CN110448561A - 一种手性双噁唑啉金属配合物的用途 - Google Patents
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- 239000002184 metal Substances 0.000 title description 6
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 26
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- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 14
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 11
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- 238000010189 synthetic method Methods 0.000 description 4
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- CLSUSRZJUQMOHH-UHFFFAOYSA-L platinum dichloride Chemical compound Cl[Pt]Cl CLSUSRZJUQMOHH-UHFFFAOYSA-L 0.000 description 2
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 2
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
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- WRXCXOUDSPTXNX-UHFFFAOYSA-N 9-methyladenine Chemical compound N1=CN=C2N(C)C=NC2=C1N WRXCXOUDSPTXNX-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
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- CMKUYTPTVAHAFD-UHFFFAOYSA-N O1C(=NCC1)[Zn] Chemical class O1C(=NCC1)[Zn] CMKUYTPTVAHAFD-UHFFFAOYSA-N 0.000 description 1
- 229910018885 Pt—Au Inorganic materials 0.000 description 1
- 235000013832 Valeriana officinalis Nutrition 0.000 description 1
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- 229940041181 antineoplastic drug Drugs 0.000 description 1
- GNHQSAUHXKRQMC-UHFFFAOYSA-N benzene;chlorine Chemical compound [Cl].C1=CC=CC=C1 GNHQSAUHXKRQMC-UHFFFAOYSA-N 0.000 description 1
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- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
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- 238000011835 investigation Methods 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- GZAJJDUWYRDMPO-UHFFFAOYSA-N methylsulfinylmethane;platinum Chemical compound [Pt].CS(C)=O GZAJJDUWYRDMPO-UHFFFAOYSA-N 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000004424 polypyridyl Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940127224 quinoline drug Drugs 0.000 description 1
- 150000003303 ruthenium Chemical class 0.000 description 1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- 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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- 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
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- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/003—Compounds containing elements of Groups 2 or 12 of the Periodic Table without C-Metal linkages
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
一种手性铂配合物(I)的用途,其用作抗癌试剂在A5499(肺癌)、KB(鼻咽癌)、KB‑VIn(抗耐药性鼻咽癌)、MDA‑MB‑231(人乳腺癌细胞)及MCF‑7(乳腺癌细胞)试验中均显示出较好的的抑制活性，其化学式如下：一种手性锌配合物(I)的用途,其用作抗癌试剂在A549(肺癌)、KB(鼻咽癌)和KB‑VIn(抗耐药性鼻咽癌)、人乳腺癌细胞MDA‑MB‑231及乳腺癌细胞MCF‑7试验中均显示出较好的抑制活性，其化学式如下：
Description
一、技术领域
本发明涉及一种金属噁唑啉有机配位化合物(配合物)的用途，特别涉及含铂及锌双噁唑啉配合物的用途，确切地说是一种含铂及锌双噁唑啉金属配合物在医药领域中的用途。
二、背景技术
金属铂及锌双噁唑啉配合物因其在抗癌和分子磁体、荧光材料等方面的潜在应用价值已引起人们的广泛关注。其合成方法近年来有许多文献报道。【1-7】
1.A Comparative Antimicrobial Study In Between a Quinoline Drug andIts Complexes:Spectral,Kinetic,and Molecular Modeling Investigations,Al-Hazmi,Gamil A.A.；Saad,Fawaz A.Synthesis and Reactivity in Inorganic,Metal-Organic,and Nano-Metal Chemistry(2015),45(11),1743-1757.
2.One-pot synthesis of dual-emitting BSA-Pt-Au bimetallicnanoclusters for fluorescence ratiometric detection of mercury ions andcysteine,Ding,Shou-Nian；Guo,Yun-Xia From Analytical Methods(2015),7(14),5787-5793.
3.Five coordinate platinum(II)in[Pt(bpy)(cod)(Me)][SbF6]:a structuraland spectroscopic study,Klein,Axel；Neugebauer,Michael；Krest,Alexander；Luening,Anna；Garbe,Simon；Arefyeva,Natalia；Schloerer,Nils,Inorganics(2015),3(2),118-138.
4.Synthesis and Reactivity of Platinum(II)cis-Dialkyl,cis-AlkylChloro,and cis-Alkyl Hydrido Bis-N-heterocyclic Carbene Chelate Complexes,Brendel,Matthias；Engelke,Rene；Desai,Vidya G.；Rominger,Frank；Hofmann,Peter,Organometallics(2015),34(12),2870-2878.
5.The Challenge of Deciphering Linkage Isomers in Mixtures ofOligomeric Complexes Derived from 9-Methyladenine and trans-(NH3)2PtII Units,Ibanez,Susana；Mihaly,Bela；Sanz Miguel,Pablo J.；Steinborn,Dirk；Pretzer,Irene；Hiller,Wolf；Lippert,Bernhard Chemistry-A European Journal(2015),21(15),5794-5806.
6.Polypyridyl ruthenium complexes containing anchoring nitrile groupsas TiO2sensitizers for application in solar cells,Mecchia Ortiz,Juan H.；Longo,Claudia；Katz,Nestor E.Inorganic Chemistry Communications(2015),55,69-72.
7.One-step multicomponent synthesisof chiral oxazolinyl-zinccomplexes，Mei Luo,Jing Cheng Zhang,Wen Min Pang,and King Kuok Hii.(2017),11,81-89.
三、发明内容
本发明旨在提供一种Pt-N及Zn-N金属有机配合物作为抗癌药物以应用于医药领域，所要解决的技术问题是遴选铂及锌配合物，并研究其在抗肺癌、口腔癌、乳腺癌及乳腺癌细胞的活性。
本发明所称的铂配合物一种是由双-(4(R)-异丙基-4,5-二氢化-2-噁唑啉基)-乙腈锌与Pt(DMSO)2Cl2反应制备的由以下化学式所示的配合物：
化学名称：双-(4(S)-异丙基-4,5-二氢化-2-噁唑啉基)-乙腈锌氯化铂配合物，简称配合物(I)。
本发明所称的锌配合物一种是由邻二氰基苯与L-苯甘氨醇在56mol％氯化锌作用下制备的由以下化学式所示的配合物：
化学名称：双-(4(S)-苯基-4,5-二氢化-2-噁唑啉基)-氯化锌配合物，简称配合物(II)。
铂配合物(I))的合成反应如下：
本配合物(I)合成方法包括合成和分离，所述的合成是称取双-(4(R)-异丙基-4,5-二氢化-2-噁唑啉基)-乙腈锌0.2662g用30mL二氯甲烷做溶剂溶解，再加入Pt(DMSO)2Cl20.3406g，室温下反应60小时后停止反应，过滤，加入二氯甲烷、石油醚及无水乙醇，自然挥发得一种新型的铂配合物单晶。
锌配合物(II)的合成反应如下：
本配合物(II)的合成方法包括合成和分离，所述的合成是称取无水ZnCl2 3.0g(22.06mmol),40mL氯苯,邻二氰基苯3.353g(26.17mmol),L-苯甘氨醇8.492g(61.91mmol))将混合物在高温下回流72h,停止反应,减压以除去溶剂,,将剩余物用水溶解,并用CHCl3(20mLx2)萃取,有机相用无水硫酸钠干燥,旋转除去溶剂,将粗产品用石油醚/二氯甲烷(1:8)柱层析,得白色晶体。
本合成方法一步得到目标产物，工艺简单，操作方便。该配合物(I)及(II)A5499(肺癌)、KB(鼻咽癌)、KB-VIn(抗耐药性鼻咽癌)、MDA-MB-231(人乳腺癌细胞)及MCF-7(乳腺癌细胞)试验中均显示出较好的的抑制活性。
四、附图说明
图1双-(4(R)-异丙基-4,5-二氢化-2-噁唑啉基)-乙腈锌氯化铂配合物晶体的X-衍射分析图。
图2双-(4(S)-苯基-4,5-二氢化-2-噁唑啉基)-氯化锌配合物晶体的X-衍射分析图。
五、具体实施方式
1.二氯化铂二甲亚砜配合物
在100mL两口瓶中,加入二氯化铂1.2042g,10mLDMSO，二氯甲烷30mL,将混合物回流60h,停止反应,静止，得二甲亚砜铂配合物固体,产率45％；元素分析：测试值：C:11.78％,H:2.91％；计算值：C:11.38％,H 2.86％；IR(KBr):1157,1134，450,430。
2.双-(4-(R)-异丙基-4,5-二氢化-2-噁唑啉基)-乙腈锌配合物的制备
在100mL两口瓶中,无水无氧条件下,加入无水ZnCl2 0.45g(3.30mmol),40mL氯苯,四腈乙烯1.0g(7.81mmol),D-缬氨醇4g,将混合物在高温下回流24h,停止反应,减压以除去溶剂,,将剩余物用水溶解,并用CHCl3(20mLx2)萃取,有机相用无水硫酸钠干燥,旋转除去溶剂,将粗产品用石油醚/二氯甲烷(4:1)柱层析,得白色晶体，产率52％；[a]5 D＝-305.9°(c＝0.26,CH2Cl2)：1HNMR(500MHz,CDCl3,27℃),δ(ppm)＝4.35(t,4H),4.16(t,J＝1Hz,4H),3.81～3.83(m,4H),1.62～1.66(m,4H)，0.74～0.87(dd,J＝7Hz,6.5Hz,24H)；13CNMR(75MHz,CDCl3)170.6(x2),118.6(x2),73.0(x4),68.9(x4),68.5(x4),31.8(x4),19.2(x4),15.7(x4)。IR:3443(s),2963(s),2200(s),1609(s),1533(s),1484(s),1432(s),1391(m),1371(w),1341(w),1312(w),1251(m),1222(m),1117(m),1075(s),953(m),744(m),566(w),528(w),457(w)；元素分析理论值：C:57.00％,H,6.83％,N,14.24％；实测值：C:56.80％,H,6.79％,N,14.35％。
3.一氯化(4(R)-异丙基-4,5-二氢化-2-噁唑啉基)-乙腈铂配合物晶体(I)的制备
称取双-(4(R)-异丙基-4,5-二氢化-2-噁唑啉基)-乙腈锌0.2662g用30mL二氯甲烷做溶剂溶解，再加入Pt(DMSO)2Cl2 0.3406g，室温下反应60小时后停止反应，过滤，加入二氯甲烷、石油醚及无水乙醇，自然挥发得一种新型的铂配合物单晶；产率85％,熔点：320-322℃；[a]5 D＝-923.1°(c＝0.156,CH3OH)；元素分析C16H26N3O3PtSCl：测试值：C:33.60％,H:4.73％,N:7.05％,S:5.58％；计算值：C:33.66％,H 4.59％,N:7.36％；S:5.61％；IR(KBr):3443,2961,2924,2210,1627,1531,1485,1450,1390,1245,1135,1081,1023,960,805,731,567,445；
配合物晶体数据如下：
晶体典型的键长数据：
晶体典型的键角数据：
4.双-(4(S)-苯基-4,5-二氢化-2-噁唑啉基)-氯化锌配合物(II)的制备在100mL两口瓶中,无水无氧条件下,加入无水ZnCl2 3.0g(22.06mmol),40mL氯苯,邻二氰基苯3.353g(26.17mmol),L-苯甘氨醇8.492g(61.91mmol))将混合物在高温下回流72h,停止反应,减压以除去溶剂,,将剩余物用水溶解,并用CHCl3(20mLx2)萃取,有机相用无水硫酸钠干燥,旋转除去溶剂,将粗产品用石油醚/二氯甲烷(1:8)柱层析,得白色晶体，产率86％；m.p.>250℃(dec),[α]25 D＝-54.9°(c＝0.0364,EtOH).δH(600MHz,CDCl3,27℃)7.77-7.79(m,2H),7.55-7.56(m,2H),7.18-7.28(m,10H),5.28(t,J＝9.2Hz,2H),4.68(t,J＝9.2Hz,2H),4.10(t,J＝8.4Hz,2H),δC(150MHz,CDCl3)163.5,140.3,129.4(x2),128.4,127.0(x2),126.0,125.3(x2),73.9,68.3.νmax(cm-1)3447,3058,2965,2907,1650,1639,1592,1495,1473,1455,1379，1363，1318，1308，1278，1238，1207,1153,1120,1067,1020,991,945,760,704,648,594,556.实验值：C:56.92,H:3.92,N:5.41％；C24H20Cl2N2O2Zn理论值：C:57.11,H:3.99,N:5.55％。
配合物晶体数据如下：
晶体典型的键长数据：
晶体典型的键角数据：
5.抗癌活性应用
本发明依据目标设计合成的锌配合物在多种癌细胞如：A549(肺癌)、口腔癌、口腔细胞癌、乳腺癌及乳腺癌细胞试验中均显示出较强的抑制活性(ED50＜10.0μg/mL)。因此，预期本发明的化合物可用于治疗多种癌症，例如肺癌、乳腺癌及乳腺癌细胞。本发明化合物的部分抗癌活性测试结果见表1。
表1.铂及锌配合物(I)的抗癌活性数据(IC50值)
Claims (2)
1.一种有如下化学式(I)所示的手性铂配合物的用途,其特征在于可用作抗癌试剂在A5499(肺癌)、KB(鼻咽癌)、KB-VIn(抗耐药性鼻咽癌)、MDA-MB-231(人乳腺癌细胞)及MCF-7(乳腺癌细胞)试验中均显示出较好的的抑制活性，其结构式如下：
2.一种有如下化学式(II)所示的手性锌配合物的用途,其特征在于可用作抗癌试剂在A549(肺癌)、KB(鼻咽癌)和KB-VIn(抗耐药性鼻咽癌)、MDA-MB-231(人乳腺癌细胞)及MCF-7(乳腺癌细胞)试验中均显示出较好的抑制活性，其结构式如下：
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