CN106243183B - 熊果酸-硫化氢供体试剂衍生物及其合成方法 - Google Patents
熊果酸-硫化氢供体试剂衍生物及其合成方法 Download PDFInfo
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- CN106243183B CN106243183B CN201610621159.4A CN201610621159A CN106243183B CN 106243183 B CN106243183 B CN 106243183B CN 201610621159 A CN201610621159 A CN 201610621159A CN 106243183 B CN106243183 B CN 106243183B
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- compound
- ursolic acid
- hydrogen sulfide
- alkali
- aprotic polar
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- 229910000037 hydrogen sulfide Inorganic materials 0.000 title claims abstract description 26
- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 21
- 238000010189 synthetic method Methods 0.000 title abstract description 5
- 229940125904 compound 1 Drugs 0.000 claims abstract description 21
- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 0.000 claims abstract description 16
- 239000003513 alkali Substances 0.000 claims abstract description 16
- 239000002798 polar solvent Substances 0.000 claims abstract description 16
- PLSAJKYPRJGMHO-UHFFFAOYSA-N ursolic acid Natural products CC1CCC2(CCC3(C)C(C=CC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(=O)O PLSAJKYPRJGMHO-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229940096998 ursolic acid Drugs 0.000 claims abstract description 16
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 239000012043 crude product Substances 0.000 claims abstract description 7
- 230000002194 synthesizing effect Effects 0.000 claims abstract 2
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 238000001308 synthesis method Methods 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 17
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
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- 150000001875 compounds Chemical class 0.000 claims description 13
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 13
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种熊果酸‑硫化氢供体试剂衍生物及其合成方法。该衍生物的合成方法为:取熊果酸、α,ω‑二溴烷烃和碱在非质子极性溶剂中反应,得到化合物1;取化合物1、硫化氢供体试剂和碱在非质子极性溶剂中反应,得到目标物粗品;其中,反应在加热或不加热的条件下进行。合成得到的衍生物具有下述通式(I)所示结构:其中,n为2~8;R为 或
Description
技术领域
本发明涉及医药技术领域,具体涉及一种熊果酸-硫化氢供体试剂衍生物及其合成方法。
背景技术
硫化氢是相继于CO和NO之后的一个新的生物活性气体分子,是支持生命的重要角色,在生命活动中具有不可替代的生理调节作用,控制多种细胞内信号传导过程并发挥积极的调节作用。目前关于硫化氢的潜在治疗性应用主要集中在神经、心血管***,如治疗高血压、治疗心脏缺血性疾病,治疗动脉粥样硬化,与非甾体类抗炎药联用,用于降低代谢、防止低氧性损伤等。
硫化氢供体在生理条件下可以水解自发放出H2S或在半胱氨酸(GSH)作用下释放H2S,GSH可以接受硫化物的S硫原子形成GSSH,然后通过3-巯基丙酮酸硫转移酶(3-MST)催化产生H2S。H2S的生物学效应及信号通路机制的研究揭示了其作为信号分子涉及在心血管***、神经***、循环***等许多器官的细胞信号转导,对机体内多个生理过程都有影响。
天然产物熊果酸在天然植物中较广泛的存在,具有镇静、抗炎、护肝、抗肿瘤等活性。Kim等研究了熊果酸对多种肿瘤细胞系的抑制增殖活性(Kim YK,Yoon SK,RyuSY.Cytotoxic triterpenes from stem bark of Physocarpus intermedius.PlantaMedica,2000,66,485.),结果表明,熊果酸对所测试的肿瘤细胞有明显的细胞毒作用,其对黑色素瘤B16-F0、卵巢癌SK–OV-3、结肠癌HCT-1 5、脑瘤XF498、非小细胞肺癌A549和黑色素瘤SK-MEL-2的ED50(μg/ml)分别为4.6、3.6、4.4、4.9、4.3和4.6。吴其年等探讨了熊果酸对人乳腺癌细胞(MCF-7)增殖抑制和诱导凋亡的作用,以及凋亡发生与细胞内Ca2+浓度变化的关系(Silva,M.,David,J.P.,Silva,L.C.R.C.,Santos,R.A.F.,David,J.M.,Lima,L.S.,Reis,P.S.,Fontana,R..Bioactive oleanane,lupane and ursane triterpene acidderivatives.Molecules,2012,17,12197-12205.)。结果显示,熊果酸对MCF-7细胞的增殖具有抑制作用,且呈剂量依赖性,其IC50为36.18μM。此外,在20μM和30μM浓度下,熊果酸使细胞凋亡率显著升高,并且,熊果酸处理组的Ca2+浓度明显高于对照组,显示其诱导凋亡作用可能依赖于细胞内Ca2+水平的上调。
目前尚未见有将熊果酸与硫化氢供体试剂经烷烃链连接的衍生物及其合成方法的相关报道。
发明内容
本发明要解决的技术问题是提供一类结构新颖的熊果酸-硫化氢供体试剂衍生物及其合成方法。
本发明涉及具有下述通式(I)所示结构的熊果酸-硫化氢供体试剂衍生物或其药学上可接受的盐:
其中,
n为2~8;
R为
本发明所述熊果酸-硫化氢供体试剂衍生物的合成方法为:取熊果酸、α,ω-二溴烷烃和碱在非质子极性溶剂中反应,得到化合物1;取化合物1、硫化氢供体试剂和碱在非质子极性溶剂中反应,得到目标物粗品;其中,反应在加热或不加热的条件下进行。
更为具体的合成方法,包括以下步骤:
1)取熊果酸、α,ω-二溴烷烃和碱在非质子极性溶剂中反应,所得反应物除去溶剂,残余物分散于乙酸乙酯、二氯甲烷或***中,经洗涤,无水硫酸钠干燥,过滤后,收集滤液,滤液浓缩后得到化合物1;
2)取化合物1、硫化氢供体试剂和碱在非质子极性溶剂中反应,所得反应物除去溶剂,残余物分散于乙酸乙酯、二氯甲烷或***中,经洗涤,无水硫酸钠干燥,过滤后,收集滤液,滤液浓缩后得到目标物粗品。
上述具体的合成方法的步骤1)和步骤2)中,所述的洗涤优选是依次用盐酸、水、饱和食盐水进行洗涤,或者是依次用盐酸、饱和食盐水进行洗涤。
本发明所述合成方法中合成得到的化合物1的结构式如下所示:
其中,n为2~8。
上述方法中合成得到的化合物1为化合物1的粗品,为了提高化合物1的纯度同时减少后续反应中产生更多的副产物,优选是将所得化合物1的粗品经硅胶薄层色谱或硅胶柱层析纯化后再用于后续操作。在将其进行硅胶薄层色谱或上硅胶柱层析时,通常用由体积比为2~10:1的石油醚(PE)和乙酸乙酯(EA)组成的洗脱剂洗脱,收集洗脱液,洗脱液减压蒸除溶剂,得到纯化后的目标物。所述组成洗脱剂的石油醚和乙酸乙酯的体积比优选为2~5:1。
由上述方法制得的是式(I)化合物的粗品,可采用现有常规的纯化方法对其进行纯化以提高式(I)化合物的纯度。通常采用硅胶薄层色谱或硅胶柱层析来进行纯化,在将制得的目标化合物粗品硅胶薄层色谱或上硅胶柱层析时,通常用由体积比为2~10:1的石油醚(PE)和乙酸乙酯(EA)组成的洗脱剂洗脱,收集洗脱液,洗脱液减压蒸除溶剂,得到纯化后的目标物。所述组成洗脱剂的石油醚和乙酸乙酯的体积比优选为2~5:1。
本发明所述的合成方法中,所述的α,ω-二溴烷烃可以是1,2-二溴乙烷、1,3-二溴丙烷、1,4-二溴丁烷、1,5-二溴戊烷、1,6-二溴己烷、1,7-二溴庚烷或1,8-二溴辛烷。
本发明所述的合成方法中,所述的碱可以是碳酸钾、三乙胺、碳酸钠、碳酸氢钠、碳酸氢钾或碳酸铯。当碱的选择为碳酸铯时,可以获得更高的产率;从成本及产率综合考虑,优选碱为碳酸钾。
本发明所述的合成方法中,所述的非质子极性溶剂可以是N,N-二甲基甲酰胺(DMF)、甲苯和吡啶中的一种或两种以上的组合,当非质子极性溶剂的选择是上述两种以上的组合时,它们之间的配比可以为任意配比。所述非质子极性溶剂的用量通常为能够溶解参加反应的原料即可。
本发明所述的合成方法中,所述的硫化氢供体试剂具体可以是5-对羟基苯基-1,2-二硫杂环戊烯-3-硫酮(ADT-OH)、(R)-硫辛酸(R-lipoic acid)或4-羟基硫代苯甲酰胺(TBZ),它们的结构式分别如下所示:
本发明所述的合成方法中,所述熊果酸、α,ω-二溴烷烃和碱的反应优选是在低于或等于40℃的条件下进行,申请人在实验中发现,当反应在20~40℃条件下进行时,可以在较短的时间内获得较高的产率,同时副反应较少;所述化合物1、硫化氢供体试剂和碱的反应在低于或等于65℃的条件下进行,更优选是在35~65℃条件下进行,这样可以在较短的时间内获得较高的产率,并尽量减少副产物的生成。在上述限定温度条件下,反应是否完全可以通过薄层层析跟踪检测。
本发明所述的合成方法中,所述熊果酸、α,ω-二溴烷烃和碱的物质的量之比为:1:1~5:0.5~3;所述化合物1、硫化氢供体试剂和碱的物质的量之比为:1:1~3:1~5。
申请人发现,在化合物1、硫化氢供体试剂和碱的反应中,加入催化剂碘化钾(KI)可以进一步提高目标物的产率。所述碘化钾的加入量为化合物1物质的量的0.1~1倍。
与现有技术相比,本发明提供了一系列结构新颖的熊果酸-硫化氢供体试剂衍生物及其合成方法,同时,申请人还考察了这些衍生物对肝癌肿瘤细胞株及慢性骨髓性白血病细胞的抑制活性,结果表明,其中个别化合物对慢性骨髓性白血病细胞K562具有一定的抑制活性。
具体实施方式
下面结合具体实施例对本发明作进一步的详述,以更好地理解本发明的内容,但本发明并不限于以下实施例。
本发明所述的具有下述通式(I)所示结构的熊果酸-硫化氢供体试剂衍生物按下述合成路线进行合成:
其中:
α,ω-二溴烷烃可以是1,2-二溴乙烷、1,3-二溴丙烷、1,4-二溴丁烷、1,5-二溴戊烷、1,6-二溴己烷、1,7-二溴庚烷或1,8-二溴辛烷;
非质子极性溶剂可以是N,N-二甲基甲酰胺、甲苯或吡啶;
碱可以是碳酸钾、三乙胺、碳酸钠、碳酸氢钠、碳酸氢钾或碳酸铯;
硫化氢供体试剂具体可以是5-对羟基苯基-1,2-二硫杂环戊烯-3-硫酮(ADT-OH)、(R)-硫辛酸(R-lipoic acid)或4-羟基硫代苯甲酰胺(TBZ),它们的结构式分别如下所示:
化合物1和化合物2中的n为2~8;
化合物2中的R为
实施例1:化合物1a的合成
将熊果酸(1.0g,2.19mmol)溶于无水DMF(5mL),加入1,6-二溴己烷(2.67mL,10.95mmol)、K2CO3(302.78mg,2.19mmol),30℃反应24h。减压蒸除溶剂,残余物分散乙酸乙酯(50mL)中,依次用HCl(1N)、水、饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,柱层析分离(VPE:VEA=3:1),得化合物1a(1.207g,89%,白色固体)。
Yield:1.207g,89%,white solid;Rf=0.629(Petroluem ether:EtOAc=3:1).M.p 102-104℃.1H NMR(500MHz,CDCl3)δ(ppm):5.22(s,1H,12-H),3.98(m,2H,OCH2),3.40(m,2H,CH2-Br),3.20(dd,J=11.0,4.9Hz,1H,3-H),2.20(s,1H,18-H),2.02-072(m,35H),1.07,0.98,0.94,0.91,0.85,0.77 and 0.74(7s,each 3H,7×CH3).13C NMR(125MHz,CDCl3)δ(ppm):177.7,138.3,125.6,79.2,64.1,55.3,53.0,48.2,47.7,42.2,39.7,39.2,39.0,38.9,38.8,37.1,36.9,33.8,33.2,32.8,30.8,28.6,28.3,28.1,27.9,27.3,25.4,24.4,23.7,23.4,21.3,18.5,17.2,15.6.HRMS(ESI)m/z:[M+Na]+calcd for C36H59BrO3Na641.3545;found 641.3553.
实施例2:化合物1b的合成
将熊果酸(1.0g,2.19mmol)溶于无水DMF(5mL),加入1,8-二溴辛烷(1.84mL,10.95mmol)、K2CO3(302.78mg,2.19mmol),30℃反应24h。减压蒸除溶剂,残余物分散乙酸乙酯(50mL)中,依次用HCl(1N)、水、饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,柱层析分离(VPE:VEA=4:1),得化合物1b(1.162g,82%,白色固体)。
Yield:1.162g,82%,white solid;Rf=0.500(Petroluem ether:EtOAc=4:1).M.p 90-92℃.1H NMR(500MHz,CDCl3)δ(ppm):5.22(s,1H,12-H),3.97(m,2H,OCH2),3.39(m,2H,CH2-Br),3.20(dd,J=10.9,4.7Hz,1H,3-H),2.21(d,J=11.4Hz,1H,18-H),2.02-0.69(m,35H),1.07,0.98,0.93,0.91,0.85,0.77 and 0.74(7s,each 3H,7×CH3).13C NMR(125MHz,CDCl3)δ(ppm):177.7,138.3125.6,79.1,64.3,55.3,53.0,48.2,47.7,42.2,39.7,39.2,39.0,38.9,38.8,37.1,36.9,34.0,33.2,32.9,30.8,29.2,28.8,28.7,28.3,28.2,28.1,27.3,26.1,24.4,23.7,23.4,21.3,18.5,17.3,17.2,15.8,15.6.HRMS(ESI)m/z:[M+H]+calcd for C38H64BrO3 647.4039;found 647.4047.
实施例3:化合物2a的合成
将化合物1a(500mg,0.81mmol)溶于DMF(5mL),加入ADT-OH(182.60mg,0.81mmol)、K2CO3(335.83mg,2.43mmol)、KI(13.28mg,0.08mmol),65℃反应24h。减压蒸除溶剂,残余物分散在乙酸乙酯(50mL),依次用HCl(1N)、水、饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,柱层析分离(VPE:VEA=3:1),得化合物2a(226mg,37%,橙色固体)。
Yield:226mg,37%,orange solid;Rf=0.579(Petroluem ether:EtOAc=3:1).M.p 83-85℃.1H NMR(400MHz,CDCl3)δ(ppm):7.60(d,J=8.9Hz,2H,Ar-H),7.39(s,1H),6.96(d,J=8.9Hz,2H,Ar-H),5.23(s,1H,12-H),4.02(m,4H,2×OCH2),3.21(dd,J=11.1,4.4Hz,1H,3-H),2.22(d,J=11.3Hz,1H,18-H),2.12-0.65(m,31H),1.08,0.98,0.94,0.90and 0.85(5s,each 3H,5×CH3),0.76(d,6H,2×CH3).13C NMR(100MHz,CDCl3)δ(ppm):215.1,177.7,173.2,162.6,138.3,134.6,128.7,125.6,124.1,115.5,79.0,68.3,64.1,55.3,53.0,48.2,47.6,42.2,39.6,39.2,39.0,38.8,38.7,37.0,36.8,33.2,30.8,29.1,28.6,28.2,28.1,27.3,25.9,25.7,24.3,23.6,23.4,21.3,18.4,17.2,17.1,15.7,15.5.HRMS(APCl)m/z:[M+H]+calcd for C45H65O4S3,765.4045;found 765.4009.
实施例4:化合物2b的合成
将化合物1b(500mg,0.77mmol)溶于DMF(5mL),加入ADT-OH(174.97mg,0.77mmol)、K2CO3(319.24mg,2.31mmol)、KI(13.28mg,0.08mmol),65℃反应24h。减压蒸除溶剂,残余物分散在乙酸乙酯(50mL),依次用HCl(1N)、水、饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,柱层析分离(VPE:VEA=3:1),得化合物2b(98mg,16%,橙色固体)。
Yield:98mg,16%,orange solid;Rf=0.469(Petroluem ether:EtOAc=3:1).M.p 64-66℃.1H NMR(500MHz,CDCl3)δ(ppm):7.59(d,J=8.7Hz,2H,Ar-H),7.38(s,1H),6.94(d,J=8.8Hz,2H,Ar-H),5.22(s,1H,12-H),4.06-3.89(m,4H,2×OCH2),3.20(dd,J=11.1,4.6Hz,1H,3-H),2.21(d,J=11.3Hz,1H,18-H),2.11-0.66(m,35H),1.06,0.96,0.93,0.89,0.85,0.75 and 0.74(7s,each 3H,7×CH3).13C NMR(125MHz,CDCl3)δ(ppm):215.1,177.7,173.2,162.7,138.3,134.6,128.7,125.6,124.0,115.5,79.1,68.5,64.3,55.3,53.0,48.2,47.6,42.2,39.7,39.2,39.0,38.8,38.7,37.1,36.8,33.2,30.8,29.4,29.2,29.1,28.6,28.2,28.1,27.3,26.1,26.0,24.3,23.6,23.4,21.3,18.4,17.2,17.1,15.7,15.6.HRMS(APCl)m/z:[M+H]+calcd for C47H69O4S3,793.4358;found 793.4322.
实施例5:化合物2c的合成
将化合物1a(500mg,0.81mmol)溶于DMF,加入(R)-lipoic acid(182.60mg,0.81mmol)、K2CO3(335.85mg,2.43mmol),50℃反应24h。减压蒸除溶剂,残余物分散在乙酸乙酯(50mL),依次用HCl(1N)、水、饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,柱层析分离(VPE:VEA=3:1),得化合物2c(567mg,94%,淡黄色固体)。
Yield:567mg,94%,yellow solid;Rf=0.475(Petroluem ether:EtOAc=3:1).M.p 62-64℃.1H NMR(400MHz,CDCl3)δ(ppm):5.21(s,1H,12-H),4.10-3.91(m,4H,2×OCH2),3.55(dd,J=8.0,6.5Hz,1H,3-H),3.23-3.04(m,3H),2.44(td,J=12.3,6.1Hz,1H),2.29(t,J=7.4Hz,2H),2.21(dd,J=26.0,9.4Hz,1H,18-H),2.05-0.63(m,38H),1.06,0.97,0.84,0.76 and 0.73(5s,each 3H,CH3),0.95-0.89(m,6H,2×CH3).13C NMR(100MHz,CDCl3)δ(ppm):177.6,173.6,138.3,125.6,79.0,64.3,64.1,56.4,55.3,52.9,48.1,47.6,42.1,40.3,39.6,39.1,38.9,38.8,38.7,38.5,37.0,36.8,34.6,34.1,33.1,30.7,28.8,28.6,28.5,28.2,28.0,27.3,25.8,25.7,24.7,24.3,23.6,23.3,21.2,18.4,17.2,17.1,15.7,15.5.HRMS(APCl)m/z:[M+H]+calcd for C44H73O5S2,745.4899;found 745.4876.
实施例6:化合物2d的合成
将化合物1b(500mg,0.77mmol)溶于DMF,加入(R)-lipoic acid(158.87mg,0.77mmol)、K2CO3(319.27mg,2.31mmol),50℃反应24h。减压蒸除溶剂,残余物分散在乙酸乙酯(50mL),依次用HCl(1N)、水、饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,柱层析分离(VPE:VEA=3:1),得化合物2d(222mg,37%,淡黄色固体)。
Yield:222mg,37%,yellow solid;Rf=0.583(Petroluem ether:EtOAc=3:1).M.p 49-51℃.1H NMR(400MHz,CDCl3)δ(ppm):5.23(s,1H,12-H),4.09-3.90(m,4H,2×OCH2),3.56(dd,J=8.1,6.4Hz,1H,3-H),3.26-3.06(m,3H),2.46(dd,J=12.4,6.0Hz,1H),2.31(t,J=7.4Hz,2H),2.23(d,J=11.3Hz,1H,18-H),2.05-0.64(m,42H),1.08,0.99,0.94,0.91,0.85,0.78 and 0.75(7s,each 3H,7×CH3).13C N MR(100MHz,CDCl3)δ(ppm):177.6,173.5,138.2,125.5,78.9,64.4,64.2,56.3,55.2,52.9,48.0,47.5,42.0,40.2,39.6,39.1,38.9,38.7,38.6,38.5,37.0,36.7,34.6,34.1,33.1,30.7,29.1,28.8,28.6,28.2,28.0,27.2,26.0,25.9,24.7,24.2,23.5,23.3,21.2,18.3,17.1,17.0,15.7,15.5.HRMS(APCl)m/z:[M+H]+calcd for C46H77O5S2,773.5212;found 773.5183.
实施例7:化合物2e的合成
将化合物1a(250mg,0.40mmol)溶于DMF(5mL),加入TBZ(61.2mg,0.40mmol)、K2CO3(56mg,0.40mmol),35℃反应12h。减压蒸除溶剂,残余物分散在乙酸乙酯(50mL),依次用HCl(1N)、水、饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,柱层析分离(VPE:VEA=3:1),得化合物2e(102mg,37%,浅黄色固体)。
Yield:102mg,37%,yellow solid;Rf=0.224(Petroluem ether:EtOAc=3:1).M.p 79-81℃.1H NMR(500MHz,CDCl3)δ(ppm):7.87(d,J=8.9Hz,2H,Ar-H),7.49(s,1H,NH),6.83(d,J=8.9Hz,2H,Ar-H),5.20(s,1H,12-H),3.97(m,4H,2×OCH2),3.18(dd,J=11.4,4.3Hz,1H,3-H),2.19(d,J=11.2Hz,1H,18-H),2.04-0.64(m,30H),1.04,0.95,0.91,0.86,0.83,0.73 and 0.72(7s,each 3H,CH3).13C NMR(125MHz,CDCl3)δ(ppm):201.2,177.8,162.5,138.3,131.1,129.3,125.6,114.0,79.1,68.2,64.2,60.5,55.2,52.9,48.1,47.6,42.1,39.6,39.1,38.9,38.8,38.7,37.0,36.8,33.1,30.7,29.3,28.5,28.2,28.0,27.2,25.9,25.7,24.3,23.6,23.3,21.2,18.4,17.2,17.1,15.8,15.5,14.2.HRMS(ESI)m/z:[M+Na]+calcd for C43H64NO4S,690.4556;found 690.4571.
实施例8:化合物2f的合成
将化合物1b(250mg,0.38mmol)溶于DMF,加入TBZ(58.14mg,0.38mmol)、K2CO3(52mg,0.38mmol),35℃反应12h。减压蒸除溶剂,残余物分散在乙酸乙酯(50mL),依次用HCl(1N)、水、饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,柱层析分离(VPE:VEA=3:1),得到化合物2f(69mg,24%,浅黄色固体)。
Yield:69mg,24%,yellow solid;Rf=0.167(Petroluem ether:EtOAc=3:1).M.p 83-85℃.1H NMR(500MHz,CDCl3)δ(ppm):7.88(d,J=8.9Hz,2H,Ar-H),7.81(s,1H,NH),7.45(s,1H,NH),6.86-6.82(d,J=8.9Hz,2H,Ar-H),5.21(t,J=3.4Hz,1H,12-H),4.10-3.82(m,4H,2×OCH2),3.20-3.03(m,1H,3-H),2.20(d,J=11.2Hz,1H,18-H),2.04-0.65(m,34H),1.05,0.96,0.92,0.87,0.84,0.74 and 0.72(7s,each 3H,7×CH3).13C NMR(125MHz,CDCl3)δ(ppm):201.2,177.7,162.4,138.2,131.0,129.1,125.4,113.9,79.0,68.2,64.1,55.1,52.8,48.0,47.5,42.0,39.5,39.0,38.8,38.7,38.6,36.9,36.7,33.0,30.6,29.2,29.1,29.0,28.5,28.1,27.9,27.1,25.9,25.8,24.2,23.5,23.2,21.1,18.3,17.1,17.0,15.6,15.4.HRMS(ESI)m/z:[M+Na]+calcd for C45H68NO4S,718.4869;found718.4881.
实施例9:化合物2a的合成
重复实施例3,不同的是:用甲苯替代DMF,用碳酸铯替代K2CO3,且不加入催化剂KI。
所得产物(189mg,31%,橙色固体)经过核磁鉴定为化合物2a,其结构式如下所示:
实施例10:化合物2b的合成
重复实施例4,不同的是:用吡啶替代DMF,用碳酸氢钾替代K2CO3。
所得产物(49mg,8%,橙色固体)经过核磁鉴定为化合物2b,其结构式如下所示:
实施例11:化合物2c的合成
重复实施例5,不同的是:用吡啶和甲苯的组合物(由甲吡啶和甲苯按1:5的体积比组成)替代DMF,用三乙胺替代K2CO3,且将残余物分散于***中。
所得产物(512mg,85%,淡黄色固体)经过核磁鉴定为化合物2c,其结构式如下所示:
实施例12:化合物2e的合成
重复实施例7,不同的是:用甲苯和DMF的组合物(由甲苯和DMF按1:1的体积比组成)替代DMF,用碳酸钠替代K2CO3,且将残余物分散于二氯甲烷中。
所得产物(80mg,29%,浅黄色固体)经过核磁鉴定为化合物2e,其结构式如下所示:
申请人对本发明所述化合物2a~2f对人肝癌肿瘤细胞株及慢性骨髓性白血病细胞的增殖抑制活性进行了实验:
1、细胞株与细胞培养
本实验选用人肝癌细胞BEL-7402、慢性骨髓性白血病细胞K562以及人正常肝细胞L-O2等3种人类细胞株。
所有细胞株均培养在含10wt%小牛血、100U/mL青霉素、100U/mL链霉素的RPMI-1640培养液内,置37℃含体积浓度5%CO2孵箱中培养。
2、待测化合物的配制
所用的受试药物的纯度≥95%,将其DMSO储液用生理缓冲液稀释后配制成200μmol/L的终溶液,其中助溶剂DMSO的终浓度≤1%,测试该浓度下化合物对各种肿瘤细胞生长的抑制程度。
3、细胞生长抑制实验(MTT法)
(1)取对数生长期的肿瘤细胞,经胰蛋白酶消化后,用含10%小牛血清的培养液配制成浓度为5000个/mL的细胞悬液,以每孔190μL接种于96孔培养板中,使待测细胞密度至1000~10000孔(边缘孔用无菌PBS填充);
(2)5%CO2,37℃孵育24h,至细胞单层铺满孔底,每孔加入一定浓度梯度的药物10μL,每个浓度梯度设4个复孔;
(3)5%CO2,37℃孵育48小时,倒置显微镜下观察;
(4)每孔加入10μL的MTT溶液(5mg/mL PBS,即0.5%MTT),继续培养4h;
(5)终止培养,小心吸去孔内培养液,每孔加入150μL的DMSO充分溶解甲瓒沉淀,振荡器混匀后,在酶标仪用波长为570nm,参比波长为450nm测定各孔的光密度值;
(6)同时设置调零孔(培养基、MTT、DMSO),对照孔(细胞、相同浓度的药物溶解介质、培养液、MTT、DMSO)。
(7)根据测得的光密度值(OD值),来判断活细胞数量,OD值越大,细胞活性越强。利用公式:
计算化合物对各细胞株生长的抑制率,其结果如以下表1所示。
表1:各化合物对不同细胞株的IC50值(μM)
注:实验数据为3次实验的平均值,Nd表示受试化合物对此细胞检测不到抑制活性。
Claims (8)
1.具有下述式(I)所示结构的熊果酸-硫化氢供体试剂衍生物或其药学上可接受的盐:
2.权利要求1所述熊果酸-硫化氢供体试剂衍生物的合成方法,其特征在于:取熊果酸、1,6-二溴己烷和碱在非质子极性溶剂中反应,得到化合物1;取化合物1、4-羟基硫代苯甲酰胺和碱在非质子极性溶剂中反应,得到目标物粗品;其中,反应在加热或不加热的条件下进行,化合物1的结构式如下所示:
其中,n为6。
3.根据权利要求2所述的合成方法,其特征在于:包括以下步骤:
1)取熊果酸、1,6-二溴己烷和碱在非质子极性溶剂中反应,所得反应物除去溶剂,残余物分散于乙酸乙酯、二氯甲烷或***中,经洗涤,无水硫酸钠干燥,过滤后,收集滤液,滤液浓缩后得到化合物1;
2)取化合物1、4-羟基硫代苯甲酰胺和碱在非质子极性溶剂中反应,所得反应物除去溶剂,残余物分散于乙酸乙酯、二氯甲烷或***中,经洗涤,无水硫酸钠干燥,过滤后,收集滤液,滤液浓缩后得到目标物粗品。
4.根据权利要求2或3所述的合成方法,其特征在于:所得化合物1经硅胶薄层色谱或硅胶柱层析纯化后再用于后续操作。
5.根据权利要求2或3所述的合成方法,其特征在于:还包括将目标物粗品进行纯化的步骤:具体是将制得的目标物粗品进行硅胶薄层色谱或硅胶柱层析,得到纯化后的目标物。
6.根据权利要求2或3所述的合成方法,其特征在于:所述的碱为碳酸钾、三乙胺、碳酸钠、碳酸氢钠、碳酸氢钾或碳酸铯。
7.根据权利要求2或3所述的合成方法,其特征在于:所述的非质子极性溶剂为N,N-二甲基甲酰胺、甲苯和吡啶中的一种或两种以上的组合。
8.根据权利要求2或3所述的合成方法,其特征在于:在化合物1、硫化氢供体试剂和碱的反应中,加入催化剂碘化钾。
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