CN116970007A - 一种镍配合物及用途 - Google Patents
一种镍配合物及用途 Download PDFInfo
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- CN116970007A CN116970007A CN202310950372.XA CN202310950372A CN116970007A CN 116970007 A CN116970007 A CN 116970007A CN 202310950372 A CN202310950372 A CN 202310950372A CN 116970007 A CN116970007 A CN 116970007A
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- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229910052759 nickel Inorganic materials 0.000 title claims abstract description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000013078 crystal Substances 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- KWXIPEYKZKIAKR-UHFFFAOYSA-N 2-amino-4-hydroxy-6-methylpyrimidine Chemical compound CC1=CC(O)=NC(N)=N1 KWXIPEYKZKIAKR-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003446 ligand Substances 0.000 claims abstract description 6
- 230000001093 anti-cancer Effects 0.000 claims abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 238000002447 crystallographic data Methods 0.000 claims 1
- 229910002804 graphite Inorganic materials 0.000 claims 1
- 239000010439 graphite Substances 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 abstract description 5
- 201000007270 liver cancer Diseases 0.000 abstract description 3
- 208000014018 liver neoplasm Diseases 0.000 abstract description 3
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- -1 2-amino-4-hydroxy-6-methylpyrimidine nickel metal complex Chemical class 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910018553 Ni—O Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- GFHNAMRJFCEERV-UHFFFAOYSA-L cobalt chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Co+2] GFHNAMRJFCEERV-UHFFFAOYSA-L 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
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
- C07F15/04—Nickel compounds
- C07F15/045—Nickel 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- 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
一种镍配合物，其化学式如下：该镍配合物晶体(I)的合成方法是配体2‑氨基‑4‑羟基‑6‑甲基嘧啶(0.6g,2.34mmol)溶解在25mL的水、25mL的甲醇及30mLDMF溶液中，搅拌5分钟后，再加入NiCl2.6H2O(0.556g,2.34mmol)，32小时后，停止反应，自然挥发，8天后有浅绿色晶体析出；镍配合物晶体(I)的用途，可以作为抗癌试剂，在肝癌的抗肿瘤活性中取得了一定的抗癌活性，其IC50值达9.263±0.108。
Description
技术领域
本发明涉及一种镍配合物的制备及合成方法，具体地说是2-氨基-4-羟基-6-甲基嘧啶镍金属配合物的制备及合成方法。
背景技术
2-氨基-4-羟基-6-甲基嘧啶镍配合物是一种新型的镍配合物，其可用作抗癌试剂。类似文献报道已有许多，见参考文献[1-10]:
1.J.A Drewry,P.T Gunning.Coord Chem Rev.255,459-472(2011).
2.C.Fitzmaurice,D.Dicker,A.Pain,et al.JAMA Oncol.2015,505-527(2013).
3.A.Scibior,L.Pietrzyk,Z.Plewa,et at.J Trace Elem Med Biol.61,126508(2020).
4.E.A Hillard,G.Jaouen.Organometallics.30,20-27(2011).
5.I.G.Voinea,D.Ficai,A.Ficai.Chemistry Proceedings.7,74(2022).
6.S.Jürgens,A.Casini.Chimia.71,92-101(2017).
7.C.E.Carraher,M.R.Roner.J Organomet Chem.751,67-82(2014).
8.S.P.Mulcahy,E.Meggers Top Organomet Chem.32,141-153(2010).
9.S.A.D.et al.Appl Organomet Chem.1,19(2022).
10.C.Bonaccorso,T.Marzo,L.A Mendola D.Pharmaceuticals.13,1(2020)。
发明内容
本发明旨在为不对称合成领域特别是制备手性药物化合物提供一种合成方法，所要解决的技术问题是遴选合适的配体2-氨基-4-羟基-6-甲基嘧啶一步合成双核镍金属配合物。
(一)本发明所称的化合物是以下化学式(Ⅰ)配合物：
其化学名称：2-氨基-4-羟基-6-甲基嘧啶双核镍金属配合物复合物，简称配合物(I)。该配合物的合成方法，包括合成、分离和纯化，所述的合成是分别称取配体2-氨基-4-羟基-6-甲基嘧啶溶解在25mL的水、25mL的甲醇及30mLDMF和溶液中。再加入NiCl2.6H2O(0.949g,3.99mmol)回流反应30h后，停止反应。热过滤后得到红棕色的晶体。
该反应的反应机理可推测如下：
配体：2-氨基-4-羟基-6-甲基嘧啶在六水合氯化钴及无水甲醇和DMF溶液中，回流30小时候，得到镍配合物。这个配合物是4个镍原子通过两个镍原子形成的双核配合物分子之间再通过氢键形成一个大分子复合物。经X-衍射，NMR,IR及元素分析确定其结构。该配合物在肝癌的抗肿瘤活性中显示了一定的性能。
附图说明
图1是目标化合物I的晶体结构图。
具体实施方式
1.镍配合物I的制备
配体(0.6g,2.34mmol)溶解在无水甲醇溶液30mL再加入DMF 20mL溶液中，搅拌5分钟后，再加入NiCl2.6H2O(0.556g,2.34mmol)，32小时后，停止反应，自然挥发。8天后有浅绿色晶体析出；产率：78.7％,m.p.186–188℃；IR(KBr,n,cm-1):3474(-OH),3375(-NH2),3283(-CH2),1652(-C6H6),1598(-C6H6O),1438(C＝C),1363(-CH3),1100(-C-N),1039(C-O),683(-Ni-O),594(-Ni-N).EA分析[Ni4C80H100N16O22]calculated％of C：51.31,H：5.30,N：11.90and found％C：51.08,％H：5.34,％N：11.41；ESI[Ni4C80H100N16O22]:calculated：1872.5436；found:1872.5428；
化合物的晶体数据如下：
2.晶体典型的键长数据：
晶体典型的键长数据：
2.抗癌活性应用
本发明依据活性天然产物的结构设计合成的钯配合物在癌细胞如肝癌SMMC-7721试验中均显示出一定的抑制活性，抗癌活性测试结果用IC50(uM)表示，见表1。
表1.钯配合物(I)的抗癌活性数据
Claims (4)
1.一种镍配合物，其化学式如下：
2.权利要求1所述的镍配合物晶体(I)，在293(2)K温度下，在牛津X-射线单晶衍射仪上，用经石墨单色器单色化的MoKα射线以ω-θ扫描方式收集衍射数据，其特征在于：晶体属三斜晶系，P-1；晶胞参数 alpha＝85.220(3)°；beta＝63.611(2)°； gamma＝79.781°。
3.由权利要求1所述的镍配合物晶体(I)的合成方法包括反应、分离和纯化，其特征是配体2-氨基-4-羟基-6-甲基嘧啶(0.6g,2.34mmol)溶解在25mL的水、25mL的甲醇及30mLDMF溶液中；搅拌5分钟后，再加入NiCl2.6H2O(0.556g,2.34mmol)，32小时后，停止反应，自然挥发；8天后有浅绿色晶体析出。
4.由权利要求1所述的镍配合物晶体(I)的用途，其特征在于：可以作为抗癌试剂，在肝癌的抗肿瘤活性中取得了一定的抗癌活性，其IC50值达9.263±0.108。
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