WO2013086804A1 - 四吡啶基卟啉桥联十字形四核铂配合物及其制备方法和抗肿瘤活性 - Google Patents
四吡啶基卟啉桥联十字形四核铂配合物及其制备方法和抗肿瘤活性 Download PDFInfo
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- WO2013086804A1 WO2013086804A1 PCT/CN2012/071443 CN2012071443W WO2013086804A1 WO 2013086804 A1 WO2013086804 A1 WO 2013086804A1 CN 2012071443 W CN2012071443 W CN 2012071443W WO 2013086804 A1 WO2013086804 A1 WO 2013086804A1
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- bridged
- tetrapyridylporphyrin
- platinum
- tetranuclear
- platinum complex
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 100
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 230000000259 anti-tumor effect Effects 0.000 title abstract description 15
- DWJFGGVNPNGBBN-UHFFFAOYSA-N N1C=2C=C(N=3)C=CC=3C=C(N3)C=CC3=CC(=N3)C=CC3=CC1=CC=2C1=CC=NC=C1 Chemical compound N1C=2C=C(N=3)C=CC=3C=C(N3)C=CC3=CC(=N3)C=CC3=CC1=CC=2C1=CC=NC=C1 DWJFGGVNPNGBBN-UHFFFAOYSA-N 0.000 title abstract 2
- 238000010668 complexation reaction Methods 0.000 title 1
- 239000003446 ligand Substances 0.000 claims abstract description 26
- 238000001338 self-assembly Methods 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 7
- 229940079593 drug Drugs 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 3
- 229910002651 NO3 Inorganic materials 0.000 claims abstract description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims abstract description 3
- SBTXZBOBSRZUPE-UHFFFAOYSA-N 5,10,15,20-tetrapyridin-2-yl-21,23-dihydroporphyrin Chemical compound c1cc2nc1c(-c1ccccn1)c1ccc([nH]1)c(-c1ccccn1)c1ccc(n1)c(-c1ccccn1)c1ccc([nH]1)c2-c1ccccn1 SBTXZBOBSRZUPE-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000002246 antineoplastic agent Substances 0.000 claims description 11
- 229940041181 antineoplastic drug Drugs 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 8
- 239000003560 cancer drug Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000002244 precipitate Substances 0.000 claims description 7
- 238000005119 centrifugation Methods 0.000 claims description 6
- DNZSHSJERXNJGX-UHFFFAOYSA-N chembl3040240 Chemical compound C1=CC(C(=C2C=CC(N2)=C(C=2C=CN=CC=2)C=2C=CC(N=2)=C(C=2C=CN=CC=2)C2=CC=C3N2)C=2C=CN=CC=2)=NC1=C3C1=CC=NC=C1 DNZSHSJERXNJGX-UHFFFAOYSA-N 0.000 claims description 6
- 150000003057 platinum Chemical class 0.000 claims description 6
- 238000006298 dechlorination reaction Methods 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims description 4
- 206010038038 rectal cancer Diseases 0.000 claims description 4
- 201000001275 rectum cancer Diseases 0.000 claims description 4
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 201000006585 gastric adenocarcinoma Diseases 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims description 2
- 230000003127 anti-melanomic effect Effects 0.000 claims description 2
- 208000025848 malignant tumor of nasopharynx Diseases 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 108091081406 G-quadruplex Proteins 0.000 abstract description 7
- 206010028980 Neoplasm Diseases 0.000 abstract description 6
- 201000011510 cancer Diseases 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 3
- 230000008685 targeting Effects 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 210000004881 tumor cell Anatomy 0.000 abstract description 2
- 108700020796 Oncogene Proteins 0.000 abstract 1
- 108010017842 Telomerase Proteins 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000004294 195Pt NMR spectroscopy Methods 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical group N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 229930002875 chlorophyll Natural products 0.000 description 1
- 235000019804 chlorophyll Nutrition 0.000 description 1
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000005291 magnetic effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 1
- -1 porphyrin compounds Chemical group 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Definitions
- the present invention relates to a type of tetranuclear platinum complex which utilizes supramolecular self-assembly to synthesize tetrapyridylporphyrin bridged and has excellent antitumor activity, and a preparation method thereof, and particularly relates to tetranuclear platinum having a cross structure The preparation method of the complex and its antitumor activity.
- G-quadruplex DNA Since G-quadruplex DNA has been found to be a potential anti-tumor target, designing new anti-cancer drugs targeting G-quadruplex DNA is an important frontier in the research of cancer-targeted therapeutic drugs in recent years. one. Although small progress has been made in small molecule stabilizers for G-quadruplex DNA, how to obtain ligands/complexes of small molecule G-quadruplex DNA with higher affinity and selectivity is still A huge challenge for chemists and biologists. Metal complexes have many advantages that are difficult to compare with small organic molecules, such as rigid-flexible geometrical changes and rich electrochemical properties, as well as optical, magnetic and catalytic properties.
- the metal complex in addition to the II-II accumulation of G-quadruplex DNA, the metal complex can stabilize the G-quadruplex structure by forming a covalent bond with the base or the phosphate backbone. Achieve anti-tumor effects. This has led to the constant search for suitable anti-tumor drugs in metal complexes.
- the bridging ligand tetrapyridylporphyrin is a kind of conjugated skeleton macrocyclic compound formed by the connection of four pyrrole rings through a pyridylmethyl group, which ensures that the complex has a unique geometric configuration-cross structure.
- porphyrin compounds form the core of biological macromolecules such as hemoglobin, cytochrome and chlorophyll, and participate in a series of important processes in the organism.
- Metalloporphyrins not only have unique biological activities, but also have a special affinity with cancer cells and are used as anticancer drugs in medicine.
- the present invention synthesizes a tetranuclear platinum complex bridged by tetrapyridylporphyrin by supramolecular self-assembly, which has high anticancer activity and targeting property.
- the invention designs a class of tetranuclear platinum complexes with tetrapyridylporphyrin as bridging ligand and cross structure, systematically summarizes the antitumor effect of the complex, and lays a theoretical foundation for the development of new antitumor metal drugs. .
- the antitumor drug provided by the present invention is a tetrapyridylporphyrin bridged cruciform tetranuclear platinum complex formed by self-assembly of supramolecules, and the structural formula is as shown in Formula I:
- the preparation method of the tetrapyridylporphyrin bridged cruciform tetranuclear platinum complex is to assemble a monodentate platinum ligand and a bridging ligand, tetrapyridylporphyrin, by supramolecular self-assembly.
- the tetrapyridylporphyrin bridges the cross-type tetranuclear platinum complex, so that the complex has high antitumor activity.
- the synthesis method is prepared by using supramolecular self-assembly and the planar configuration of Pt(II) and the unique geometry of the intermediate bridging ligand tetrapyridylporphyrin.
- 1 represents the structural formula of the bridged ligand tetrapyridylporphyrin
- 2 represents the structural formula of the monodentate platinum ligand in which the chloride ion is replaced by nitrate
- 3 represents the quadruplex of the product tetrapyridylporphyrin bridge.
- Step (1) The temperature of low temperature centrifugation can be 3-6 ° C
- Step (2) The molar ratio of the tetrakis(4-pyridyl)porphyrin TPyP to the step (1) monodentate platinum ligand is 0.2:1 0.25:1.
- Step (2) After the reaction is completed, the reaction solution is concentrated under reduced pressure, and a mixed solvent of anhydrous ethanol and anhydrous diethyl ether is added, and a purple precipitate appears immediately; the solid substance is obtained by centrifugation, and dried under vacuum to obtain a tetrapyridylporphyrin bridge. Cross-shaped tetranuclear platinum complex.
- Tetrapyridylporphyrin bridged cruciform tetranuclear platinum complex tetra(4-pyridyl)porphyrin TPyP having a molar ratio of 0.25 times that of a monodentate platinum ligand is dissolved in an appropriate amount of trifluoro Ethanol was added dropwise to the above dechlorinated supernatant. After the addition is completed, trifluoroethanol is added to the system until the solution is clear and transparent without turbidity. The whole reaction is protected by nitrogen at 60 degrees and protected from light for 2-4 days. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and an appropriate amount of anhydrous ethanol and anhydrous diethyl ether are added to stand. A purple precipitate appeared. The solid matter was obtained by centrifugation and dried under vacuum to obtain a tetrapyridylporphyrin bridged cruciform tetranuclear platinum complex.
- the tetrapyridylporphyrin bridged cruciate tetranuclear platinum complex obtained by the present invention can be applied to the preparation of an anticancer drug.
- anticancer drugs may be anti-colorectal cancer drugs, anti-gas adenocarcinoma drugs, anti-melanoma cancer drugs, anti-nasopharynx cancer drugs or anti-rectal cancer drugs.
- the invention synthesizes and characterizes a series of tetrapyridyl ruthenium having a cross configuration by a supramolecular self-assembly method using a simple and easy monodentate platinum ligand as a prosthetic ligand and a bridging ligand tetrapyridylporphyrin. Porphyrin bridged tetranuclear platinum complex.
- HCT-8 human colorectal cancer cells
- BGC-823 human gastric adenocarcinoma cells
- A375 human melanoma cancer cells
- KB human nasopharyngeal carcinoma cells
- HT-29 human rectal cancer cells
- Example 1 The compound prepared in Example 1 was subjected to the following test:
- the cell lines used in this experiment are as follows: Human colorectal cancer cells (HCT-8), human gastric adenocarcinoma cells (BGC-823), human melanoma cancer cells (A375), human nasopharyngeal carcinoma cells (KB) and human rectal cancer cells (HT-29).
- the cells were cultured in DMEM medium containing 10% fetal bovine serum containing 100 units of penicillin per ml and 100 micrograms of streptomycin.
- the cells were seeded in a 10 cm diameter dish and cultured in a 37-degree, 5% C0 2 environment. When the cells are full, they are passaged by trypsinization.
- Cytotoxicity test Cytotoxicity was determined by the MTT method. The cells were digested with 0.25% trypsin to form a single cell suspension, and the number of viable cells was counted using a hematocrit plate. The viable cell concentration was adjusted to 5 ⁇ 10 4 per ml. Inoculated in a 96-well culture plate, 160 ⁇ L per well, cultured for 24 hours. After that, different concentrations of trinuclear platinum complexes were added, placed at 37 degrees, incubated in an incubator containing 5% C0 2 for 48 hours, and added to MTT 20 ⁇ l per well 4 hours before the end, and discarded 4 hours later.
- % survival average OD value of the drug well / average OD value of the control well X 100%.
- the tetrapyridyl bridged tetranuclear platinum complex obtained in the above examples was used for screening of various tumor cells, indicating that the complex has excellent antitumor activity.
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- 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
本发明公开了一种具有十字形结构的四核铂配合物及其制备方法，以及其用于制备治疗人癌症的药物的用途。所述配合物通过将氯离子被硝酸根取代的单齿铂配体与桥联配体四吡啶基卟啉进行自组装而制备得到。该制备方法简单易行，成本较低，在一般化学实验室均可完成，生产过程对环境无污染。所述配合物具有优异的肿瘤细胞靶向性，诱导癌基因的富G序列形成G-四联体结构，抑制端粒酶的活性，具有很高的抗肿瘤活性。
Description
技术领域
[0001] 本发明涉及一类利用超分子自组装来合成四吡啶基卟啉桥联的且具有优异抗肿瘤活 性的四核铂配合物及其制备方法， 具体涉及具有十字型结构的四核铂配合物的制备方法及其 抗肿瘤活性。
背景技术
[0002] 自从人们发现 G-四链体 DNA是潜在的抗肿瘤靶标以来， 以 G-四链体 DNA为靶点设 计新抗癌药物， 是近年来癌症靶向治疗药物研究中的重要前沿领域之一。 尽管 G-四链体 DNA 的小分子稳定剂取得了很大的进展， 但是如何获得亲和能力更高、 选择性更好的小分 子 G-四链体 DNA 的配体 /配合物， 依然是化学家和生物学家面临的一个巨大的挑战。 由于 金属配合物具有很多有机小分子难以比拟的优点， 如刚柔相济的几何结构变化和丰富的电化 学性质， 同时还具有光学、 磁学以及催化等多种性能。 在结合模式方面， 金属配合物除了能 与 G-四链体 DNA通过 II - II堆积作用外， 还能通过与碱基或者磷酸根骨架形成共价键的方 式稳定 G-四链体结构， 进而达到抗肿瘤的效果。 这均使得人们不断在金属配合物里寻找合 适的抗肿瘤药物。
[0003] 铂类配合物作为抗肿瘤药物的研究开始于二十世纪六十年代， 在顺铂基础上铂类似 物的设计合成与抗肿瘤活性筛选一直是抗肿瘤药物研究领域的热点。 结构不同的各种铂类配 合物其抗肿瘤活性也有高低之分， 造成这种活性的差异与配合物结构的亲脂性有重要关系。 而动力学惰性的 Pt(II)配位构型为正方形， 为我们下一步的自组装提供了一个模板。
[0004] 桥联配体四吡啶基卟啉是一类由四个吡咯环通过吡啶次甲基相连形成的共轭骨架大 环化合物， 保证配合物具有一类独特的几何构型-十字型结构。 在自然界， 卟啉化合物构成 了血红蛋白、 细胞色素及叶绿素等生物大分子的核心部分， 参与生物体内一系列重要过程。 金属卟啉不仅具有独特的生物活性， 而且与癌细胞有特殊的亲和力， 在医学上用作抗癌药 物。
[0005] 本发明通过超分子自组装合成以四吡啶基卟啉为桥联的四核铂配合物， 使其具有高 的抗癌活性以及靶向性。
发明内容
[0006] 本发明目的是提供具有抗肿瘤活性的四吡啶基卟啉桥联十字形四核铂配合物。
[0007] 本发明的另一个目的在于提供该十字形四核铂配合物的制备方法及其在制备抗肿瘤 药物中的应用。 发明通过设计出一类以四吡啶基卟啉为桥联配体且具有十字型结构的四核铂 配合物， 系统的总结该配合物的抗肿瘤效果， 为发展新型抗肿瘤金属药物奠定理论基础。
[0008] 本发明提供的抗肿瘤药物， 是利用超分子自组装而成的四吡啶基卟啉桥联十字形四 核铂配合物， 结构通式如式 I所示：
式 I
j, sl
[0009] 其反应通式如下：
一、 四吡啶基卟啉桥联的四核铂配合物的合成：
1 2
反应式中， 1 表示桥联配体四吡啶基卟啉的结构式， 2 表示氯离子被硝酸根取代的单齿铂配 体的结构通式， 3表示产物四吡啶基卟啉桥联的四核铂配合物的结构通式；
反应步骤概述如下：
四吡啶基卟啉桥联的四核铂配合物的制备：
( 1 ) 单齿铂配体脱氯： 将单齿铂配体溶于水中再加入硝酸银， 在氮气保护下避光反应 24-48 小时， 低温离心， 弃去沉淀， 保留清液；
(2) 四吡啶基卟啉桥联的十字形四核铂配合物的制备： 将四 (4-吡啶基)卟啉 TPyP溶解于三 氟乙醇中， 逐滴滴加入步骤 （1 ) 脱氯后的清液中； 滴加完毕后再往体系中补加三氟乙醇至 溶液呈澄清透明没有浑浊产生， 整个反应在氮气的保护下， 于 60-80度避光反应 2-4天； 反 应结束后， 浓縮、 沉淀、 到四吡啶基卟啉桥联的十字形四核铂配合物；
其中步骤 （1 ) 低温离心的温度可以为 3-6°C
步骤 （2) 所述的四 (4-吡啶基)卟啉 TPyP与步骤 （1 ) 单齿铂配体的摩尔比为 0.2:1 0.25:1。 步骤 （2) 反应完毕后， 减压浓縮反应液， 加入无水乙醇和无水乙醚的混合溶剂， 立刻出现 紫色沉淀； 离心得到固体物质， 真空干燥， 即得到四吡啶基卟啉桥联的十字形四核铂配合 物。
[0010] 优选的制备方法如下：
( 1 ) 单齿铂配体脱氯： 将单齿铂配体溶于适量的水中再加入等量的硝酸银， 在氮气保护下 避光反应 24-48小时， 用低温离心机离心， 弃去沉淀， 保留清液。
[0011] (2) 四吡啶基卟啉桥联的十字形四核铂配合物： 将摩尔比为单齿铂配体 0.25倍的四 (4-吡啶基)卟啉 TPyP溶解于适量的三氟乙醇， 逐滴滴加入上述脱氯后的清液中。 滴加完毕 后再往体系中补加三氟乙醇至溶液呈澄清透明没有浑浊产生， 整个反应在氮气的保护下， 于 60度避光反应 2-4天。 反应完毕后， 减压浓縮反应液， 加入适量的无水乙醇和无水乙醚， 立
刻出现紫色沉淀。 离心得到固体物质， 真空干燥， 即得到四吡啶基卟啉桥联的十字形四核铂 配合物。
[0012] 本发明所获得的四吡啶基卟啉桥联十字形四核铂配合物， 可以应用于制备抗癌药 物。 这些抗癌药物可以为抗结直肠癌药物、 抗胃腺癌药物、 抗黑素瘤癌药物、 抗鼻咽癌药物 或抗直肠癌药物。
[0013] 本发明的技术效果：
本发明以简单易合的单齿铂配体为辅基配体与桥联配体四吡啶基卟啉， 通过超分子自组装的 方法合成和表征了一系列具有十字构型的四吡啶基卟啉桥联的四核铂配合物。 通过对人结直 肠癌细胞 (HCT-8)、 人胃腺癌细胞 (BGC-823)、 人黑素瘤癌细胞 (A375)、 人鼻咽癌细胞 (KB)以 及人直肠癌细胞 (HT-29)的 MTT筛选， 得到的数据表明该类化合物具有优异的抗肿瘤活性。 具体实施方式
[0014] 以下结合实施例对本发明进行详细的描述。
[0015] 实施例 1四吡啶基卟啉桥联的十字形四核铂配合物的制备：
将 0.40毫摩尔量的 DPA铂 (II)配合物溶于 15毫升水中， 在氮气保护下于暗处加入 0.40毫摩 尔量的硝酸银， 60°C搅拌 36小时， 反应完毕后， 离心弃去沉淀， 保留清液。 将 0.10毫摩尔 的四 (4-吡啶基)卟啉溶于 10 毫升的三氟乙醇， 逐滴滴加至上述清液当中， 滴加完毕后补加 10毫升的三氟乙醇， 确保没有浑浊出现。 反应液在氮气保护下于 60度避光反应 2天。 反应 结束后， 减压浓縮反应液至 5毫升， 加适量的无水乙醇和无水乙醚， 立即析出紫色固体， 离 心得紫色固体， 产物真空干燥。 产率: 85%。 元素分析(％)。 理论值： C88H78N28024Pt4 · 8¾0 (2836.2): C, 37.27; H, 3.34; N, 13.83. 实验值： C, 37.51; H, 3.48; N, 13.85. 195Pt NMR (D20, δ /ppm): -794.85, and K2PtCl4被用作内标物（ δ =0).
采用实施例 1制备的化合物进行如下试验：
细胞系以及培养条件： 本实验所用的细胞系如下： 人结直肠癌细胞 (HCT-8)、 人胃腺癌细胞 (BGC-823) , 人黑素瘤癌细胞 (A375)、 人鼻咽癌细胞 (KB)以及人直肠癌细胞 (HT-29)。 细胞用 含 10%胎牛血清的 DMEM培养基培养， 其中含有每毫升 100单位青霉素和 100 微克链霉 素， 细胞接种于直径为 10 厘米 的培养皿后， 37度、 5% C02环境中培养， 细胞长满时用胰 蛋白酶消化法进行传代。
[0016] 细胞毒性测试： 细胞毒性采用 MTT法测定 。 将细胞用 0.25%胰蛋白酶消化成单细胞 悬液， 采用血球计算版进行活细胞数， 调整活细胞浓度为 5 X 104每毫升接种于 96孔培养 板， 每孔 160 微升， 培养 24小时之后， 再分别加入不同浓度的三核铂配合物， 置 37度， 在含 5% C02的培养箱中孵育 48小时， 于结束前 4小时加入 MTT 20微升每孔， 4小时后弃 上清液， 加入 DMSO 100微升每孔， 振荡 10分钟左右， 置酶标仪测定 OD值， 波长设置为 570 纳米和 607 纳米双波长。 按下列公式计算存活率， 同时作图并求得半数杀伤浓度 (IC50) , 评价药物的细胞毒性。
[0017] 存活率％=加药孔平均 OD值 /对照孔平均 OD值 X 100%。
[0018] 结果如表 1所示。
[0019] 表 1. 实施例 1的十字形四核铂配合物对各种癌细胞的 /C5。值
上述实施例获得的产物四吡啶基桥联的四核铂配合物， 用于各种肿瘤细胞的筛选， 表明该配 合物具有优异的抗肿瘤活性。
Claims
权 利 要 求 书
配合物， 其特征在于结构通式如式 I所示:
式 I
2. 如权利要求 1 所述的四吡啶基卟啉桥联十字形四核铂配合物的制备方法， 其特征在于是 利用超分子自组装， 将单齿铂配体， 与桥联配体即四吡啶基卟啉， 组装成四吡啶基卟啉桥联 十字型四核铂配合物。
3. 如权利要求 1 所述的四吡啶基卟啉桥联十字形四核铂配合物的制备方法， 其特征在于反 应通式如下：
四吡啶基卟啉桥联的四核铂配合物的合成：
1 2 3
反应式中， 1 表示桥联配体四吡啶基卟啉的结构式， 2 表示氯离子被硝酸根取代的单齿铂配 体的结构通式， 3表示产物四吡啶基卟啉桥联的四核铂配合物的结构通式。
4. 根据权利要求 3 所述的四吡啶基卟啉桥联的十字形四核铂配合物的制备方法， 其特征在 于反应步骤如下：
四吡啶基卟啉桥联的四核铂配合物的制备：
( 1 ) 单齿铂配体脱氯： 将单齿铂配体溶于水中再加入硝酸银， 在氮气保护下避光反应 24-48 小时， 低温离心， 弃去沉淀， 保留清液；
(2) 四吡啶基卟啉桥联的十字形四核铂配合物的制备： 将四 (4-吡啶基)卟啉 TPyP溶解于三 氟乙醇中， 逐滴滴加入步骤 （1 ) 脱氯后的清液中； 滴加完毕后再往体系中补加三氟乙醇至 溶液呈澄清透明没有浑浊产生， 整个反应在氮气的保护下， 于 60-100 度避光反应 2-4 天； 反应结束后， 浓縮、 沉淀、 到四吡啶基卟啉桥联的十字形四核铂配合物。
5. 如权利要求 4所述的制备方法， 其特征在于步骤 （1 ) 所述的低温离心的温度为 3-6°C。
6. 如权利要求 4所述的制备方法， 其特征在于步骤 （2) 所述的四 (4-吡啶基)卟啉 TPyP与步 骤 ( 1 ) 单齿铂配体的摩尔比为 0.20:1 0.25:1。
7. 如权利要求 4所述的制备方法， 其特征在于步骤 （2) 所述的反应完毕后， 减压浓縮反应 液， 加入无水乙醇和无水乙醚的混合溶剂， 立刻出现紫色沉淀； 离心得到固体物质， 真空干 燥， 即得到四吡啶基卟啉桥联的十字形四核铂配合物。
8. 如权利要求 1 所述的四吡啶基卟啉桥联十字形四核铂配合物在制备抗癌药物方面的应 用。
9. 如权利要求 1 所述的应用， 其特征在于所述的抗癌药物为抗结直肠癌药物、 抗胃腺癌药 物、 抗黑素瘤癌药物、 抗鼻咽癌药物或抗直肠癌药物。
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| WO2015191797A1 (en) * | 2014-06-11 | 2015-12-17 | Board Of Regents, The University Of Texas System | Texaphyrin-pt(iv) conjugates and compositions for use in overcoming platinum resistance |
| KR102053750B1 (ko) * | 2018-07-27 | 2019-12-09 | 건국대학교 산학협력단 | 신규한 나프탈이미드-포르피린 유도체, 이를 포함하는 수은 이온 검출용 조성물 및 이를 이용한 수은 이온 검출 방법 |
| KR20190141901A (ko) * | 2018-06-15 | 2019-12-26 | 건국대학교 산학협력단 | 다양한 치환기를 갖는 신규한 포르피린 유도체, 이를 포함하는 시안 이온 검출용 조성물 및 이를 이용한 시안 이온 검출 방법 |
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| CN108066340B (zh) * | 2016-11-10 | 2020-10-27 | 中国科学院化学研究所 | 药物组合物 |
| CN108066341B (zh) * | 2016-11-10 | 2020-10-30 | 中国科学院化学研究所 | 化合物在制备抗癌药物中的用途 |
| CN109251206B (zh) * | 2018-09-21 | 2022-02-08 | 上海大学 | 水溶性铂-卟啉配合物及其制备方法 |
| CN109678905B (zh) * | 2018-12-22 | 2020-06-12 | 吉林大学 | 一种配位驱动的自组装超分子笼、制备方法及其应用 |
| CN109481696B (zh) * | 2018-12-22 | 2020-10-02 | 吉林大学 | 用于癌症光动力治疗和化学治疗的药物及其制备方法 |
| CN110330499A (zh) * | 2019-07-30 | 2019-10-15 | 北京科技大学 | 一种多吡啶功能基团修饰卟啉ttpp的制备方法及应用 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015191797A1 (en) * | 2014-06-11 | 2015-12-17 | Board Of Regents, The University Of Texas System | Texaphyrin-pt(iv) conjugates and compositions for use in overcoming platinum resistance |
| CN106572991A (zh) * | 2014-06-11 | 2017-04-19 | 德克萨斯州大学系统董事会 | 用于克服铂耐受性的德克萨卟啉‑pt(iv)缀合物及组合物 |
| US10406167B2 (en) | 2014-06-11 | 2019-09-10 | Board Of Regents, The University Of Texas System | Texaphyrin-Pt(IV) conjugates and compositions for use in overcoming platinum resistance |
| US11389459B2 (en) | 2014-06-11 | 2022-07-19 | Board Of Regents, The University Of Texas System | Texaphyrin-Pt(IV) conjugates and compositions for use in overcoming platinum resistance |
| KR20190141901A (ko) * | 2018-06-15 | 2019-12-26 | 건국대학교 산학협력단 | 다양한 치환기를 갖는 신규한 포르피린 유도체, 이를 포함하는 시안 이온 검출용 조성물 및 이를 이용한 시안 이온 검출 방법 |
| KR102119011B1 (ko) | 2018-06-15 | 2020-06-04 | 건국대학교 산학협력단 | 다양한 치환기를 갖는 신규한 포르피린 유도체, 이를 포함하는 시안 이온 검출용 조성물 및 이를 이용한 시안 이온 검출 방법 |
| KR102053750B1 (ko) * | 2018-07-27 | 2019-12-09 | 건국대학교 산학협력단 | 신규한 나프탈이미드-포르피린 유도체, 이를 포함하는 수은 이온 검출용 조성물 및 이를 이용한 수은 이온 검출 방법 |
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