic stirring is selected, and 200-300 revolutions per minute are carried out; the organic solvent is dimethyl sulfoxide, N' -dimethylformamide or tetrahydrofuran.
9. Use of the replication protein a-targeted platinum compound of claim 1 or 2 in the preparation of an anti-tumor medicament.
10. The use of claim 9, wherein the neoplasm is lung cancer or cervical cancer.
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