CN107793454B - 一种芳烃钌配合物及其制备方法与应用 - Google Patents
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- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
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Abstract
本发明公开了一种芳烃钌配合物，采用R1R2R3PIP为主配体，所述R1、R2、R3独立地选自‑Cl,‑F,‑Br,‑I,‑CF3,‑NO2,‑OCH3,‑OH,‑COOH,‑CH3,‑N(CH3)2,‑C2H2,‑SO2CH3、碳原子数为1～6的烷基或碳原子为1～6的取代烷基、吡啶基或取代吡啶基、呋喃基或取代呋喃基、吡咯基或取代吡咯基、噻唑或取代噻唑基；其中，所述苯基、吡啶基、呋喃基、噻唑的取代基均独立的选自羟基、硝基、卤素、氨基、羧基、氰基、巯基、碳原子数为3～8的环烷基、SO3H、碳原子数为1～6的烷基、碳原子数为2～6的链烯基、碳原子为2～6的链炔基、羟基(C1‑C6)烷基、氨基(C1‑C6)烷基、CO2R’、CONR’R’、COR’、SO2R’R’、(C1‑C6)烷氧基、(C1‑C6)烷硫基、‑N＝NR’、NR’R’或三氟(C1‑C6)烷基中的任一种。
Description
技术领域
本发明涉及合成化学技术领域，尤其是涉及一种芳烃钌配合物，本发明还涉及一种芳烃钌配合物的制备方法与应用。
背景技术
芳烃钌配合物具有经典的“钢琴凳”空间结构，是一类以强疏水性的苯或者取代苯作为辅助配体，通过苯环上π轨道上的电子与中心金属钌形成共价键的小分子金属有机化合物。从1967年，Winkhaus和Singer首次合成芳烃钌(II)化合物[1]开始，国内外就有大量文献报道各种不同结构类型的芳烃钌配合物的合成和抗肿瘤的作用。
Kondapi等人报道以[(η6-C6H6)Ru(DMSO)Cl2]2 +为代表的芳烃钌配合物对人结肠癌Colo-205细胞和乳腺癌ZR-75-1细胞均表现出良好的抑制作用，同时对DNA具有很强的亲和力，还能抑制拓扑异构酶II来抑制肿瘤细胞的生长与增殖，显示此类配合物的特性[]Vashisht GYN,Konuru N,KondapiAK.Topoisomerase II antagonism and anticanceractivity of coordinated derivatives of[RuCl2(C6H6)(dmso)][J].Arch.Biochem.Biophys,2002,401(1):53-62]。
Dyson等人报道的一类以金刚烷胺为配体的芳烃钌(II)配合物是通过[RuCl2(η6-arene)]2(0.64mmol)和PTA(1.28mmol)在甲醇溶液中加热回流24小时得到,产率85-95％。[Scolaro C,Bergamo A,Brescacin L,Delfino R,Cocchietto M,Laurenczy G,GeldbachTJ,Sava G,Dyson PJ.In vitro and in vivo evaluation of ruthenium(II)-arenePTAcomplexes.[J].J Med Chem,2005,48:4161–4171]此类配合物对TS/A老鼠腺癌细胞有一定活性(IC50 60～300μM)，对人体正常细胞毒性较小(IC50>300μM)。其中RAPTA-B([Ru(η6-C6H6)(pta)Cl2])和RAPTA-C([Ru(η6-p-C6H4MeiPr)(pta)Cl2])通过调控线粒体和p53–JNK多种细胞信号通路，调高p21的水平和减少细胞周期蛋白E的量，导致肿瘤细胞发生G2/M期阻滞，继而诱导细胞凋亡。[Chatterjee S,Kundu S,Bhattacharyya A,Hartinger CG,DysonPJ,The ruthenium(II)–arene compound RAPTA-C induces apoptosis in EAC cellsthrough mitochondrial and p53–JNK pathways.[J].J Biol Inorg Chem,2008,13:1149–1155]体内实验发现RAPTA-C能在患有MCa乳腺癌的CBA老鼠体内通过抑制血管生成来抑制肿瘤增殖和转移。[Nowak-Sliwinska P,Van BJR,Casini A.Organometa llicruthnium(II)arene compounds with antiangiogenic activity[J].J.Med.Chem.2011,54(11):3895-3902]
Sadler等人报道的乙二胺配位的芳烃钌(II)配合物是通过[RuCl2(η6-arene)]2(0.64mmol)和乙二胺衍生物(2.0mmol)在甲醇溶剂中搅拌1.5小时，后加入NH4PF6，过滤，取滤液于冰箱中重结晶6小时得到。产率37.7％。这类化合物在体外实验中对A2780人卵巢癌有很好活性，但没有交叉耐药性。该化合物可以紧密结合DNA的鸟嘌呤，是抗肿瘤细胞活性实现靶向定位的重要途径。[Morris RE,Aird RE,del Socorro Murdoch P,Chen H,Cum-mings J,Hughes ND,Parsons S,Parkin A,Boyd G,Jodrel lD I,Sadler PJ.Inhibitionof cancer cell growth by ruthenium(II)arene complexes.J Med Chem,2001,44:3616–3621]其中RM175([(η6-biphenyl)Ru(eth-ylenediamine)-Cl]+)通过促进细胞-细胞再粘连和降低金属蛋白酶(MMPs)的释放来抑制肿瘤的侵袭与转移。[Bergamo A,Masi A,Peacock AF,Habtemariam A,Sadler PJ,Sava GJ.In vivo tumour and metastasisreduction and in vitro effects on invasion assays of the ruthenium RM175andosmium AFAP51organometallics in the mammary cancer model Inorg.Biochem,2010,104:79-86，[Habtemariam A,Melchart M,Fernandez R,Parsons S,Oswald IDH,ParkinA,Fabbiani FPA,Davidson JE,Dawson A,Aird RE,Jodrell DI,Sadler PJ.Structure-activity relationships for cytotoxic ruthenium(II)arene complexes containingN,N-,N,O-,and O,O-che-lating ligands.J.Med Chem,2006,49:6858–6868]Sadler等人报道的2,4-戊二酮配位的芳烃钌(II)配合物[(η6-arene)Ru(β-diketonate)Cl]通过[RuCl2(η6-arene)]和乙酰丙酮钠在丙酮中搅拌50min得到，产率61.2％。这类配合物在体外实验中对人卵巢癌A2780细胞的IC50值取决于芳环辅助配体的种类，在同类配体下，芳环为对甲基异丙基苯活性最高，[(η6-p-cymene)Ru(β-diketonate)Cl]对人卵巢癌细胞A2780的IC50为17μM，具有良好的抗肿瘤作用。
国内毛宗万教授等人报道的咔啉配位的芳烃钌(II)配合物是通过[RuCl2(η6-arene)]0mmol)和咔啉衍生物(2.00mmol)在甲醇溶液中回流2.5小时得到。产率78％。此类配合物在体外的抗肿瘤活性比卡铂类高3～12倍，没有交叉耐药性，对正常细胞毒性小，对顺铂耐药的细胞A549cisR具有较高活性，对正常人非成纤维细胞HLF具有较低毒性。该类配合物通过下调CDK 1和cyclin B1的表达，直接靶向CDK 1(细胞周期素依赖性激酶)，导致肿瘤细胞发生G2M期阻滞，还能够通过跟线粒体有关的通路诱导肿瘤细胞凋亡并能提高细胞内活性氧物质ROS的量。[He L，Liao SY,Tan CP,Ye RR,Xu YW，Zhao M,，Ji LN，MaoZW.Ruthenium–Arene–β-Carboline Complexes as Potent Inhibitors of Cyclin-Dependent Ki-nase 1:Synthesis,Characterization and Anticancer MechanismStudies.Chem.Eur.J,2013,19,12152–12160
国内苏炜教授等人报导的缩氨基硫脲化合物配位的3个芳烃钌(II)配合物[(η6-p-cymene)Ru(R-BzTSC)Cl]Cl(BzTSC＝苯甲醛缩氨基硫脲，R＝H,CH3and C6H5)是通过[RuCl2(η6-p-cymene)](0.05mmol)和苯甲醛缩氨基硫脲(0.1mmol)在丙酮溶液中45℃加热回流6小时得到。产率39％。此类芳烃钌(II)配合物在体外实验中对鼻咽癌、肺癌、乳腺癌和卵巢癌细胞均有很好的抗增殖活性。其中配合物[(η6-p-cymene)Ru(C6H5-BzTSC)Cl]Cl的活性最好，IC50值分别为20μM,31μM,10μM和34μM[Su W,Zhou Q,Huang YM,et al.Synthesis,crystal and electronic structure,anticancer activity of ruthenium(II)arenecomplexes withthiosemicarbazones[J].Appl.Organometal.Chem.2013,27(5):307-312.]。
目前的芳烃钌配合物，根据配体的不同，通常针对不同的肿瘤的作用不同，因此，对于不同的肿瘤症状，需要研发出不同的芳烃钌配合物。
发明内容
本发明的目的之一，在于提出一种芳烃钌配合物，对多种肿瘤株具有高抑制作用。
为解决上述技术问题，本发明采用以下技术方案予以实现：一种芳烃钌配合物，采用R1R2R3PIP为主配体，结构式如下：
其中,所述R1、R2、R3独立地选自-H,-Cl,-F,-Br,-I,-CF3,-NO2,-OCH3,-OH,-COOH,-CH3,-N(CH3)2,-C2H2,-SO2CH3、碳原子数为1～6的烷基或碳原子为1～6的取代烷基、苯基或取代苯基、吡啶基或取代吡啶基、呋喃基或取代呋喃基、吡咯基或取代吡咯基、噻唑或取代噻唑基；其中，所述苯基、吡啶基、呋喃基、噻唑的取代基均独立的选自羟基、硝基、卤素、氨基、羧基、氰基、巯基、碳原子数为3～8的环烷基、SO3H、碳原子数为1～6的烷基、碳原子数为2～6的链烯基、碳原子为2～6的链炔基、羟基(C1-C6)烷基、氨基(C1-C6)烷基、CO2R’、CONR’R’、COR’、SO2R’R’、(C1-C6)烷氧基、(C1-C6)烷硫基、-N＝NR’、NR’R’或三氟(C1-C6)烷基中的任一种；其中，所述R’独立的选自H、碳原子数为1～6的烷基或苯基。
进一步，所述芳烃钌配合物的化学式为[(η6-p-cymene)Ru(RPIP)Cl]Y，其中R包括R1、R2、R3，结构式如下。
其中,所述Y选自氯离子、碘离子、溴离子、高氯酸根、六氟合磷酸根，硒酸根中任一种，优选氯离子。
进一步，更为具体的，所述芳烃钌配合物的结构式可为：
本发明的另一目的在于提出一种芳烃钌配合物的制备方法，工艺简单，易于推广。
所述芳烃钌配合物的制备方法，采用微波合成法。
进一步，所述芳烃钌配合物的制备方法包括步骤：
i)由RuCl3与1-甲基-4-异丙基-1,3-环己二烯30-180℃下，微波辐射15s-60min，或者30-180℃下回流1h-7d，制备得到[(η6-p-cymene)RuCl]2Cl2，
ii)[(η6-p-cymene)RuCl]2Cl2和菲并咪唑衍生物在溶剂中，30-180℃下，微波辐射15s-60minh或者30-180℃下回流1h-7d得到[(η6-p-cymene)Ru(RPIP)Cl]Cl。
进一步，步骤ii中，用[(η6-p-cymene)RuCl]2Cl2与菲并咪唑衍生物在二氯甲烷溶剂中反应。
本发明的另一目的在于提出一种芳烃钌配合物的应用，所述芳烃钌配合物在抑制肿瘤中的应用。尤其是在抑制乳腺癌、脑胶质瘤、白血病、鼻咽癌和肺腺癌中的应用，具有良好的肿瘤抑制效果。
本发明的所述芳烃钌配合物，通过采用了RPIP为主配体，并结合其他结构，能够形成多个具有抗肿瘤效果的产物群体，其在抗肿瘤，尤其是转移性肿瘤，如乳腺癌、脑胶质瘤、白血病、鼻咽癌和肺腺癌中，具有良好的抗肿瘤效果。能够为抗击肿瘤提供一个可挖掘参考的研究方向。
此外，本申请中还公开了所述芳烃钌配合物的制备方法，整体简便快捷，易于扩大生产。
附图说明
图1为RAP051的ESI-MS图谱；
图2为RAP051的1H NMR图谱；
图3为RAP051的13C NMR图谱；
图4为RAP09的ESI-MS图谱；
图5为RAP09的1H NMR图谱；
图6为RAP09的13C NMR图谱；
图7为RAP143的ESI-MS图谱；
图8为RAP143的1H NMR图谱；
图9为RAP143的13C NMR图谱；
图10为RAP271的ESI-MS图谱；
图11为RAP271的1H NMR图谱；
图12为RAP271的13C NMR图谱；
图13为RAP211的ESI-MS图谱；
图14为RAP211的1H NMR图谱；
图15为RAP211的13C NMR图谱；
图16为RAP052的ESI-MS图谱；
图17为RAP052的1HNMR图谱；
图18为RAP052的13CNMR图谱；
图19为RAP061的ESI-MS图谱；
图20为RAP061的1H NMR图谱；
图21为RAP061的13C NMR图谱；
图22为RAP031的ESI-MS图谱；
图23为RAP031的1H NMR图谱；
图24为RAP031-X的13C NMR图谱；
图25为RAP141的ESI-MS图谱；
图26为RAP141的1H NMR图谱；
图27为RAP141的13C NMR图谱；
图28为RAP201的ESI-MS图谱；
图29为RAP201的1H NMR图谱；
图30为RAP201的13C NMR图谱；
图31为RAP041的ESI-MS图谱；
图32为RAP041的1H NMR图谱；
图33为RAP041的13C NMR图谱；
图34为RAP062的ESI-MS图谱；
图35为RAP062的1HNMR图谱；
图36为RAP062的13CNMR图谱；
图37为RAP032的ESI-MS图谱；
图38为RAP032的1H NMR图谱；
图39为RAP032的13C NMR图谱；
图40为RAP203的ESI-MS图谱；
图41为RAP203的1H NMR图谱；
图42为RAP203的13C NMR图谱；
图43为RAP01的ESI-MS图谱；
图44为RAP01的1HNMR图；
图45为RAP01的13C NMR图谱；
图46为RAP13的ESI-MS图谱；
图47为RAP13的1H NMR图谱；
图48为RAP13的13C NMR图谱；
图49为RAP073的ESI-MS图谱；
图50为RAP073的1HNMR图谱；
图51为RAP073的13CNMR图谱；
图52为RAP093的ESI-MS图谱；
图53为RAP093的1H NMR图谱；
图54为RAP093的13C NMR图谱；
图55为RAP04的ESI-MS图谱；
图56为RAP04的1HNMR图谱；
图57为RAP04的13CNMR图谱；
图58为RAP07的ESI-MS图谱；
图59为RAP07的1H NMR图谱；
图60为RAP07的13C NMR图谱；
图61为RAP22的ESI-MS图谱；
图62为RAP22的1H NMR图谱；
图63为RAP22的13C NMR图谱；
图64为RAP33的ESI-MS图谱；
图65为RAP33的1H NMR图谱；
图66为RAP33的13C NMR图谱；
图67为RAP83的ESI-MS图谱；
图68为RAP83的1H NMR图谱；
图69为RAP83的13C NMR图谱；
图70为RAP27的ESI-MS图谱；
图71为RAP27的1H NMR图谱；
图72为RAP27的13C NMR图谱；
图73为实施例36芳烃钌化合物RAP07对MDA-MB-231迁移的抑制对比效果图；
图74为实施例37芳烃钌化合物RAP07对MDA-MB-231侵袭的抑制对比效果图；
图75为实施例38具有亚二倍体DNA的凋亡细胞的含量测量，细胞周期分布效果图。
具体实施方式
为让本领域的技术人员更加清晰直观的了解本发明，下面将结合附图，对本发明作进一步的说明。
实施例1
[(η6-p-cymene)RuCl]2Cl2的制备
RuCl3与1-甲基-4-异丙基-1,3-环己二烯，50℃下，微波辐射30min，抽滤，得到[(η6-p-cymene)RuCl]2Cl2。
实施例2
[(η6-p-cymene)Ru(o-ClPIP)Cl]Cl(编号RAP051)的合成：
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体o-ClPIP(0.2mmol,66.1mg)，60℃下，微波辐射15s，得亮橙黄色固体124.5mg，即为[(η6-p-cymene)Ru(o-ClPIP)Cl]Cl(RAP051)，产率97.9％。
RAP051的ESI-MS图谱如图1-图3所示，ESI-MS(in MeOH,m/z):636(Cal.)，601(Foundfor[M-Cl]+)，565(Found for[M-2Cl-H]+)。1H NMR(500MHz,DMSO-d6)δ9.89(d,J＝5.2Hz,1H)，9.32(d,J＝8.1Hz,1H)，8.20(dd,J＝8.2,5.3Hz,1H)，8.01(s,1H)，7.69(dd,J＝23.2,8.0Hz,1H)，7.63–7.55(m,1H)，6.37(d,J＝6.2Hz,1H)，6.13(d,J＝6.2Hz,1H)，2.23(d,J＝9.5Hz,1H)，1.47–1.06(m,1H)，0.91(d,J＝6.9Hz,3H)。13C NMR(126MHz,DMSO-d6)δ154.24(s),152.11–148.43(m)，143.64(s)，134.16–132.32(m)，131.98(s)，130.89(s)，130.55(d,J＝85.9Hz)，127.95(s)，126.70(s)，104.28(s)，103.57(s)，86.73(s)，84.38(s)，22.13(s)，18.77(s)。
实施例3
[(η6-p-cymene)Ru(PIP)Cl]Cl(编号RAP09)的合成：
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体PIP(0.2mmol,59.2mg)，60℃下，微波辐射30min，得橙黄色固体，113mg，产率91.0％.ESI-MS(in MeOH,m/z):592(Cal.),567(Found for[M-Cl]+).1H NMR(500MHz,DMSO-d6)δ9.85(d,J＝5.2Hz,1H),9.45(s,1H),8.48(d,J＝7.9Hz,1H),8.19(dd,J＝8.1,5.3Hz,1H),7.59(dd,J＝20.7,13.2Hz,1H),7.55(dd,J＝20.2,13.0Hz,1H),6.35(d,J＝6.2Hz,1H),6.12(d,J＝6.2Hz,1H),2.82–2.52(m,1H),2.23(d,J＝19.7Hz,2H),1.30–1.06(m,1H),0.89(t,J＝15.6Hz,3H).13C NMR(126MHz,DMSO-d6)δ153.53(s),143.02(s),132.60(s),130.03(s),128.99(s),126.74(s),126.05(s),103.79(s),102.91(s),86.19(s),83.91(s),73.23–27.78(m),21.53(d,J＝16.7Hz),18.24(s).
实施例4
(η6-p-cymene)Ru(p–NO2PIP)Cl]Cl(RAP143)的合成
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体p–NO2PIP(0.2mmol,68.2mg)，60℃下，微波辐射60min，得黄色固体，124.3mg，产率96.05％.ESI-MS(in MeOH,m/z):647(Cal.),612(Found for[M-Cl]+),576(Found for[M-2Cl-H]+).1H NMR(500MHz,DMSO)δ9.88(d,J＝4.8Hz,2H),9.41(s,2H),8.69(d,J＝8.8Hz,2H),8.42(d,J＝8.9Hz,2H),8.19(dd,J＝8.2,5.3Hz,2H),6.36(d,J＝6.4Hz,2H),6.14(d,J＝6.3Hz,2H).13C NMR(126MHz,DMSO)δ154.44(s),148.27(s),143.96(s),133.25(s),128.09(s),126.73(s),124.80(s),104.48(s),103.32(s),86.68(s),84.50(s),30.90(s),22.12(s),18.72(s).
实施例5
[(η6-p-cymene)Ru(o–CH3PIP)Cl]Cl(RAP271)的合成:
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体o–CH3PIP(0.2mmol,62.0mg)，30℃下，微波辐射30min，得橙黄色固体，118.5mg，产率96.2％.ESI-MS(in MeOH,m/z):616(Cal.),581(Found for[M-Cl]+),1H NMR(500MHz,DMSO)δ9.88(dd,J＝5.2,0.8Hz,2H),9.39(s,1H),8.20(dd,J＝8.2,5.3Hz,1H),7.99(d,J＝7.3Hz,1H),7.48–7.38(m,1H),6.37(d,J＝6.4Hz,1H),6.13(d,J＝6.3Hz,1H).13C NMR(126MHz,DMSO)δ153.66(s),143.02(s),137.21(s),132.57(s),131.35(s),129.80(s),126.08(d,J＝13.1Hz),126.08(d,J＝13.1Hz),103.77(s),103.41(d,J＝91.3Hz),103.04(s),86.22(s),85.04(d,J＝295.9Hz),83.87(s),30.38(s),21.63(s),21.08(s),18.27(s).
实施例6
[(η6-p-cymene)Ru(o–COOHPIP)Cl]Cl(RAP211)的合成:
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体o-COOHPIP(0.2mmol,68.0mg)，60℃下，微波辐射30min，得橙黄色固体，110.8mg，产率85.8％.ESI-MS(in MeOH,m/z):646(Cal.),611(Found for[M-Cl]+),1H NMR(500MHz,DMSO)δ9.88(dd,J＝5.3,1.1Hz,2H),9.21(d,J＝8.1Hz,2H),8.20(dd,J＝8.3,5.3Hz,2H),8.09(d,J＝7.5Hz,2H),8.00(dd,J＝7.7,1.1Hz,1H),7.74(td,J＝7.6,1.3Hz,2H),7.67(td,J＝7.6,1.2Hz,2H).13C NMR(126MHz,DMSO)δ168.97(s),154.14(s),153.84(s),143.48(s),133.81(s),133.81(s),132.70(s),132.70(s),131.54(s),131.54(s),130.95(s),130.80(s),130.31(d,J＝7.9Hz),130.31(d,J＝7.9Hz),126.71(s),104.34(s),103.46(s),86.84(s),86.72(s),85.98(s),84.40(s),49.06(s),30.89(s),22.14(s),18.54(d,J＝51.5Hz).
实施例7
[(η6-p-cymene)Ru(m-ClPIP)Cl]Cl(RAP052)的合成：
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体m-ClPIP(0.2mmol,66.1mg)，180℃下，微波辐射30min，得亮橙黄色固体，124.5mg，产率97.9％.ESI-MS(in MeOH,m/z):636(Cal.),601(Found for[M-Cl]+),565(Found for[M-2Cl-H]+).1H NMR(500MHz,DMSO-d6).δ9.85(d,J＝5.2Hz,1H),9.33(d,J＝85.0Hz,1H),8.53(s,1H),8.42(t,J＝24.6Hz,1H),8.19(dd,J＝8.1,5.3Hz,1H),8.07–8.04(m,1H),7.80–7.49(m,1H),6.35(d,J＝6.1Hz,2H),6.13(s,2H),2.69–2.52(m,1H),2.23(d,J＝21.0Hz,3H),0.89(t,J＝16.2Hz,6H).13C NMR(126MHz,DMSO-d6)δ153.55(s),153.55(s),143.12(s),143.12(s),133.78(s),132.57(s),130.93(s),130.14–129.64(m),126.10(d,J＝11.6Hz),125.22(s),103.81(s),102.87(s),86.26(d,J＝19.7Hz),83.93(s),30.16(d,J＝55.3Hz),21.54(d,J＝17.4Hz),18.23(s).
实施例8
[(η6-p-cymene)Ru(o-BrPIP)Cl]Cl(RAP061)的合成：
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体o-BrPIP(0.2mmol,74.8mg)，60℃下，微波辐射30min，得亮橙黄色固体，127.0mg，产率93.4％.ESI-MS(in MeOH,m/z):680(Cal.),645(Found for[M-Cl]+),609(Found for[M-2Cl-H]+).1H NMR(500MHz,DMSO-d6)δ9.90(d,J＝5.2Hz,2H),9.30(d,J＝6.7Hz,2H),8.24(dd,J＝26.7,8.3,5.2Hz,2H),7.89(dd,J＝7.7,3.6Hz,2H),7.63(t,J＝7.5Hz,H),7.54(dd,J＝15.5,7.8Hz,H),6.38(d,J＝6.2Hz,2H),6.32–6.10(m,2H),2.70–2.58(m,1H),2.51(s,3H),0.93(t,J＝10.9Hz,6H).13C NMR(126MHz,DMSO-d6)δ153.91(s),151.88(s),143.19(s),132.97(d,J＝127.9Hz),132.42(d,J＝8.0Hz),131.60(s),127.92(s),126.31(s),121.87(s),103.88(s),103.04–98.30(m),86.23(s),83.90(s),30.38(s),21.65(s),18.26(s).
实施例9
[(η6-p-cymene)Ru(o-CF3PIP)Cl]Cl(RAP031)的合成：
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体o-CF3PIP(0.2mmol,72.8mg)，60℃下，微波辐射30min，得草绿色固体，127.0mg，产率94.8％.ESI-MS(in MeOH,m/z):670(Cal.),635(Found for[M-Cl]+).1H NMR(500MHz,DMSO-d6)δ9.96–9.56(m,2H),9.25(t,J＝15.9Hz,1H),8.28–8.11(m,2H),8.01(d,J＝7.9Hz,1H),7.95–7.87(m,1H),7.85–7.77(m,1H),6.38(t,J＝8.6Hz,1H),6.14(t,J＝10.1Hz,1H),2.64(td,J＝13.9,7.1Hz,1H),2.26–2.15(m,2H),0.93(d,J＝6.9Hz,4H).13C NMR(126MHz,DMSO-d6)δ153.71(s),143.13(s),132.56–132.09(m),126.82(s),126.23(s),103.89(s),102.94(s),86.27(d,J＝16.9Hz),83.90(s),30.39(s),21.65(s),18.24(s).
实施例10
[(η6-p-cymene)Ru(o–NO2PIP)Cl]Cl(RAP141)的合成：
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体o–NO3PIP(0.2mmol,68.2mg)，60℃下，微波辐射30min，得橙黄色固体，122.5mg，产率94.7％.ESI-MS(in MeOH,m/z):647(Cal.),612(Found for[M-Cl]+),576(Found for[M-2Cl-H]+).1H NMR(500MHz,DMSO)δ9.86(dd,J＝9.2,8.6Hz,2H),9.24(d,J＝6.6Hz,2H),8.29(dd,J＝7.8,1.2Hz,2H),8.17(dd,J＝8.2,5.3Hz,2H),8.05(d,J＝8.0Hz,2H),7.96–7.85(m,2H),7.81–7.74(m,2H),6.35(d,J＝6.4Hz,2H),6.11(d,J＝6.4Hz,2H).13C NMR(126MHz,DMSO)δ156.03(s),150.83(s),145.31(s),134.78(s),133.31(s),128.35(s),126.45(s),105.95(s),105.03(s),88.24(s),85.93(s).
实施例11
[(η6-p-cymene)Ru(o–OCH3PIP)Cl]Cl(RAP201)的合成:
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体o–OCH3PIP(0.2mmol,65.2mg)，60℃下，微波辐射30min，得橙色固体，118.6mg，产率93.8％.ESI-MS(in MeOH,m/z):647(Cal.),632(Found for[M-Cl]+),561(Found for[M-2Cl-H]+).1H NMR(500MHz,DMSO)δ9.88(dd,J＝5.3,1.2Hz,2H),9.43(s,2H),8.20(ddd,J＝13.3,7.9,3.4Hz,2H),8.20(ddd,J＝13.6,8.0,3.5Hz,2H),7.55(ddd,J＝8.4,7.3,1.8Hz,2H),7.40–7.24(m,2H),7.18(td,J＝7.6,1.0Hz,2H),6.36(d,J＝6.5Hz,2H),6.13(d,J＝6.4Hz,2H).13C NMR(126MHz,DMSO)δ158.76(s),155.75(s),152.81(s),145.05(s),134.73(s),134.73(s),133.89(s),128.07(s),122.89(s),120.04(s),114.12(s),105.84(s),105.00(s),88.30(d,J＝15.5Hz),85.96(s),58.04(s),41.81(dt,J＝26.5,12.5Hz),41.47(d,J＝12.9Hz),41.36(s),41.23(s),41.11(d,J＝21.0Hz),32.40(s),23.56(d,J＝17.8Hz),20.28(s).
实施例12
[(η6-p-cymene)Ru(o-FPIP)Cl]Cl(RAP041)的合成：
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体o-FPIP(0.2mmol,62.8mg，60℃下，微波辐射30min，得橙黄色固体，112.3mg，产率90.5％.ESI-MS(in MeOH,m/z):620(Cal.),585(Found for[M-Cl]+),549(Found for[M-2Cl-H]+).1H NMR(500MHz,DMSO)δ9.87(dd,J＝5.3,1.2Hz,2H),9.40(d,J＝7.3Hz,2H),8.31(td,J＝7.7,1.7Hz,1H),8.19(dd,J＝8.3,5.3Hz,2H),7.61(tdd,J＝7.1,5.1,1.8Hz,1H),7.54–7.37(m,2H).13C NMR(126MHz,DMSO)δ162.32(s),155.81(s),155.81(s),150.72(s),145.20(s),134.67(s),134.67(s),134.15(s),132.69(s),132.69(s),128.19(s),128.19(s),127.07(s),120.15(s),118.67(d,J＝21.4Hz),105.83(s),105.83(s),105.05(s),105.05(s),88.30(d,J＝13.7Hz),88.25(s),87.50(s),85.93(s),85.93(s),42.53–41.51(m),41.51–41.43(m),41.36(s),41.19(s),41.02(s),32.40(s),23.56(d,J＝17.7Hz),20.28(s),19.86(s).
实施例13
[(η6-p-cymene)Ru(m-BrPIP)Cl]Cl(RAP062)的合成：
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体m-BrPIP(0.2mmol,74.8mg)，60℃下，微波辐射30min，得亮橙黄色固体126.0mg，产率92.6％.ESI-MS(in MeOH,m/z):680(Cal.),645(Found for[M-Cl]+).1H NMR(500MHz,DMSO)δ9.88(dd,J＝5.3,1.1Hz,2H),9.43(s,2H),8.65(t,J＝1.7Hz,2H),8.54–8.40(m,2H),8.21(dd,J＝8.2,5.3Hz,2H),7.71(ddd,J＝8.0,1.9,0.8Hz,1H),7.54(t,J＝7.9Hz,2H),6.36(d,J＝6.4Hz,2H),6.13(d,J＝6.4Hz,2H).13C NMR(126MHz,DMSO)δ154.36(s),143.74(s),133.23(s),131.73(s),129.52(s),126.70(s),126.14(s),122.83(s),104.43(s),103.38(s),86.68(s),84.46(s),30.89(s),22.12(s),18.73(s).
实施例14
[(η6-p-cymene)Ru(m-OHPIP)Cl]Cl(RAP032)的合成：
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体o-OHPIP(0.2mmol,62.4mg)，60℃下，微波辐射30min，得亮橙黄色固体，115.0mg，产率93.0％.ESI-MS(in MeOH,m/z):618(Cal.),583(Found for[M-Cl]+),548(Found for[M-2Cl-H]+).1H NMR(500MHz,DMSO)δ9.85(d,J＝5.1Hz,2H),9.39(s,2H),8.18(dd,J＝8.2,5.3Hz,2H),7.91(d,J＝7.8Hz,2H),7.84(s,1H),7.39(t,J＝7.9Hz,2H),6.96(dd,J＝8.0,2.0Hz,2H),6.34(d,J＝6.3Hz,2H),6.12(d,J＝6.3Hz,2H).13C NMR(126MHz,DMSO)δ158.36(s),153.93(s),143.45(s),133.00(s),130.53(s),126.50(s),118.06(s),117.63(s),113.95(s),104.25(s),103.41(s),86.69(s),84.40(s),30.88(s),22.10(s),18.74(s).
实施例15
(η6-p-cymene)Ru(p–OCH3PIP)Cl]Cl(RAP203)的合成：
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体p–OCH3PIP(0.2mmol,65.2mg)，60℃下，微波辐射30min，得橙色固体，124.2mg，产率98.3％.ESI-MS(in MeOH,m/z):632(Cal.),597(Found for[M-Cl]+),561(Found for[M-2Cl-H]+).1H NMR(500MHz,DMSO-d6)δ9.85(dd,J＝5.3,1.0Hz,1H),9.43(s,1H),8.43(d,J＝8.5Hz,1H),8.17(dd,J＝8.2,5.3Hz,1H),7.16(d,J＝8.9Hz,1H),6.34(d,J＝6.4Hz,1H),6.11(d,J＝6.4Hz,1H),3.86(s,2H),2.59(tt,J＝18.6,9.2Hz,1H),2.19(s,1H),0.89(d,J＝6.9Hz,3H).13C NMR(126MHz,DMSO-d6)δ162.90(s),155.41(d,J＝43.1Hz),144.91(s),134.63(s),130.47–128.84(m),128.06(s),124.12(s),116.49(s),105.82(s),104.91(s),88.22(s),85.97(s),57.43(s),32.42(s),23.64(s),20.27(s).
实施例16
[(η6-p-cymene)Ru(IP)Cl]Cl(RAP01)的合成:
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体IP(0.2mmol,44.0mg)，60℃下，微波辐射30min，得土黄色固体82.9mg，产率78.8％。ESI-MS(in MeOH,m/z):526(Cal.),491(Found for[M-Cl]+),455(Found for[M-2Cl-H]+).1HNMR(500MHz,DMSO)δ9.85(dd,J＝5.3,1.0Hz,1H),9.25(dd,J＝8.2,0.8Hz,1H),8.64(s,1H),8.18(dd,J＝8.2,5.3Hz,1H),6.35(d,J＝6.4Hz,1H).13C NMR(126MHz,DMSO)δ154.02(s),144.36(s),143.50(s),132.79(s),126.61(s),124.17–123.68(m),104.30–104.21(m),103.54–103.33(m),86.70(s),84.38(s),30.87(s),22.10(s),18.73(s).
实施例17
[(η6-p-cymene)Ru(p–C2H2PIP)Cl]Cl(RAP13)的合成：
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体p–C2H2PIP(0.2mmol,64.2mg)，60℃下，微波辐射30min，得黑褐固体，108.5mg，产率86.7％.ESI-MS(in MeOH,m/z):626(Cal.),591(Found for[M-Cl]+).1H NMR(500MHz,DMSO-d6).1H NMR(500MHz,DMSO)δ10.46–9.87(m,1H),9.61(d,J＝8.1Hz,1H),8.50–8.08(m,2H),8.16–7.72(m,1H),6.44(d,J＝6.2Hz,1H),6.22(d,J＝6.1Hz,1H),5.80(dd,J＝19.0,6.4Hz,1H),2.50(dt,J＝3.7,1.8Hz,2H),2.23(s,2H),1.10–0.89(m,3H).13C NMR(126MHz,DMSO)δ159.52(s),149.96(s),143.79(s),141.12(s),137.27(s),134.49(s),131.33(s),129.68(s),106.84(s),87.97(s),86.30(s),83.89–30.19(m),23.81(s),20.29(s)
实施例18
[(η6-p-cymene)Ru(o-OHPIP)Cl]Cl(RAP032)的合成：
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体o-OHPIP(0.2mmol,62.4mg)，60℃下，微波辐射30min，得亮橙黄色固体，115.0mg，产率93.0％.ESI-MS(in MeOH,m/z):618(Cal.),583(Found for[M-Cl]+),548(Found for[M-2Cl-H]+).1H NMR(500MHz,DMSO-d6)1H NMR(500MHz,DMSO)δ10.12–9.94(m,1H),9.81(d,J＝5.0Hz,3H),9.39(s,2H),8.52(d,J＝7.6Hz,1H),8.13(dd,J＝8.0,5.4Hz,2H),7.32(t,J＝6.7Hz,1H),7.03–6.97(m,2H),6.34(d,J＝6.2Hz,2H),6.11(d,J＝6.1Hz,3H).13C NMR(126MHz,DMSO-d6)δ157.86(s),143.20(s),132.96(s),126.21(s),119.39(s),117.31(s),103.72(d,J＝98.7Hz),103.33(s),86.75(d,J＝20.7Hz),84.37(s),30.66(d,J＝54.9Hz),22.08(t,J＝12.4Hz),18.54(d,J＝50.2Hz).
实施例19
[(η6-p-cymene)Ru(p–IPIP)Cl]Cl(RAP073)的合成:
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体p–I(0.2mmol,84.2mg)，60℃下，微波辐射30min，得土黄色固体，111.7mg，产率76.7％.ESI-MS(in MeOH,m/z):728(Cal.),693(Found for[M-Cl]+),657(Found for[M-2Cl-H]+).1H NMR(500MHz,DMSO)δ9.85(d,J＝5.1Hz,2H),9.32(s,2H),8.19(dd,J＝6.3,4.5Hz,2H),8.00(t,J＝8.6Hz,2H),6.35(d,J＝6.3Hz,2H),6.13(t,J＝9.0Hz,2H).13C NMR(126MHz,DMSO)δ154.89–152.55(m),143.55–142.52(m),137.91(s),133.35–131.58(m),128.42(s),126.41–124.64(m),104.31–103.57(m),103.27–101.94(m),86.20(s),83.91(s),80.30–78.86(m),48.57(s),30.38(s),21.60(s),18.24(s).
实施例20
[(η6-p-cymene)Ru(p–N(CH3)2PIP)Cl]Cl(RAP093)的合成:
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,61.2mg)，配体p–N(CH3)2PIP(0.2mmol,68.2mg)，60℃下，微波辐射30min，得亮红色固体，120.7mg，产率93.6％.ESI-MS(in MeOH,m/z):645(Cal.),610(Found for[M-Cl]+)1H NMR(500MHz,DMSO)δ9.89(dd,J＝5.3,1.0Hz,2H),8.58(dd,J＝7.9,1.4Hz,1H),8.21(dd,J＝8.2,5.3Hz,1H),7.41–7.36(m,1H),7.04(ddd,J＝15.1,8.2,4.2Hz,2H),6.58–6.20(m,2H),6.36(d,J＝6.4Hz,2H),6.14(d,J＝6.4Hz,2H).13C NMR(126MHz,DMSO)δ155.71–153.66(m),153.17(s),151.37(s),142.57(s),132.42(s),127.94(s),125.82(s).
实施例21
化合物[(η6-p-cymene)Ru(p-FPIP)Cl]Cl(RAP04)的合成
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,58.3mg)，配体p-FPIP(0.22mmol,69.1mg)，60℃下，微波辐射30min，得黄色固体132.5mg,产率81.3％,ESI-MS:m/z 585,([M]+)；1H NMR(500MHz,DMSO-d6)δ9.86(dd,J＝5.3,1.1Hz,1H),9.03(dd,J＝4.3,1.7Hz,1H),8.57–8.49(m,1H),8.19(dd,J＝8.2,5.3Hz,1H),7.46(t,J＝8.8Hz,1H),6.35(d,J＝6.5Hz,1H),6.13(d,J＝6.4Hz,1H),2.21(s,3H),0.91(d,J＝6.9Hz,6H).13CNMR(126MHz,DMSO-d6)δ153.66(s),143.10(s),132.63(s),129.18(s),129.11(s),126.15(s),103.90(s),102.95(s),86.26(s),84.02(s),30.47(s),21.69(s),18.31(s).
实施例22
化合物[(η6-p-cymene)Ru(p-BrPIP)Cl]Cl(RAP07)的合成
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,58.3mg)，配体p-BrPIP(0.22mmol,82.5mg)，60℃下，微波辐射30min，得黄色固体132.5mg,产率99.3％.ESI-MS:m/z 647.1,([M]+)；1H NMR(500MHz,DMSO-d6)δ9.82(d,J＝4.6Hz,1H),9.31(d,J＝7.0Hz,1H),8.38-8.33(m,1H),8.16(dd,J＝8.2,5.3Hz,1H),7.80(d,J＝8.6Hz,1H),6.33(d,J＝6.4Hz,1H),6.11(d,J＝6.4Hz,1H),2.20(s,3H),0.88(t,J＝12.3Hz,6H).13C NMR(126MHz,DMSO-d6)δ153.28(s),142.98(s),132.38(s),131.99(s),128.53(s),125.99(s),103.72(s),102.95(s),86.23(s),83.93(s),30.42(s),21.63(s),18.28(s).
实施例23
化合物[(η6-p-cymene)Ru(p-SO2CH3PIP)Cl]Cl(RAP22)的合成
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,58.3mg)，配体p-SO2CH3PIP(0.22mmol,82.4mg)，60℃下，微波辐射30min，得黄色固体132.5mg,产率85.1％.ESI-MS:m/z 645.2,([M-Cl]+)；1H NMR(500MHz,DMSO-d6)δ9.88(dd,J＝5.2,0.8Hz,1H),8.73(d,J＝8.6Hz,1H),8.21(dd,J＝8.1,5.3Hz,1H),8.18–8.14(m,1H),6.36(d,J＝6.4Hz,1H),6.13(d,J＝6.4Hz,1H),3.49–3.27(m,3H),2.21(s,3H),0.93(t,J＝9.9Hz,6H).13C NMR(126MHz,DMSO-d6)δ153.98(s),143.45(s),127.84(s),127.40(s),126.31(s),86.27(s),84.05(s),43.51(s),30.47(s),21.70(s),18.32(s).
实施例24
化合物[(η6-p-cymene)Ru(p-OHPIP)Cl]Cl(RAP33)的合成
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,58.3mg)，配体p-OHPIP(0.22mmol,68.7mg)，60℃下，微波辐射30min，得黄色固体132.5mg,产率93.5％；1H NMR(500MHz,DMSO-d6)δ9.83(d,J＝4.5Hz,1H),8.29(d,J＝8.7Hz,1H),8.17(dd,J＝8.2,5.3Hz,1H),6.99(d,J＝8.8Hz,1H),6.33(d,J＝6.4Hz,1H),6.10(d,J＝6.3Hz,1H),2.19(s,3H),2.08(s,1H),1.18(d,J＝6.9Hz,3H).13C NMR(126MHz,DMSO-d6)δ160.21(s),143.48(s),133.20(s),129.24(s),126.68(s),116.51(s),104.48(s),100.77(s),86.19(s),84.62(s),31.09(s),22.30(s),18.94(s).
实施例25
化合物[(η6-p-cymene)Ru(p-CF3PIP)Cl]Cl(RAP83)的合成
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,58.3mg)，配体p-CF3PIP(0.22mmol,80.1mg)，60℃下，微波辐射30min，得黄色固体132.5mg,产率87.3％；1H NMR(500MHz,DMSO-d6)δ9.86(dt,J＝11.9,5.9Hz,1H),8.67(d,J＝8.1Hz,1H),8.18(dd,J＝8.2,5.3Hz,1H),7.95(t,J＝9.8Hz,1H),6.34(d,J＝6.5Hz,1H),6.13(t,J＝8.2Hz,1H),2.20(s,1H),1.91(s,1H),0.89(t,J＝7.1Hz,3H).13C NMR(126MHz,DMSO-d6)δ154.47(s),143.98(s),133.38(s),128.00(s),126.86(s),126.68(s),104.57(s),103.61(s),86.90(s),84.65(s),31.09(s),22.31(s),18.94(s).
实施例26
化合物[(η6-p-cymene)Ru(p-CH3PIP)Cl]Cl(RAP27)的合成
取实施例1得到的取水芹烯前体[(η6-p-cymene)RuCl]2Cl2(0.1mmol,58.3mg)，配体p-CH3PIP(0.22mmol,68.3mg)，60℃下，微波辐射30min，得黄色固体132.5mg,产率91.2％；ESI-MS(in MeOH,m/z):618(Cal.),581(Found for[M-Cl]+)1H NMR(500MHz,DMSO-d6)δ9.83(dt,J＝10.9,5.5Hz,1H),9.41(s,1H),8.34(t,J＝9.9Hz,1H),8.16(dt,J＝14.2,7.1Hz,1H),7.39(t,J＝9.8Hz,1H),6.34(t,J＝10.0Hz,1H),6.12(t,J＝8.2Hz,1H),2.40(s,3H),2.20(s,1H),0.88(t,J＝6.5Hz,3H).13C NMR(126MHz,DMSO-d6)δ154.19(s),143.64(s),140.55(s),133.26(s),130.26(s),127.40(s),127.02(s),126.71(s),104.47(s),103.60(s),86.89(s),84.62(s),31.08(s),22.30(s),21.72(s),18.94(s).
实施例27
[(η6-p-cymene)Ru(p-BrPIP)Cl]PF6的合成
[(η6-p-cymene)Ru(p-BrPIP)Cl]Cl甲醇溶解，加入饱和六氟合磷酸铵饱和水溶液，得到沉淀，过滤，柱层析得到芳烃钌化合物的六氟合磷酸盐。
实施例28
[(η6-p-cymene)Ru(p-BrPIP)Cl]ClO4的合成
[(η6-p-cymene)Ru(p-BrPIP)Cl]Cl甲醇溶解，加入饱和高氯酸钠饱和水溶液，得到沉淀，过滤，柱层析得到芳烃钌化合物的高氯酸盐。
实施例29
[(η6-p-cymene)Ru(p-BrPIP)Cl]SeO3的合成
[(η6-p-cymene)Ru(p-BrPIP)Cl]Cl甲醇溶解，加入饱和硒酸钠饱和水溶液，得到沉淀，过滤，柱层析得到芳烃钌化合物的硒酸盐。
实施例30
[(η6-p-cymene)Ru(p-BrPIP)Cl]PF6的合成
[(η6-p-cymene)Ru(p-BrPIP)Cl]Cl甲醇溶解，加入饱和六氟合磷酸铵饱和水溶液，得到沉淀，过滤，柱层析得到芳烃钌化合物的六氟合磷酸盐。
实施例31
[(η6-p-cymene)Ru(p-BrPIP)Cl]PF6的合成
[(η6-p-cymene)Ru(p-BrPIP)Cl]Cl甲醇溶解，加入饱和六氟合磷酸铵饱和水溶液，得到沉淀，过滤，柱层析得到芳烃钌化合物的六氟合磷酸盐。
实施例32
芳烃钌化合物对MDA-MB-231高侵袭性乳腺癌细胞生长的抑制
采用MTT实验方法评价芳烃钌化合物对MDA-MB-231高侵袭性乳腺癌细胞生长的抑制。一般的方法是：取指数生长期的MDA-MB-231高侵袭性乳腺癌细胞细胞，弃去培养基，用PBS洗涤2次，然后用1mL胰酶消化成单个细胞悬液，细胞计数，加入培养基稀释细胞浓度为1.5×104个/mL，接种到96孔培养板中，每孔加200μL，细胞数约为3×103个。每组设6个复孔，重复2次。在37℃、5％的CO饱和湿度培养箱中孵育16h，细胞贴壁后，吸去上清液，加入新的DMEM培养基，同时加入不同浓度的化合物(化合物的终浓度分别是5、10、20、40和80μM)，每孔总体积200μL。继续培养72h后，每孔加入20μL的MTT(5mg/mL)，37℃继续培养4h，小心吸弃孔内上清液。然后每孔加入150μL的DMSO，振荡10min，使甲攒结晶完全溶解后，用酶标仪测定波长在490nm下各孔的吸光度值，按照如下公式计算细胞生一长活力:
细胞存活率％＝实验组A490/对照组A490×100％
根据所测得的各细胞存活率，采用IC50计算软件计算样品对肿瘤的半数抑制浓度(IC50)。
表1芳烃钌化合物对MDA-MB-231高侵袭性乳腺癌细胞生长的抑制
| 编号 | RAP07 | RAP083 | RAP273 | RAP093 | RAP073 | RAP062 | 顺铂 |
| IC50 | 8.33±0.6 | 6.27±0.29 | 9.6±0.3 | 6.4±0.16 | 3.2±0.1 | 9.2±0.3 | 17.8±0.9 |
实施例33
芳烃钌化合物对C6脑胶质瘤细胞生长的抑制
采用MTT实验方法评价芳烃钌化合物对C6脑胶质瘤细胞生长的抑制。一般的方法是：取指数生长期的C6脑胶质瘤细胞，弃去培养基，用PBS洗涤2次，然后用1mL胰酶消化成单个细胞悬液，细胞计数，加入培养基稀释细胞浓度为1.5×104个/mL，接种到96孔培养板中，每孔加200μL，细胞数约为3×103个。每组设6个复孔，重复2次。在37℃、5％的CO2饱和湿度培养箱中孵育16h，细胞贴壁后，吸去上清液，加入新的DMEM培养基，同时加入不同浓度的化合物(化合物的终浓度分别是5、10、20、40和80μM)，每孔总体积200μL。继续培养72h后，每孔加入20μL的MTT(5mg/mL)，37℃继续培养4h，小心吸弃孔内上清液。然后每孔加入150μL的DMSO，振荡10min，使甲攒结晶完全溶解后，用酶标仪测定波长在490nm下各孔的吸光度值，按照如下公式计算细胞生一长活力:
细胞存活率％＝实验组A490/对照组A490×100％
根据所测得的各细胞存活率，采用IC50计算软件计算样品对肿瘤的半数抑制浓度(IC50)。
表2芳烃钌化合物对C6脑胶质瘤细胞生长的抑制
| 编号 | RAP04 | RAP07 | RAP083 | RAP031 | RAP143 | RAP062 | RAP093 | 替莫唑胺 |
| IC50 | 1.2±0.3 | 5.6±0.2 | 4.5±0.07 | 5.3±0.12 | 2.4±0.05 | 5.4±0.17 | 5.6±0.11 | 258.9±15.5 |
实施例34
芳烃钌化合物对CNE-1鼻咽癌细胞生长的抑制
采用MTT实验方法评价芳烃钌化合物对CNE-1鼻咽癌细胞生长的抑制。一般的方法是：取指数生长期的CNE-1鼻咽癌细胞，弃去培养基，用PBS洗涤2次，然后用1mL胰酶消化成单个细胞悬液，细胞计数，加入培养基稀释细胞浓度为1.5×104个/mL，接种到96孔培养板中，每孔加200μL，细胞数约为3×103个。每组设6个复孔，重复2次。在37℃、5％的CO2饱和湿度培养箱中孵育16h，细胞贴壁后，吸去上清液，加入新的DMEM培养基，同时加入不同浓度的化合物(化合物的终浓度分别是5、10、20、40和80μM)，每孔总体积200μL。继续培养72h后，每孔加入20μL的MTT(5mg/mL)，37℃继续培养4h，小心吸弃孔内上清液。然后每孔加入150μL的DMSO，振荡10min，使甲攒结晶完全溶解后，用酶标仪测定波长在490nm下各孔的吸光度值，按照如下公式计算细胞生一长活力:
细胞存活率％＝实验组A490/对照组A490×100％
根据所测得的各细胞存活率，采用IC50计算软件计算样品对肿瘤的半数抑制浓度(IC50)。
表3芳烃钌化合物对CNE-1鼻咽癌细胞生长的抑制
| 编号 | RAP073 | RAP093 | RAP082 | RAP201 | RAP062 | 顺铂 |
| IC50 | 3.3±0.07 | 11.9±0.73 | 13.8±0.4 | 17.4±0.47 | 15.70±0.11 | 19.1±0.5 |
实施例35
芳烃钌化合物对A549肺腺癌细胞生长的抑制
采用MTT实验方法评价芳烃钌化合物对A549肺腺癌细胞生长的抑制。一般的方法是：取指数生长期的A549肺腺癌细胞，弃去培养基，用PBS洗涤2次，然后用1mL胰酶消化成单个细胞悬液，细胞计数，加入培养基稀释细胞浓度为1.5×104个/mL，接种到96孔培养板中，每孔加200μL，细胞数约为3×103个。每组设6个复孔，重复2次。在37℃、5％的CO2饱和湿度培养箱中孵育16h，细胞贴壁后，吸去上清液，加入新的DMEM培养基，同时加入不同浓度的化合物(化合物的终浓度分别是5、10、20、40和80μM)，每孔总体积200μL。继续培养72h后，每孔加入20μL的MTT(5mg/mL)，37℃继续培养4h，小心吸弃孔内上清液。然后每孔加入150μL的DMSO，振荡10min，使甲攒结晶完全溶解后，用酶标仪测定波长在490nm下各孔的吸光度值，按照如下公式计算细胞生一长活力:
细胞存活率％＝实验组A490/对照组A490×100％
根据所测得的各细胞存活率，采用IC50计算软件计算样品对肿瘤的半数抑制浓度(IC50)。
表4芳烃钌化合物对A549肺腺癌细胞生长的抑制
| 编号 | RAP031 | RAP052 | RAP042 | RAP143 | RAP062 | 顺铂 |
| IC50 | 26.9±0.6 | 36.6±0.67 | 25.01±4.3 | 11.8±0.9 | 6.59±2.26 | 93.1±0.9 |
实施例36
芳烃钌化合物对EC-1食道癌细胞生长的抑制
采用MTT实验方法评价芳烃钌化合物对EC-1食道癌细胞生长的抑制。一般的方法是：取指数生长期的EC-1食道癌细胞，弃去培养基，用PBS洗涤2次，然后用1mL胰酶消化成单个细胞悬液，细胞计数，加入培养基稀释细胞浓度为1.5×104个/mL，接种到96孔培养板中，每孔加200μL，细胞数约为3×103个。每组设6个复孔，重复2次。在37℃、5％的CO2饱和湿度培养箱中孵育16h，细胞贴壁后，吸去上清液，加入新的DMEM培养基，同时加入不同浓度的化合物(化合物的终浓度分别是5、10、20、40和80μM)，每孔总体积200μL。继续培养72h后，每孔加入20μL的MTT(5mg/mL)，37℃继续培养4h，小心吸弃孔内上清液。然后每孔加入150μL的DMSO，振荡10min，使甲攒结晶完全溶解后，用酶标仪测定波长在490nm下各孔的吸光度值，按照如下公式计算细胞生一长活力:
细胞存活率％＝实验组A490/对照组A490×100％
根据所测得的各细胞存活率，采用IC50计算软件计算样品对肿瘤的半数抑制浓度(IC50)。
表5芳烃钌化合物对EC-1食道癌细胞生长的抑制
| 编号 | RAP04 | RAP07 | RAP083 | RAP273 | RAP11 | 顺铂 |
| IC50 | 18.2±0.5 | 18.1±1.7 | 6.9±0.2 | 18.4±11.7 | 34.1±2.7 | 9.4±0.21 |
实施例35烃钌化合物对HaCaT细胞生长的抑制
采用MTT实验方法评价芳烃钌化合物对HaCaT细胞生长的抑制。一般的方法是：取指数生长期的HaCaT细胞，弃去培养基，用PBS洗涤2次，然后用1mL胰酶消化成单个细胞悬液，细胞计数，加入培养基稀释细胞浓度为1.5×104个/mL，接种到96孔培养板中，每孔加200μL，细胞数约为3×103个。每组设6个复孔，重复2次。在37℃、5％的CO2饱和湿度培养箱中孵育16h，细胞贴壁后，吸去上清液，加入新的DMEM培养基，同时加入不同浓度的化合物(化合物的终浓度分别是5、10、20、40和80μM)，每孔总体积200μL。继续培养72h后，每孔加入20μL的MTT(5mg/mL)，37℃继续培养4h，小心吸弃孔内上清液。然后每孔加入150μL的DMSO，振荡10min，使甲攒结晶完全溶解后，用酶标仪测定波长在490nm下各孔的吸光度值，按照如下公式计算细胞生一长活力:
细胞存活率％＝实验组A490/对照组A490×100％
根据所测得的各细胞存活率，采用IC50计算软件计算样品对肿瘤的半数抑制浓度(IC50)。
表5芳烃钌化合物对HaCaT细胞生长的抑制
| 编号 | RAP031 | RAP083 | RAP061 | RAP093 | RAP062 | 顺铂 |
| IC50 | >100 | >100 | >100 | >100 | 37.3±1.99 | 17.1±0.8 |
实施例36
芳烃钌化合物RAP07对MDA-MB-231迁移的抑制
先用marker笔在6孔板背后，用直尺比着，均匀得划横线，大约每隔0.5～1cm一道，横穿过孔，每孔至少穿过5条线；在每个孔中加入约5×105个细胞，具体数量因细胞不同而不同，掌握为过夜能铺满；第二天用枪头比着直尺，尽量垂至于背后的横线划痕，枪头要垂直，不能倾斜；用PBS洗细胞3次，去除划下的细胞，加入用培养基稀释的不同浓度药物(0,5，10和20μM)无血清培养基；放入37度5％CO2培养箱，培养。按0，6，12，24小时取样，拍照。对比不同浓度药物处理后，划痕愈合的情况，如图73所示。
实施例37
芳烃钌化合物RAP07对MDA-MB-231侵袭的抑制
取50μL FITC-gelatin于3cm玻璃皿中，放入37度细胞培养箱中30min使FITC-gelatin充分凝结。加入0.5％戊二醛，室温下避光孵育30min，然后用新配的5mg/mLNaBH4室温下处理至无气泡产生，PBS洗涤3次；取指数生长期的肿瘤细胞，弃去培养基，用PBS洗涤2次，然后用1mL胰酶消化成单个细胞悬液，细胞计数，加入无血清培养基稀释细胞浓度为5×104个/mL，取1mL细胞悬液于每个皿中，待细胞贴壁后，换用培养基稀释的不同浓度药物(0,5，10和20μM)无血清培养基继续培养24h。激光共聚焦显微镜下拍照，观察肿瘤细胞在FITC-gelatin上穿孔的数目，如图74所示。
实施例38
芳烃钌化合物RAP07诱导的MDA-MB-231高侵袭性乳腺癌细胞S-期阻滞
采用流式细胞分析芳烃钌化合物RAP07诱导的MDA-MB-231高侵袭性乳腺癌细胞周期阻滞。一般方法是：胰蛋白酶处理过或未处理过的细胞用PBS培养液洗一次，用70％的乙醇在-20℃条件下过夜进行固定。固定完的细胞用PBS培养液洗，碘化丙啶溶液(PI)避光四小时染色。染色后的细胞用Epics XL-MCL流式细胞分析仪(Beckman Coulter,Mi-ami,FL)观察细胞的周期变化，细胞周期分布则是用MultiCycle软件(Phoenix Flow Systems,SanDiego,CA)进行分析的。具有亚二倍体DNA的凋亡细胞的含量是通过测量细胞周期中的G1峰，效果如图75所示。每个样品可以记录10000个细胞。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (3)
1.一种芳烃钌配合物，其特征在于：所述芳烃钌配合物的结构式为：
2.如权利要求1所述芳烃钌配合物的制备方法，其特征在于，包括步骤：
i)由RuCl3与1-甲基-4-异丙基-1，3-环己二烯30-180℃下，微波辐射15s-60min，或者30-180℃下回流1h-7d，制备得到[(η6-p-cymene)RuCl]2Cl2，
ii)[(η6-p-cymene)RuCl]2Cl2和菲并咪唑衍生物在溶剂中，30-180℃下，微波辐射15s-60minh或者30-180℃下回流1h-7d得到[(η6-p-cymene)Ru(RPIP)Cl]Cl。
3.如权利要求2中所述芳烃钌配合物的制备方法，其特征在于：步骤ii中，用[(η6-p-cymene)RuCl]2Cl2与菲并咪唑衍生物在二氯甲烷溶剂中反应。
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| US15/947,865 US10358455B2 (en) | 2017-05-19 | 2018-04-09 | Arene ruthenium complex, preparation method and utilization thereof |
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| CN111875643A (zh) * | 2020-08-10 | 2020-11-03 | 重庆医科大学 | 一种新型的钌芳烃配合物及其制备方法和抗肿瘤应用 |
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