WO2021051709A1 - 一种锇配合物、制备方法及其应用 - Google Patents

一种锇配合物、制备方法及其应用 Download PDF

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WO2021051709A1
WO2021051709A1 PCT/CN2019/129735 CN2019129735W WO2021051709A1 WO 2021051709 A1 WO2021051709 A1 WO 2021051709A1 CN 2019129735 W CN2019129735 W CN 2019129735W WO 2021051709 A1 WO2021051709 A1 WO 2021051709A1
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osmium complex
osmium
mixed solution
preparing
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张平玉
胡仁涛
张黔玲
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深圳大学
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    • 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
    • C07F15/002—Osmium compounds
    • C07F15/0026—Osmium compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering
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    • C09K2211/18—Metal complexes
    • C09K2211/185—Metal complexes of the platinum group, i.e. Os, Ir, Pt, Ru, Rh or Pd

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  • the invention relates to the technical field of transition metal complexes, in particular to an osmium complex, a preparation method and its application.
  • the lowest energy absorption of this complex belongs to the mixed transition of MLCT and ILCT.
  • the MLCT transition runs through the entire transition process and has a longer wavelength UV absorption.
  • the longer-wavelength MLCT absorption peak makes the excitation wavelength of the complex in the determination of resonance Raman spectroscopy correspondingly prolonged, making it more suitable for the analysis of biological samples, enhancing tissue penetration and biocompatibility.
  • metal anti-cancer drugs such as platinum-containing anti-cancer drugs are widely used clinically, and ruthenium and osmium complexes will become one of the most promising anti-cancer drugs.
  • the molecular structure of osmium complexes is very good. Due to its plasticity, it is easy to introduce other molecular active groups on the ligand, so its performance is also plastic.
  • the synthesis of a new type of osmium complex with superior stability and anti-tumor activity is of great significance in the fields of medicine and materials.
  • the osmium complex prepared in the prior art has low stability and low anti-tumor activity.
  • the purpose of the present invention is to provide an osmium complex, a preparation method and application thereof, and aims to solve the problems of poor stability and low anti-tumor activity of the existing osmium complex.
  • X is Cl -, Br - and I - any one of a, M - is PF 6 -.
  • a preparation method of osmium complex which comprises the following steps:
  • the osmium complex precursor and 5-chloro-2-phenylazopyridine are added to ethylene glycol according to a predetermined ratio, and after reacting under predetermined reaction conditions, the target anion is added to obtain the osmium complex.
  • the method for preparing the osmium complex wherein the step of adding ammonium chloroosmate and bipyridine to an organic solvent to react to obtain a mixed solution specifically includes:
  • Ammonium chloroosmate and bipyridine are added to an organic solvent, and the reaction is refluxed for a first predetermined time under the protection of an inert gas, and a mixed solution is obtained after the reaction.
  • the method for preparing the osmium complex wherein the step of adding a reducing agent to the mixed solution to react to obtain an osmium complex precursor specifically includes:
  • the aqueous solution of the reducing agent is added to the mixed solution, placed in a refrigerator at 4°C, overnight to obtain an osmium complex precursor.
  • the predetermined ratio is that the molar ratio of the osmium complex precursor to 5-chloro-2-phenylazopyridine is 1:1 to 1.2.
  • the predetermined reaction condition is set at a temperature of 120-140°C under the protection of an inert gas.
  • the first predetermined time is 4-8 hours.
  • a Raman probe wherein the Raman probe is prepared by using an osmium complex.
  • the osmium complex provided by the present invention has extremely high structural stability, hardly fluoresces, has strong cytotoxicity to tumor cells, and is selective to cancer cells, and can be applied to Raman imaging of tumor cells field.
  • Fig. 1 is a flow chart of the preparation method of the osmium complex provided by the embodiment of the present invention.
  • Fig. 2 is a synthetic pathway diagram of an osmium complex provided by an embodiment of the present invention.
  • Fig. 3 is an ultraviolet and fluorescence spectrum diagram of an osmium complex provided by an embodiment of the present invention.
  • Fig. 4 is an infrared spectrogram of a complex provided by an embodiment of the present invention.
  • Figure 5 is a histogram of the content distribution of the starvation complex in different parts of the cell provided by an embodiment of the present invention.
  • Fig. 6 is the Raman spectrum of the Hunger complex provided in the embodiment of the present invention in solution and in cells.
  • Fig. 7 is a Raman imaging image of the Hunger complex provided by the embodiment of the present invention in lung cancer cells.
  • B is the CH peak, representing the entire cell area
  • C and D are the bpy auxiliary ligand and the main ligand respectively.
  • N N
  • E is the superimposed image of B, C, and D.
  • the present invention provides an osmium complex, which has a structure as shown in the following formula:
  • X is Cl -, Br - and I - any one of a, M - is PF 6 -.
  • the osmium and the ligand are connected by an osmium-nitrogen bond, which enhances the stability between the parent and the ligand.
  • the osmium in the above structure is positively divalent, which makes the structure of the complex more stable and suitable for preparing Raman probes.
  • the present invention also provides a method for preparing an osmium complex, including the steps:
  • step S10 the mixture obtained in step S10 is refluxed and reacted under the protection of inert gas.
  • a certain amount of reducing agent is added to the mixed solution, stirred evenly, placed in a refrigerator at 4°C, and allowed to stand overnight.
  • a black precipitate was obtained after filtration, and the black precipitate was washed with water and ether to obtain an osmium complex precursor.
  • the reducing agent is sodium dithionite, ammonium sulfite and the like.
  • the specific reaction mechanism in this step is: the nitrogen atom with the higher electron cloud density on the 2,2-bipyridine ligand provides electrons and ammonium chloroosmate forms a seven-coordinated bond with a metal ligand (ie, an osmium-nitrogen bond)
  • a metal ligand ie, an osmium-nitrogen bond
  • the intermediate, the chloride ion is removed, and the process is repeated again, which is a typical bimolecular association mechanism similar to S N 2 nucleophilic substitution, in which the positive trivalent osmium is reduced by sodium hydrosulfite to form a more stable divalent Osmium, eventually forming an osmium complex precursor [Os(bpy) 2 Cl 2 ].
  • the osmium complex precursor and 5-chloro-2-phenylazopyridine were weighed in a certain proportion and added to the ethylene glycol, and the reaction temperature was set to 120°C under the protection of argon. Heat to reflux for a predetermined time. After the reaction, the temperature of the solution is lowered to room temperature, and an aqueous solution of ammonium hexafluorophosphate is added to it to precipitate a black solid, that is, an osmium complex.
  • the molar ratio of the osmium complex precursor: 5-chloro-2-phenylazopyridine is 1:1 to 1.2. Appropriately increasing the amount of the main ligand can cause the problem of deviation caused by insufficient raw material purity.
  • the specific reaction mechanism in this step is: the nitrogen atom with a higher electron cloud density on the main ligand (5-chloro-2-phenylazopyridine) provides electrons and forms an osmium-nitrogen bond with the vacancy of the osmium precursor, resulting in seven
  • the coordinated intermediate, the chlorine leaves, and the other nitrogen atom repeats the process.
  • the two osmium-nitrogen bonds form a ring with the ligand on the right side, and then form a salt with the hexafluorophosphate to form the target osmium complex. It is also based on the bimolecular association mechanism of S N 2 nucleophilic substitution.
  • the present invention also provides a Raman probe, which is prepared from the above-mentioned osmium complex.
  • the molecular probe has good light stability and hardly fluoresces by itself.
  • the invention also provides an application of the osmium complex for preparing an antitumor drug with the nucleus as the target.
  • the optical properties of the osmium complexes were preliminarily characterized by ultraviolet spectroscopy and fluorescence spectroscopy, and the absorption peak area and the position of the fluorescence emission peak were determined. It can be seen from Figure 3 that the complex has a strong absorption peak at 460-470nm. 460nm is the excitation wavelength and the fluorescence spectrum is measured, and it is found that the emission peak is extremely weak, and there is almost no fluorescence emission.
  • Table 1 shows the IC 50 values of osmium complexes and cisplatin after 48 hours of administration to various cell lines. IC 50 represents the concentration required to inhibit half of the cell proliferation and is negatively correlated with toxicity.
  • Table 1 shows that the toxicity of osmium complexes to Hep-G2 liver cancer cells and A549 lung cancer cells is higher than that of cisplatin, and its toxicity to two groups of normal cells IC 50 values much higher than the IC 50 of cancer cells, indicating that the complex selective for cancer cells, but substantially not toxic to normal cells, it is expected to be a targeted drug efficiency and low toxicity.
  • a total of 3 samples are divided into whole, nucleus and cytoplasm (packed in 1.5mL centrifuge tube), after 2 days of digestion with concentrated nitric acid, add ultrapure water to dilute to a clear solution with a nitric acid concentration of 5%. After filtering with a filter membrane, take 10mL of each solution as the final test sample, and use osmium at the same time.
  • the present invention provides an osmium complex, preparation method and application thereof.
  • the method includes the steps of adding ammonium chloroosmate and bipyridine to an organic solvent to react to obtain a mixed solution; adding a reducing agent to the mixed solution to react to obtain an osmium complex precursor;
  • the osmium complex precursor and 5-chloro-2-phenylazopyridine are added to ethylene glycol, and after reacting under predetermined reaction conditions, the target anion is added to obtain the osmium complex.
  • the osmium complex provided by the invention has extremely high structural stability, hardly fluoresces, has strong cytotoxicity to tumor cells, and is also selective to cancer cells, and can be applied in the field of Raman imaging of tumor cells.

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Abstract

一种锇配合物、制备方法及其应用。所述方法包括如下步骤：将氯锇酸铵与二联吡啶加入到有机溶剂中反应，得到混合溶液；将还原剂加入到所述混合溶液中反应，得到锇配合物前体；按照预定比例将所述锇配合物前体与5-氯-2-苯偶氮基吡啶加入到乙二醇中，在预定反应条件下反应后，加入目标阴离子，得到锇配合物。所提供的锇配合物几乎不发荧光，对肿瘤细胞有细胞毒性，对癌细胞也具有选择性，能够应用在肿瘤细胞的拉曼成像领域。

Description

一种锇配合物、制备方法及其应用 技术领域
本发明涉及过渡金属配合物技术领域，尤其涉及一种锇配合物、制备方法及其应用。
背景技术
过渡金属配合物一直是近几十年的研究热点之一，大量的含有d 6、d 8和d 10电子组态的过渡金属配合物被成功合成和研究。在已经合成的金属配合物中，以铱和钌配合物数量最多、应用最为广泛。但是研究发现饿配合物具有更加红外的吸收。P.T.Chou等人合成出一系列[Os(II)(N～N) 2(PR) 2](N～N＝2-吡啶基三唑或2-吡啶基吡唑PR＝PPh 2Me或PPhMe 2)配合物。研究表明，此配合物最低能吸收属于MLCT和ILCT混合跃迁，MLCT跃迁贯穿于整个跃迁过程中，具有较长波长的紫外吸收。其中，较长波长的MLCT吸收峰使配合物在测定共振拉曼光谱时的激发波长也相应延长，从而使其更适合生物样品的分析，增强组织穿透能力和生物相容性。
在医药上，金属抗癌药物如含铂抗癌药物是临床上广泛使用的抗肿瘤药物，而钌、锇配合物将成为最有前途的抗癌药物之一，锇配合物分子结构具有很好的可塑性，容易在配体上引入其它分子活性基团，因而其性能也具有可塑性，合成新型的、具有优越稳定性和抗肿瘤活性的锇配合物在医药、材料领域具有重大意义。现有的技术中所制备的锇配合物稳定性不高，抗肿瘤活性低。
因此，现有技术还有待于改进和发展。
发明内容
鉴于上述现有技术的不足，本发明的目的在于提供一种锇配合物、制备方法及其应用，旨在解决现有锇配合物稳定性差、抗肿瘤活性低的问题。
本发明为解决上述技术问题所采用的技术方案如下：
一种锇配合物,其中，该配合物具有如下通式：
Figure PCTCN2019129735-appb-000001
其中：X为Cl -、Br -和I -中的任一种，M -为PF 6 -。
一种锇配合物的制备方法，其中，包括步骤：
将氯锇酸铵与二联吡啶加入到有机溶剂中反应，得到混合溶液；
将还原剂加入到所述混合溶液中反应，得到锇配合物前体；
按照预定比例将所述锇配合物前体与5-氯-2-苯偶氮基吡啶加入到乙二醇中，在预定反应条件下反应后，加入目标阴离子，得到锇配合物。
所述的锇配合物的制备方法，其中，所述还原剂为连二亚硫酸钠或亚硫酸钠。
所述的锇配合物的制备方法，其中，所述步骤将氯锇酸铵与二联吡啶加入到有机溶剂中反应，得到混合溶液，具体包括：
将氯锇酸铵与二联吡啶加入到有机溶剂中，在惰性气体保护下回流反应第一预定时间，反应后得到混合溶液。
所述的锇配合物的制备方法，其中，所述步骤将还原剂加入到所述混合溶液中反应，得到锇配合物前体，具体包括：
将还原剂的水溶液加入到所述混合液中，放入4℃冰箱，过夜得到锇配合物前体。
所述的锇配合物的制备方法，其中，所述预定比例为锇配合物前体与5-氯-2-苯偶氮基吡啶的摩尔比为1:1-1.2。
所述的锇配合物的制备方法，其中，所述预定反应条件为在惰性气体保护下，设置温度120-140℃。
所述的锇配合物的制备方法，其中，所述第一预定时间为4-8小时。
一种拉曼探针，其中，所述拉曼探针采用锇配合物制备而成。
一种锇配合物的应用，其中，用于制备以细胞核为作用靶点的抗肿瘤药。
有益效果：本发明所提供的锇配合物具有极高的结构稳定性，几乎不发荧光，对肿瘤细胞的细胞毒性很强，对癌细胞也具有选择性，能够应用在肿瘤细胞的拉曼成像领域。
附图说明
图1是本发明实施实例所提供的锇配合物的制备方法流程图。
图2是本发明实施例所提供的锇配合物的合成途径图。
图3是本发明实施实例所提供的锇配合物的紫外和荧光光谱图。
图4是本发明实施实例所提供的饿配合物的红外光谱图。
图5是本发明实施实例提供的饿配合物在细胞内不同部位的含量分布柱状图。
图6是本发明实施实例所提供的饿配合物在溶液中和细胞中的拉曼光谱图。
图7是本发明实施实例所提供的饿配合物在肺癌细胞中的拉曼成像图，B是C-H峰，代表整个细胞区域，C、D分别是bpy辅助配体和主配体里N＝N键的峰，E为B、C、D的叠加图。
具体实施方式
为使本发明的目的、技术方案及优点更加清楚、明确，以下参照附图并举实施例对本发明进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明提供一种锇配合物，该配合物具有如下式所示的结构：
Figure PCTCN2019129735-appb-000002
其中，X为Cl -、Br -和I -中的任一种，M -为PF 6 -。
上述锇配合物的结构中锇与配体之间通过锇-氮键相连，增强了母体与配体之间的稳定性。同时上述结构中的锇是正二价，因此使得配合物的结构更加稳定，适于制备拉曼探针。
请参阅图1，本发明还提供了一种锇配合物的制备方法，包括步骤：
S10、将氯锇酸铵与二联吡啶加入到有机溶剂中反应，得到混合溶液；
具体来说，先将氯锇酸铵与二连吡啶溶解在有机溶剂中，制备得到混合溶液，其中所述有机溶剂可以是DMF、乙二醇等。
S20、将还原剂加入到所述混合溶液中反应，得到锇配合物前体；
具体来说，将步骤S10中得到的混合物在惰性气体保护条件下回流反应，回流反应结束后，向混合溶液中加入一定量的还原剂，搅拌均匀，放入4℃冰箱，静置过夜，抽滤后得到黑色沉淀，用水和乙醚对所述黑色沉淀进行洗涤，得到了锇配合物前体。所述还原剂为连二亚硫酸钠、亚硫酸铵等。
该步骤中具体的反应机理为：2,2-联吡啶配体上电子云密度较高的氮原子提供电子与氯锇酸铵以金属配体键(即锇-氮键)形成七配位的中间体，氯离子离去，再重复这一过程，是一个典型的类似S N2亲核取代的双分子缔合机理，其中，正三价的锇再被连二亚硫酸钠还原形成更稳定的二价锇，最终形成锇配合物前体[Os(bpy) 2Cl 2]。
S30、按照预定比例将所述锇配合物前体与5-氯-2-苯偶氮基吡啶加入到乙二醇中，在预定反应条件下反应后，加入阴离子盐，得到锇配合物。
具体来说，按照一定的比例称取锇配合物前体和5-氯-2-苯偶氮基吡啶(主配体)加入到乙二醇中，设置反应温度120℃，在氩气保护下加热回流预定时间，反应结束后将溶液温度降至室温，向其中加入六氟磷酸铵的水溶液，析出黑色固体即锇配合物。其中，锇配合物前体：5-氯-2-苯偶氮基吡啶的摩尔比为1:1-1.2，适当增加主配体的量可以原料纯度不够所带来偏差的问题。
该步骤中具体的反应机理为：主配体(5-氯-2-苯偶氮基吡啶)上电子云密度较高的氮原子提供电子与锇前体的空位形成锇-氮键，产生七配位的中间体，氯离去，另一个氮原子再重复这一过程，两个锇-氮键与右侧配体成环，再与六氟磷酸根成盐，从而形成目标锇配合物，也是基于S N2亲核取代的双分子缔合机理。
本发明还提供了一种拉曼探针，所述拉曼探针是由上述的锇配合物制备得到。该分子探针光稳定好，自身几乎不发荧光。
本发明还提供了一种锇配合物的应用，用于制备以细胞核为作用靶点的抗肿瘤药。
下面通过具体的实施例对本发明所提供的锇配合物的制备方法进行进一步的解释说明。
称取0.439g的氯锇酸铵固体和0.328g的二联吡啶粉末加入到15mL的DMF溶液中，在氮气保护下回流反应5h，冷却至室温后，往混合溶液中加入含 有6.8g连二亚硫酸钠的水溶液，混合均匀后放入冰箱，静置过夜后，抽滤，黑色沉淀用水和乙醚洗涤数次，得到锇配合物前体。
然后按计量摩尔比(1：1)称取[Os(bpy) 2Cl 2]约57.35mg和主配体(5-氯-2-苯偶氮基吡啶)约21.77mg反应,加入10mL乙二醇，设置温度为120℃，氩气保护，加热回流8h，待溶液冷却后，加入NH 4PF 6水溶液，析出黑色固体，真空抽滤后，得深黑色固体。具体合成途径见图2。
对深黑色固体进行分析：
1、ESI(m/z):359.65[M-2PF 6] 2+/2. 1H NMR(400MHz,DMSO-d 6)δ9.23(d,J＝2.2Hz,1H),9.05(d,J＝8.2Hz,1H),8.95(d,J＝8.2Hz,1H),8.67(d,J＝8.1Hz,1H),8.55(d,J＝8.0Hz,1H),8.30(t,J＝7.9Hz,1H),8.21(dd,J＝13.8,6.6Hz,2H),7.93(dd,J＝11.3,4.5Hz,1H),7.79(d,J＝6.3Hz,1H),7.72(d,J＝5.3Hz,1H),7.70–7.58(m,4H),7.58–7.53(m,1H),7.43(dt,J＝10.9,6.3Hz,3H),7.25(t,J＝7.3Hz,1H),7.18(t,J＝7.5Hz,2H),6.82(d,J＝7.7Hz,2H).
2、对产物进行紫外/荧光/红外光谱实验：
运用紫外光谱和荧光光谱对锇配合物的光学性质进行初步表征，确定其吸收峰的区域和荧光发射峰的位置，从图3可以看出，配合物在460-470nm处有强吸收峰，用460nm为激发波长测定其荧光光谱，发现其发射峰特别微弱，几乎没有荧光发射。
运用KBr压片法测定锇配合物粉末的红外光谱，如图4所示，其中约1500cm -1处为C＝C键的伸缩振动峰，1620cm -1为C＝N键的伸缩振动峰。
3、细胞毒性实验：
通过MTT实验，探究锇配合物对肝癌细胞株(Hep-G2)、肺癌细胞株(A549)和相应的正常细胞株(LO2，MRC-5)的细胞毒性。表1是锇配合物和顺铂对各种细胞株给药48h后的IC 50值。IC 50代表抑制一半细胞增殖所需要的浓度，与毒性负相关，表1中可以得出锇配合物对Hep-G2肝癌细胞和A549肺癌细胞的毒性高于顺铂，并且其对两组正常细胞的的IC 50值远远高于癌细胞的IC 50，表明配合物对癌细胞具有选择性，但对正常细胞基本没有毒性，这将有望成为一种高效低毒的靶向药物。
表1
  Hep-G2 A549 MRC-5 LO2
Os 6.3±0.7 13.4±1.7 102.4±2.7 75.2±3.9
Cis-Pt 9.5±1.7 10.2±1.8 13.5±1.5 13.2±1.3
4、细胞摄取实验：
收集孵育配合物(10μM，8h)之后的肺癌A549细胞，分成2份，利用细胞核提取试剂提取一份细胞的细胞核，剩余部分为细胞质，总共分为整体、细胞核和细胞质3份样品(分装于1.5mL离心管中)，用浓硝酸消化2天之后，加超纯水稀释至硝酸浓度为5％的澄清溶液，用滤膜过滤之后，取每份溶液10mL作为最终测试样品，并同时用锇标准溶液，联用抗坏血酸和硫脲作为抗氧化剂(防止金属锇被氧化，避免误差)，配置浓度梯度为0,10,20...1000ppb的标准溶液，测试时先用标准液测定标准曲线(R 2＝0.99997)，再依次测定细胞样品，经过计算得出配合物在细胞核的含量约为89.9ng/cell,细胞质约为9.1ng/cell,如图5所示，证明配合物大部分聚集在细胞核中。
5、拉曼成像实验：
先对锇配合物的粉末与溶液进行测试，用532nm激发得出拉曼光谱如图6所示，再对孵育锇配合物(100μM,4h)的肺癌A549细胞进行拉曼成像测试，在532nm激光激发下，选取一个细胞区域进行扫描，通过后期的Mapping处理，得出直观的拉曼图像，如图7所示，进一步表明配合物能够聚集在细胞核中。
综上所述，本发明所提供的一种锇配合物、制备方法及其应用。所述方法包括步骤，将氯锇酸铵与二联吡啶加入到有机溶剂中反应，得到混合溶液；将还原剂加入到所述混合溶液中反应，得到锇配合物前体；按照预定比例将所述锇配合物前体与5-氯-2-苯偶氮基吡啶加入到乙二醇中，在预定反应条件下反应后，加入目标阴离子，得到锇配合物。本发明所提供的锇配合物具有极高的结构稳定性，几乎不发荧光，对肿瘤细胞的细胞毒性很强，对癌细胞也具有选择性，能够应用在肿瘤细胞的拉曼成像领域。
应当理解的是，本发明的应用不限于上述的举例，对本领域普通技术人员来说，可以根据上述说明加以改进或变换，所有这些改进和变换都应属于本发明所附权利要求的保护范围。

Claims (10)

  1. 一种锇配合物,其特征在于，该配合物具有如下通式：
    Figure PCTCN2019129735-appb-100001
    其中：X为Cl -、Br -和I -中的任一种，M -为PF 6 -。
  2. 一种如权利要求1所述的锇配合物的制备方法，其特征在于，包括步骤：
    将氯锇酸铵与二联吡啶加入到有机溶剂中反应，得到混合溶液；
    将还原剂加入到所述混合溶液中,反应得到锇配合物前体；
    按照预定比例将所述锇配合物前体与5-氯-2-苯偶氮基吡啶加入到乙二醇中，在预定反应条件下反应后，加入目标阴离子，得到锇配合物。
  3. 根据权利要求2所述的锇配合物的制备方法，其特征在于，所述还原剂为连二亚硫酸钠或亚硫酸钠。
  4. 根据权利要求2所述的锇配合物的制备方法，其特征在于，所述步骤将氯锇酸铵与二联吡啶加入到有机溶剂中反应，得到混合溶液，具体包括：
    将氯锇酸铵与二联吡啶加入到有机溶剂中，在惰性气体保护下回流反应第一预定时间，反应后得到混合溶液。
  5. 根据权利要求2所述的锇配合物的制备方法，其特征在于，所述步骤将还原剂加入到所述混合溶液中反应，得到锇配合物前体，具体包括：
    将还原剂的水溶液加入到所述混合液中，放入4℃冰箱，过夜得到锇配合物前体。
  6. 根据权利要求1所述的锇配合物的制备方法，其特征在于，所述预定比例为锇配合物前体与5-氯-2-苯偶氮基吡啶的摩尔比为1:1-1.2。
  7. 据权利要求1所述的锇配合物的制备方法，其特征在于，所述预定反应条件为在惰性气体保护下，设置温度120℃-140℃。
  8. 根据权利要求4所述的锇配合物的制备方法，其特征在于，所述第一预定时间为4-8小时。
  9. 一种拉曼探针，其特征在于，所述拉曼探针采用权利要求1所述的锇配合物制备而成。
  10. 一种锇配合物的应用，其特征在于，用于制备以细胞核为作用靶点的抗肿瘤药。
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