WO2013086803A1 - 一种具有y型结构的三核铂配合物及其对人胃腺癌细胞的靶向性 - Google Patents
一种具有y型结构的三核铂配合物及其对人胃腺癌细胞的靶向性 Download PDFInfo
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- WO2013086803A1 WO2013086803A1 PCT/CN2012/071437 CN2012071437W WO2013086803A1 WO 2013086803 A1 WO2013086803 A1 WO 2013086803A1 CN 2012071437 W CN2012071437 W CN 2012071437W WO 2013086803 A1 WO2013086803 A1 WO 2013086803A1
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- ligand
- platinum complex
- trinuclear
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 107
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 51
- 201000006585 gastric adenocarcinoma Diseases 0.000 title claims abstract description 18
- 230000008685 targeting Effects 0.000 title description 8
- 239000003446 ligand Substances 0.000 claims abstract description 38
- 230000000694 effects Effects 0.000 claims abstract description 10
- 229910002651 NO3 Inorganic materials 0.000 claims abstract description 7
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 7
- 238000001338 self-assembly Methods 0.000 claims abstract description 7
- 229940079593 drug Drugs 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- 238000006298 dechlorination reaction Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002244 precipitate Substances 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
- 238000005119 centrifugation Methods 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- GPTONYMQFTZPKC-UHFFFAOYSA-N sulfamethoxydiazine Chemical compound N1=CC(OC)=CN=C1NS(=O)(=O)C1=CC=C(N)C=C1 GPTONYMQFTZPKC-UHFFFAOYSA-N 0.000 claims 1
- 108091081406 G-quadruplex Proteins 0.000 abstract description 7
- CBMYFVSIIYILRH-UHFFFAOYSA-N 2,4,6-tri-4-pyridyl-1,3,5-triazine Chemical compound C1=NC=CC(C=2N=C(N=C(N=2)C=2C=CN=CC=2)C=2C=CN=CC=2)=C1 CBMYFVSIIYILRH-UHFFFAOYSA-N 0.000 abstract 1
- 108700020796 Oncogene Proteins 0.000 abstract 1
- 108010017842 Telomerase Proteins 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 23
- 206010028980 Neoplasm Diseases 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 150000003057 platinum Chemical class 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 3
- 208000015634 Rectal Neoplasms Diseases 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 206010038038 rectal cancer Diseases 0.000 description 3
- 201000001275 rectum cancer Diseases 0.000 description 3
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 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
- 238000002474 experimental method Methods 0.000 description 2
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 2
- 238000012216 screening Methods 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
- 230000004083 survival effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000004294 195Pt NMR spectroscopy Methods 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 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
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000005291 magnetic effect Effects 0.000 description 1
- 239000002609 medium 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
- 239000000047 product Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three 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 invention relates to a trinuclear platinum complex which utilizes supramolecular self-assembly to synthesize organic hybrids and has excellent activity and targeting resistance against human gastric adenocarcinoma cells, and a preparation method thereof, in particular to a trinuclear platinum complex having a Y-type structure.
- a method for preparing a compound and its targeting to human gastric adenocarcinoma cells is referred to a trinuclear platinum complex which utilizes supramolecular self-assembly to synthesize organic hybrids and has excellent activity and targeting resistance against human gastric adenocarcinoma cells.
- the metal complex in addition to the ⁇ - ⁇ stacking of the 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.
- Platinum complexes as antitumor drugs began in the 1960s. The design and synthesis of platinum analogs on the basis of cisplatin has been a hot spot in the field of antitumor drugs. Various platinum complexes with different structures have high antitumor activity At low points, the difference in activity is related to the lipophilicity of the complex structure.
- the kinetically inert Pt(II) coordination configuration is square, providing a template for our next self-assembly.
- the bridging ligand is a series of nitrogen-containing heterocycles that ensure that the complex has a unique geometric configuration, the Y-type structure.
- the present invention has a high anticancer activity and targeting property by supramolecular self-assembly of an organic hybrid trinuclear platinum complex.
- the object of the present invention is to design a trinuclear platinum complex (organic hybrid trinuclear platinum complex) having a Y-type structure, systematically summarizing the anti-tumor effect of the complex, and laying a foundation for developing a novel anti-human gastric adenocarcinoma metal drug. Theoretical basis.
- the invention provides a trinuclear platinum complex having a Y-type structure, and has the structural formula
- the invention also provides a method for synthesizing a trinuclear platinum complex having a Y-type structure, which is a mononuclear ⁇ -type structure by using a supramolecular self-assembly to assemble a pro-ligand ligand and a bridging ligand to obtain an excellent anti-human gastric adenocarcinoma.
- a cell-active organic hybrid trinuclear platinum complex is a monodentate platinum ligand in which chloride ions are replaced by nitrate (the chloride ion is replaced by nitrate)
- the formula of Formula 1 the structural formula of the monodentate platinum ligand in which the ⁇ is substituted by nitrate
- the formula 2 represents the structural formula of the bridged ligand
- the formula 3 represents the structural formula of the trinuclear platinum complex of the final product
- X in Formula 2 and Formula 3 represents C or N.
- the light-proof reaction time of the de-chlorination process of the monodentate platinum ligand is 24 hours; the temperature of the low-temperature centrifugation is 3-6 degrees Celsius.
- the molar ratio of the bridged ligand to the dechlorinated monodentate platinum complex is 0.28:1 to 0.3:1.
- the preferred synthetic process is as follows:
- Monodentate platinum ligand [Pt(NH 3 ) 2 Cl 2 ] dechlorination Dissolve monodentate platinum ligand in an appropriate amount of water and add an equimolar amount of silver nitrate. Protect from light for 24 hours under nitrogen protection. Centrifuge the centrifuge, discard the precipitate, and keep it clear.
- Y-type structure trinuclear platinum complex A bridged ligand having a molar ratio of 0.3:1 was added to the night after dechlorination. The whole reaction is protected from nitrogen at 80-100 degrees for 2-3 days under the protection of nitrogen. After the reaction is completed, an appropriate amount of absolute ethanol is added, and then washed with the solvent for 2-5 times, and centrifuged to obtain a solid substance, that is, organic impurities. A trinuclear platinum complex.
- the trinuclear platinum complex having the Y-type structure provided by the present invention can be further developed and improved to be used for preparing an anticancer drug. It may be a drug against human gastric adenocarcinoma, human colorectal cancer, human melanoma cancer, human nasopharyngeal cancer, human rectal cancer, and the like. Especially suitable for, but not limited to Preparation of anti-human gastric adenocarcinoma drugs.
- the present invention synthesizes and characterizes a series of trinuclear Pt(II) complexes with Y configuration by a supramolecular self-assembly method using a simple and easy monodentate platinum ligand as a prosthetic ligand and a corresponding bridging ligand. Things.
- HCT-8 human colorectal cancer cells
- BGC-823 human gastric adenocarcinoma cells
- BGC-823 human melanoma cancer cells
- A375 human nasopharyngeal carcinoma cells
- HT-29 human rectal cancer cells
- Example 1 Preparation of a trinuclear platinum complex having a Y-type structure:
- 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 MTT assay. 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. Clear the solution, add DMSO 100 ⁇ l per well, shake for 10 minutes.
- the OD value was measured by a microplate reader, and the wavelength was set to 570 nm and 607 nm dual wavelength.
- the survival rate was calculated according to the following formula, and the cytotoxicity of the drug was evaluated by plotting and obtaining a half killing concentration (/Go).
- Survival rate % average OD value of the dosing hole / average OD value of the control well ⁇ 100%.
- the product organic hybrid Y-structured trinuclear platinum complex obtained in the above examples is used for screening various tumor cells, and has anti-multiple cancer cell activity, especially excellent anti-human gastric adenocarcinoma activity and targeting. Sex.
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- 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)
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Abstract
本发明公开了一种具有Y型结构的三核铂配合物及其制备方法，以及其用于制备治疗人胃腺癌药物的用途。所述配合物通过将氯离子被硝酸根取代的铂配体[Pt（NH3）2Cl（NO3）]与桥联配体（2，4，6-tri（pyridin-4-yl）-1，3，5-triazine）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。所述配合物能特异性识别人胃腺癌细胞，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，具有很高的抗人胃腺癌活性。
Description
一种具有 Y型结构的三核铂配合物及其对人胃腺癌细胞的靶向性 技术领域
本发明涉及一类利用超分子自组装来合成有机杂化且具有优异 抗人胃腺癌细胞活性及靶向性的三核铂配合物及其制备方法，具体涉 及具有 Y型结构的三核铂配说合物的制备方法及其对人胃腺癌细胞的 靶向性。
背景技术 书
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 π-π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。
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， 为我们下一歩的自组装提供 了一个模板。
桥联配体是一系列含氮的杂环，保证配合物具有一类独特的几何 构型 --Y型结构。
本发明通过超分子自组装有机杂化三核铂配合物，使其具有高的 抗癌活性以及靶向性。
发明内容
本发明目的是设计出一类具有 Y型结构的三核铂配合物 （有机 杂化三核铂配合物）， 系统的总结该配合物的抗肿瘤效果， 为发展新 型抗人胃腺癌金属药物奠定理论基础。
本发明提供了一种具有 Y型结构的三核铂配合物， 结构通式如
发明同时提供了该具有 Y型结构的三核铂配合物的合成方法， 是利用超分子自组装将辅基配体与桥联配体组装成三核 Υ型结构， 得到具有优异抗人胃腺癌细胞活性的有机杂化三核铂配合物；所述辅 基配体是氯离子被硝酸根取代的单齿铂配体（氯离子被硝酸根取代的 辟
'冃单齿铂配体 [Pt(NH3)2(N03)Cl] ); 所述桥联配体的结构式为
式中的 X表示 C或 N
以反应通式来表示为
1 2 3
反应式中， 式 1表; ί子被硝酸根取代的单齿铂配体的结构式， 式 2 表示桥联配体的结构通式， 式 3表示最终产物三核铂配合物的结构通 式； 其中式 2和式 3中的 X表示 C或N。
( 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 摩尔量的硝酸银， 在氮气保护下避光反应， 低温离心， 弃去沉淀，保 留清夜。
(2) Y型结构三核铂配合物： 往上述脱氯后的清夜中加入桥联 配体进行反应； 整个反应在氮气的保护下， 于 80-100度避光反应 2-3 天。
其中歩骤 （1 ) 中， 单齿铂配体脱氯过程的避光反应时间为 24小 时； 低温离心的温度为 3-6摄氏度。
歩骤 （2) 中， 加入的桥联配体与已脱氯的单齿铂配合物的摩尔 比为 0.28:1〜0.3:1。 歩骤（2)所述反应完毕后， 加入无水乙醇洗涤 2-5 次， 离心得到固体物质， 即所述具有 Y型结构的三核铂配合物。
优选的合成过程如下：
单齿铂配体 [Pt(NH3)2Cl2]脱氯： 将单齿铂配体溶于适量的水中再 加入等摩尔量的硝酸银， 在氮气保护下避光反应 24小时， 用低温离心 机离心， 弃去沉淀， 保留清夜。
Y型结构三核铂配合物： 往上述脱氯后的清夜中加入摩尔比为 0.3:1的桥联配体。整个反应在氮气的保护下，于 80-100度避光反应 2-3 天， 反应完毕后， 加入适量的无水乙醇， 再用该溶剂洗涤 2-5次， 离 心得到固体物质， 即有机杂化三核铂配合物。
本发明所提供的具有 Y型结构的三核铂配合物， 可进一歩发展、 改良进而应用于制备抗癌药物。 可以是抗人胃腺癌、 人结直肠癌、人 黑素瘤癌、 人鼻咽癌、 人直肠癌等的药物。 尤其适用于， 但不局限于
制备抗人胃腺癌药物。
与现有技术相比本发明的技术效果：
本发明以简单易合的单齿铂配体为辅基配体与相应的桥联配体， 通过超分子自组装的方法合成和表征了一系列具有 Y构型的三核 Pt(II)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， 得到的数据表明其具有抗多种癌细胞的 活性， 尤其具有优异的抗人胃腺癌细胞活性及靶向性。
具体实施方式
以下结合实施例对本发明进行详细的描述。
实施例 1 ： 具有 Y型结构的三核铂配合物的制备：
Y型结构三核铂配合物的合成 (I): 将 0.5毫摩尔量的顺铂溶于 6毫 升水中， 在氮气保护下于暗处加入 0.49毫摩尔量的硝酸银， 40°C搅拌 24小时， 反应完毕后， 离心弃去沉淀， 保留清夜； 往上述的清液中加 入 0.15毫摩尔的桥联配体， 整个反应在氮气保护下于 90度避光反应 3 天，反应结束后，往反应液中加入适量的无水乙醇，析出浅黄色固体， 离心得浅黄色固体， 产物真空干燥。 产率: 83%。 元素分析(％：)， 理论值： Ci8H37N15Cl3O12.5Pt3-3.5H2O (1355.17): C, 15.95; H, 2.75; N, 15.50. 实验值： C, 16.00; H, 2.77; N, 15.46. 195Pt NMR (D20, δ/ppm): -676, and K2PtCl4被用作内标物 (δ=0).
实施例 2 ： 抗肿瘤活性的实验：
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。
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（/Go), 评价 药物的细胞毒性。
存活率％ =加药孔平均 OD值 /对照孔平均 OD值 χ 100%。
结果如表 1所示。
表 1. 实施例 1的三核铂配合物对各种癌细胞的 /G。值
上述实施例获得的产物有机杂化 Y型结构三核铂配合物， 用于各 种肿瘤细胞的筛选， 其具有抗多种癌细胞的活性， 尤其具有优异的抗 人胃腺癌细胞活性及靶向性。
Claims
权 利 要 求 书
种具有 Y型结构的三核铂配合物， 其特征在于结构通式如
其中 X表示 C或N。
2、 根据权利要求 1所述的具有 Y型结构的三核铂配合物的合成方 法，其特征在于利用超分子自组装将辅基配体与桥联配体组装成三核 结构， 得到具有优异抗人胃腺癌活性的有机杂化三核铂配合物； 所述 辅基配体是氯离子被硝酸根取代的单齿铂配体；所述桥联配体的结构 式为：
其中 X表示 C或N。
3、 根据权利要求 1所述的具有 Y型结构的三核铂配合物的合成方 法， 其特征在于反应通式为：
1 2 3
反应式中， 式 1表示氯离子被硝酸根取代的单齿铂配体的结构式， 式 2 表示桥联配体的结构通式， 式 3表示最终产物三核铂配合物的结构通 式； 其中式 2和式 3中的 X表示 C或 Ν.:.
4、 根据权利要求 2或 3所述的具有 Υ型结构的三核铂配合物的合 成方法， 其特征在于反应歩骤如下：
( 1 ) 单齿铂配体脱氯： 将单齿铂配体溶于水中再加入等摩尔的 硝酸银， 在氮气保护下避光反应， 低温离心， 弃去沉淀， 保留清夜。 (2) Y型结构三核铂配合物： 往上述脱氯后的清夜中加入桥联 配体进行反应； 整个反应在氮气的保护下， 于 80-100度避光反应 2-3 天。
5、 根据权利要求 4所述的具有 Υ型结构的三核铂配合物的合成方 法， 其特征在于所述单齿铂配体脱氯的避光反应时间为 24小时。
6、 根据权利要求 4所述的具有 Υ型结构的三核铂配合物的合成方 法， 其特征在于所述的低温离心的温度为 3-6摄氏度。
7、 根据权利要求 4所述的具有 Υ型结构的三核铂配合物的合成方 法， 其特征在于所述歩骤 （2) 中加入的桥联配体与已脱氯的单齿铂 配体的摩尔比为 0.28: 1〜0.3: 1。
8、 根据权利要求 4所述的具有 Υ型结构的三核铂配合物的合成方 法， 其特征在于歩骤（2 )所述反应完毕后， 加入无水乙醇洗涤 2-5次， 离心得到固体物质， 即所述具有 Υ型结构的三核铂配合物。
9、 权利要求 1所述的具有 Υ型结构的三核铂配合物在制备抗人胃 腺癌药物中的应用。
10、根据权利要求 10所述的应用， 其特征在于所述的抗癌药物为 抗人胃腺癌药物。
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| JP2015215488A (ja) * | 2014-05-12 | 2015-12-03 | 株式会社リコー | エレクトロクロミック化合物、エレクトロクロミック組成物及び表示素子及び調光素子 |
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| CN107417734B (zh) * | 2017-07-19 | 2019-08-20 | 中山大学 | 一种具有双光子吸收特性的铂配合物及其制备方法和应用 |
| CN108948092B (zh) * | 2018-07-10 | 2020-10-09 | 中山大学 | 一种溶剂及温度驱动的基于金属有机配合物的可视化磷光分子合页及其合成方法和应用 |
| CN111635438B (zh) * | 2020-06-24 | 2023-01-24 | 江苏第二师范学院（江苏省教育科学研究院） | 多芳烃基修饰的双核铂(ii)配合物的制备方法和应用 |
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| RUBINO S. ET AL.: "Synthetic, structural and biochemical studies of polynuclear platinum(II) complexes with heterocyclic ligands.", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 44, no. 3, 2009, pages 1041 - 1048 * |
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| WO2014208775A1 (en) * | 2013-06-27 | 2014-12-31 | Ricoh Company, Ltd. | Electrochromic compound, electrochromic composition, display element, and dimming element |
| US9688706B2 (en) | 2013-06-27 | 2017-06-27 | Ricoh Company, Ltd. | Electrochromic compound, electrochromic composition, display element, and dimming element |
| CN105339376B (zh) * | 2013-06-27 | 2017-08-08 | 株式会社理光 | 电致变色化合物、电致变色组合物、显示元件和调光元件 |
| JP2015215488A (ja) * | 2014-05-12 | 2015-12-03 | 株式会社リコー | エレクトロクロミック化合物、エレクトロクロミック組成物及び表示素子及び調光素子 |
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