CN101423491A - 苊并杂环类化合物及其在制备BH3类似物类Bcl-2家族蛋白抑制剂中的应用 - Google Patents
苊并杂环类化合物及其在制备BH3类似物类Bcl-2家族蛋白抑制剂中的应用 Download PDFInfo
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- CN101423491A CN101423491A CNA2008102287462A CN200810228746A CN101423491A CN 101423491 A CN101423491 A CN 101423491A CN A2008102287462 A CNA2008102287462 A CN A2008102287462A CN 200810228746 A CN200810228746 A CN 200810228746A CN 101423491 A CN101423491 A CN 101423491A
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- bcl
- acenaphthene
- compound
- nitrile
- thiophene
- Prior art date
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- C—CHEMISTRY; METALLURGY
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Abstract
本发明涉及苊并杂环类化合物及其在制备BH3类似物类Bcl-2家族蛋白抑制剂中的应用,该化合物是在8-氧-8H-苊并[1,2-b]吡咯-9-腈的3,4,6位引入各种氧代物和硫代物,羰基化合物,酯基化合物以及酰基化合物,或进一步将9-腈取代为酸,酯酰,胺基所得到的化合物。本发明所述的上述苊并杂环类化合物模拟BH3-only蛋白,在体外和细胞内竞争性结合和拮抗Bcl-2,Bcl-xL和Mcl-1蛋白,从而诱导细胞凋亡作用,可用于制备抗癌化合物。
Description
技术领域
本发明涉及一类新的8-氧-8H-苊并[1,2-b]吡咯-9-腈的氧代、硫代、酮类或酯类取代衍生物及其在体内、体外的模拟BH3-only蛋白,竞争性结合和拮抗Bcl-2,Bcl-L和Mcl-1蛋白,从而诱导细胞凋亡作用和作为抗癌化合物的应用。
背景技术
分子靶向抗肿瘤药物正在成为继细胞毒剂类抗肿瘤药物之后,新药研发的热点和市场化的新生代产品。Bcl-2蛋白,是拮抗和逆转恶性肿瘤永生性的最重要的分子靶点。所以,特异性拮抗Bcl-2蛋白的药物,将通过专一诱导肿瘤细胞凋亡,终于实现高选择性、安全、高效、低痛苦抗癌的目标。在Bcl-2抑制剂中,以BH3类似物(BH3mimetics)的抗肿瘤效果最为显著,药效学活性最好,毒副作用最低。此外,也必须同时具备广谱拮抗Bcl-2家族蛋白的抗凋亡成员(包括Bcl-2,Bcl-xL和Mcl-1蛋白)的能力。
但到目前为止,以Bcl-2为靶点的抗肿瘤药物尚无上市产品,仅有的19个临床前Bcl-2抑制剂中,有三个效果最优的分别处于临床I,II,III期。分别是:由美国伊利诺州阿伯特实验室研发的ABT-737,Gemin X公司研发的Obatoclax(GX15-070),和美国Ascenta公司的AT-101。它们都是BH3类似物,与Bcl-2蛋白的竞争结合常数达到nM级,远远高于其它15个同类分子。但是它们都存在不足:Gossypol,Obatoclax的BH3类似程度不足,不是绝对的BH3类似物,也就是具有不依赖BAX/BAK的细胞毒性,说明存在其他的作用靶点,因此具有毒副作用。Obatoclax正因此面临淘汰。ABT-737虽然是绝对的BH3类似物,但是不能与Mcl-1作用,不能广谱抑制Bcl-2家族蛋白,因而严重限制了其使用范围。
本发明人既往研究的成果中公开了一系列8-氧-8H-苊并[1,2-b]吡咯-9-腈的苊并杂环类化合物,并指出这类化合物具有有通过诱导细胞凋亡抑制肿瘤生长的活性(中国专利,授权公告号CN1304370C)。
发明内容
本发明旨在获得更多具有良好的抑制Bcl-2家族蛋白(包括Bcl-2,Bcl-xL和Mcl-1蛋白)活性的BH3类似物。
本发明所述的苊并杂环类化合物具有如下的分子结构通式:
其中:
(I)R1=XR5、噻吩甲氧基、噻吩甲氨基、硫吗啉基,R2=H,R3=H,R4=CN、COOH、COOR6或CONHR7;
(II)R1=H,R2=XR5、噻吩甲氧基、噻吩甲氨基、硫吗啉基,R3=H,R4=CN、COOH、COOR6或CONHR7;
(III)R1=H,R2=H,R3=四氢吡喃-4-氧基、四氢噻喃-4-氧基、噻吩甲氧基、噻吩甲氨基、硫吗啉基,R4=CN;
其中:X=O、S、羰基、酯基、酰胺;
R5=a、(CH2)nAr-(o,m,p)Y,Y=CH3、NO2、Ph、F,Cl、Br、CF3、OCH3、SCH3、NH2(n=0-4);
b、四氢吡喃基、四氢噻喃基;
R6=CH3或C2H5;
R7=CH3、C2H5或Ar。
本发明的化合物合成主要分为两种途径。
第一种合成途径是以具有很好的刚性共平面性并且强缺电子的8-氧-8H-苊并[1,2-b]吡咯-9-腈为原料,与亲核试剂醇,硫醇或酚,硫酚类发生芳香氢亲核取代反应,得到3-取代,4取代或6-取代的8-氧-8H-苊并[1,2-b]吡咯-9-腈,腈基再经过水解,酯化,酰胺化得到相应的酸,酯,酰胺(分子结构通式1),反应式如下:
8-氧-8H-苊并[1,2-b]吡咯-9-腈在溶剂(四氢呋喃,乙腈,吡啶,二甲基甲酰胺或二甲基亚砜)中,与适量的醇,硫醇,酚,硫酚类亲核试剂反应,温度为20~100℃℃,反应时间0.5~24小时。冷却后减压蒸出部分溶剂后,过滤或直接柱层析即可得产品3或6-单取代氧基-8-氧代-8H-苊并[1,2-b]吡咯-9-腈。
3或6-单取代氧基-8-氧代-8H-苊并[1,2-b]吡咯-9-腈在浓硫酸的条件下水解可以得到其对应的酸类,在与相应的醇或者胺反应即可得到相应的酯类及酰胺类化合物。
第二种合成途径是以苊醌为原料,以浓硫酸作溶剂,加入液溴回流2h,得到溴代苊醌。先用溴代苊醌与醇,硫醇,酚,硫酚反应得到相应的取代苊醌。取代苊醌与乙腈在硅胶弱酸性催化的条件下反应得到3-(2-氧代-2氢-苊)-丙二腈之后,在K2CO3催化,乙腈回流0.5~6h冷却后减压蒸除部分溶剂后,过滤或直接柱层析即可制得相应的3或4-单取代氧基-8-氧代-8H-苊并[1,2-b]吡咯-9-腈。之后的水解,酯化,酰胺化条件同第一条合成路径。
第二条合成路径不同于第一条的条件在于先取代,后成环,这样可以得到3,4位两种同分异构体而不是以前的3,6位。反应式见下图:
对通过上述方法获得的化合物,我们通过多种手段检测了它们的BH3类似程度,以及它们对Mcl-1和Bcl-2的抑制作用。结果表明,本发明的上述具有新的结构的化合物具有极高的BH3类似程度,可以有效抑制Mcl-1和Bcl-2蛋白。
基于此,本发明指出上述苊并杂环类化合物可用于制备BH3类似物类Bcl-2家族蛋白抑制剂,并进一步用于制备抗肿瘤药物。所述的Bcl-2家族蛋白抑制剂或相应的抗肿瘤药物可以是化合物的单质制剂或者是有效量的所述苊并杂环类化合物与适量的药用辅剂混合形成的组合物。并可以根据药用需要,根据现有技术中的制剂方法将其制成需要的剂型。
本发明所述的上述苊并杂环类化合物及其制剂模拟BH3-only蛋白,竞争性结合和拮抗Bcl-2,Bcl-xL和Mcl-1蛋白,从而诱导细胞凋亡作用,实现其作为抗癌化合物的应用。
附图说明
本发明附图8幅:
附图1是荧光偏振方法检测化合物与FAM-Bid肽段竞争结合Bcl-2蛋白的动力学曲线;
附图2是化合物在细胞水平上干扰Bcl-2/Bax之间相互作用结果示图(不同浓度);
附图3是化合物在细胞水平上干扰Bcl-2/Bax之间相互作用结果示图(不同作用时间);
附图4是Bax蛋白与线粒体共定位检测化合物的BH3类似度阳性结果示图;
附图5是Bax蛋白与线粒体共定位检测化合物的BH3类似度阴性结果示图;
附图6是化合物依赖BAX/BAK的细胞毒性实验结果(Gossypol为非特异性对照);
附图7是化合物对Mcl-1抑制作用Western印记检测电泳图;
附图8是化合物对Bcl-2抑制作用Western印记检测电泳图。
具体实施方式
实施例1
50毫升乙腈中加入1克8-氧-8H苊并[1,2-b]吡咯-9-腈,0.47克对甲基苯酚,回流搅拌3小时,蒸出部分溶剂,层析柱分离得产品3-(对甲苯氧基)-8-氧-8H-苊并[1,2-b]吡咯-9-腈,收率40%。M.p.232-233℃;1H NMR(400M,CDCl3):δ8.916(dd,J=8.8Hz,1H),8.623(d,J=8.8Hz,1H),8.447(d,J=6.4Hz,1H),7.859(t,J=8.0Hz,1H),8.324(d,J=8.4Hz,2H),7.101(d,J=8.4Hz,2H),7.016(d,J=8.4Hz,2H),3.256(s,3H)。
实施例2
称取0.93g苯氧基苊醌,0.3g丙二腈用二氯甲烷溶解之后,加入硅胶柱中,快速淋洗,过柱完毕之后旋干得红色固体。称重10.1g,产率92%。取0.6g3-苯氧基-(2-氧代-2氢-苊)-丙二腈,加入0.08g K2CO3,20ml乙腈加热回流3h,反应完毕之后旋干反应液。层析柱分离(CH2Cl2:石油醚=2:1)得到橙红色固体,核磁检验同分异构体比例1:0.3。利用制备液相分离的到两种同分异构体。
第一组分A:M.p.265-267℃;1H NMR(400M,CDCl3):δ 8.927(d,J=8.0Hz,1H),8.630(d,J=8.8Hz,1H),8.450(d,J=7.2Hz,1H),7.876(t,J=8.0Hz,1H),7.754(t,J=8.0Hz,2H),7.392(t,J=7.6Hz,1H),7.233(d,J=7.6Hz,2H),7.028(d,J=8.4Hz,1H)。
第二组分B:M.p.282-283℃;1H NMR(400M,CDCl3):δ 9.047(dd,J=8.0Hz,1H),8.850(dd,J=7.6Hz,1H),8.213(d,J=8.2Hz,1H),7.999(t,J=8.0Hz,1H),7.561(t,J=8.0Hz,2H),7.410(t,J=7.0Hz,1H),7.251(d,J=8.8Hz,2H),6.899(d,J=8.4Hz,1H)。
实施例3
称取1.0g对甲苯氧基苊醌,0.3g丙二腈用二氯甲烷溶解之后,加入硅胶柱中,快速淋洗,过柱完毕之后旋干得红色固体。称重11.2g,产率93%。取0.7g3-苯氧基-(2-氧代-2氢-苊)-丙二腈,加入0.08g K2CO3,20ml乙腈加热回流4h,反应完毕之后旋干反应液。层析柱分离(CH2Cl2:石油醚=1:1)得到橙红色固体,核磁检验同分异构体比例1:0.4。利用制备液相分离的到两种同分异构体。
第一组分A:M.p.232-233℃;1H NMR(400M,CDCl3):δ 8.916(dd,J=8.8Hz,1H),8.623(d,J=8.8Hz,1H),8.447(d,J=6.4Hz,1H),7.859(t,J=8.0Hz,1H),8.324(d,J=8.4Hz,2H),7.101(d,J=8.4Hz,2H),7.016(d,J=8.4Hz,1H),2.351(s,3H)。
第二组分B:M.p.258-260℃;1H NMR(400M,CDCl3):δ 8.987(dd,J=8.8Hz,1H),8.858(d,J=8.8Hz,1H),8.208(d,J=8.4Hz,1H),7.986(t,J=8.0Hz,1H),8.333(d,J=8.4Hz,2H),7.112(d,J=8.4Hz,2H),6.889(d,J=8.4Hz,1H),2.349(s,3H)。
实施例4
称取1.0g间甲苯巯基苊醌,0.3g丙二腈用二氯甲烷溶解之后,加入硅胶柱中,快速淋洗,过柱完毕之后旋干得红色固体。称重12.2g,产率91%。取0.7g2-苯巯基-(2-氧代-2氢-苊)-丙二腈,加入0.08g K2CO3,20ml乙腈加热回流4h,反应完毕之后旋干反应液。层析柱分离(CH2Cl2:石油醚=1:1)得到红色固体,核磁检验同分异构体比例1:0.25。利用制备液相分离的到两种同分异构体。
第一组分A:M.p.255-257℃;1H NMR(400M,CDCl3):δ 8.826(dd,J=8.8Hz,1H),8.513(d,J=8.8Hz,1H),8.327(d,J=6.4Hz,1H),7.659(t,J=8.0Hz,1H),8.014(d,J=8.4Hz,2H),6.901(d,J=8.4Hz,2H),6.896(d,J=8.4Hz,1H),2.353(s,3H)。
第二组分B:M.p.269-271℃;1H NMR(400M,CDCl3):δ 8.877(dd,J=8.8Hz,1H),8.748(d,J=8.8Hz,1H),8.108(d,J=8.4Hz,1H),7.856(t,J=8.0Hz,1H),8.123(d,J=8.4Hz,2H),6.892(d,J=8.4Hz,2H),6.679(d,J=8.4Hz,1H),2.355(s,3H)。
实施例5
50毫升乙腈中加入1克8-氧-8H苊并[1,2-b]吡咯-9-腈,0.5克对甲基苯酚,回流搅拌6小时,蒸发部分溶剂,层析柱分离得产品6-(2-噻吩甲氧基)-8-氧-8H-苊并[1,2-b]吡咯-9-腈,收率45%。M.p.241-243℃;1H NMR(400M,CDCl3):δ 8.685(dd,J=8.7Hz,1H),8.433(d,J=8.7Hz,1H),8.014(d,J=6.4Hz,1H),7.75(t,J=8.0Hz,IH),7.251(s,J=8.4Hz,2H),6.985(d,J=8.4Hz,2H),6.232(d,J=8.4Hz,2H)。
实施例6
称取1.0g间氟苯羰基苊醌,0.4g丙二腈用二氯甲烷溶解之后,加入硅胶柱中,快速淋洗,过柱完毕之后旋干得深红色固体。称重10.5g,产率85%。取0.8g2-氟羰基-(2-氧代-2氢-苊)-丙二腈,加入0.08g K2CO3,20ml乙腈加热回流3h,反应完毕之后旋干反应液。层析柱分离(CH2Cl2:石油醚=2:1)得到深红色固体,核磁检验同分异构体比例1:0.2。利用制备液相分离得到两种同分异构体。
第一组分A:M.p.285-287℃;1H NMR(400M,CDCl3):δ 8.726(dd,J=8.8Hz,1H),8.423(d,J=8.8Hz,1H),8.015(d,J=6.4Hz,1H),7.598(t,J=8.0Hz,1H),8.003(d,J=8.4Hz,2H),6.853(d,J=8.4Hz,2H),6.756(d,J=8.4Hz,1H)。
第二组分B:M.p.269-271℃;1H NMR(400M,CDCl3):δ 8.568(dd,J=8.8Hz,1H),8.478(d,J=8.8Hz,1H),8.006(d,J=8.4Hz,1H),7.568(t,J=8.0Hz,1H),8.045(d,J=8.4Hz,2H),6.908(d,J=8.4Hz,2H),6.596(d,J=8.4Hz,1H)。
实施例7
称取1.0g苯基酰胺苊醌,0.4g丙二腈用二氯甲烷溶解之后,加入硅胶柱中,快速淋洗,过柱完毕之后旋干得深红色固体。称重11.2g,产率86%。取0.8g苯酰胺-(2-氧代-2氢-苊)-丙二腈,加入0.08g K2CO3,20ml乙腈加热回流3h,反应完毕之后旋干反应液。层析柱分离(CH2Cl2:石油醚=2:1)得到深红色固体,核磁检验同分异构体比例1:0.4。利用制备液相分离得两种同分异构体。
第一组分A:M.p.281-283℃;1H NMR(400M,CDCl3):δ 9.112(d,J=8.0Hz,1H),8.945(d,J=8.8Hz,1H),8.682(d,J=7.2Hz,1H),8.452(t,J=8.0Hz,1H),8.312(s,1H),7.986(t,J=8.0Hz,2H),7.627(t,J=7.6Hz,1H),7.433(d,J=7.6Hz,2H),7.241(d,J=8.4Hz,1H)。
第二组分B:M.p.293-294℃;1H NMR(400M,CDCl3):δ 9.213(dd,J=8.0Hz,1H),9.012(dd,J=7.6Hz,1H),8.685(d,J=8.2Hz,1H),8.428(t,J=8.0Hz,1H),8.320(s,1H),7.896(t,J=8.0Hz,2H),7.675(t,J=7.0Hz,1H),7.531(d,J=8.8Hz,2H),7.015(d,J=8.4Hz,1H)。
实施例8
称取1.0g4-四氢吡喃氧基苊醌,0.4g丙二腈用二氯甲烷溶解之后,加入硅胶柱中,快速淋洗,过柱完毕之后旋干得深红色固体。称重11.2g,产率86%。取0.8g4-四氢吡喃-(2-氧代-2氢-苊)-丙二腈,加入0.08g K2CO3,20ml乙腈加热回流9h,反应完毕之后旋干反应液。层析柱分离(CH2Cl2:石油醚=2:1)得到深红色固体,核磁检验同分异构体比例1:0.4。利用制备液相分离的到两种同分异构体。
第一组分A:M.p.230-231℃;1H NMR(400M,CDCl3):δ 8.601(d,J=8.0Hz,2H),8.134(d,J=8.8Hz,1H),7.945(dd,J=8.0Hz,1H),7.452(d,J=8.4Hz,1H),3.822(t,J=4.8Hz,4H),3.815(t,J=5.0Hz,4H),3.766(t,J=5.2Hz,1H)。
第二组分B:M.p.242-244℃;1H NMR(400M,CDCl3):δ 8.568(d,J=8.0Hz,2H),8.115(d,J=8.8Hz,1H),7.856(dd,J=8.0Hz,1H),7.326(d,J=8.4Hz,1H),3.796(t,J=4.8Hz,4H),3.807(t,J=5.0Hz,4H),3.791(t,J=5.2Hz,1H)。
实施例9
在50ml单口烧瓶中,加入60ml浓硫酸或者25ml发烟硫酸,在0~5℃下,分批加入0.05mol的3-苯氧基-8-氧-8H-苊并[1,2-b]吡咯-9-腈,1h内加完,加完后在室温继续反应16h,反应混合物为粘稠的深棕红色。然后小心缓慢的将其滴入碎冰中,同时剧烈搅拌,滴完后静置,滤饼用大量水洗涤,直至滤饼呈中性,滤饼干燥后得深黄色产品。产率96%。M.p.248℃;1H NMR(400M,CDCl3):δ 11.42(s,1H),8.965(dd,J=8.0Hz,1H),8.750(dd,J=7.8Hz,1H),8.313(d,J=8.2Hz,1H),7.999(t,J=8.2Hz,1H),7.561(t,J=8.2Hz,2H),7.410(t,J=7.0Hz,1H),7.251(d,J=8.8Hz,2H),6.963(d,J=8.4Hz,1H)。
实施例10
在100ml单口烧瓶中,依次加入0.01mol 3-苯氧基-8-氧-8H-苊并[1,2-b]吡咯-9-腈,50ml乙腈做溶剂,0.02mmol的碳酸钾做缚酸计,过量10倍的碘甲烷,氮气保护下,加热至40℃反应15h。减压蒸去乙腈,加入二氯甲烷使反应物充分溶解,过滤之后旋干滤液,得黄棕色粗产品。硅胶柱层析分离,展开剂:二氯甲烷-甲醇(40:1),得深黄色产品。产率92%。M.p.213℃;1H NMR(400M,CDCl3):δ 9.102(d,J=7.2Hz,1H),8.965(dd,J=8.0Hz,1H),8.850(dd,J=7.8Hz,1H),8.233(d,J=8.2Hz,1H),7.856(t,J=8.2Hz,1H),7.453(t,J=8.2Hz,2H),7.350(t,J=7.2Hz,1H),7.325(d,J=8.4Hz,2H),6.785(d,J=8.4Hz,1H),3.213(s,3H)。
实施例11
在100ml单口烧瓶中,依次加入0.01mol 3-甲氧基-8-8-H-苊并[1,2-b]吡咯-9-酸,50ml DMF做溶剂,0.02mmol的三乙胺,0.01mmol的(EtO)2P(=O)CN,过量10倍的叔丁胺,常温反应1h。反应完毕得到黄色固体,产率85%。M.p.237℃;1HNMR(400M,CDCl3):δ 8.746(dd,J=8.0Hz,1H),8.650(dd,J=7.8Hz,1H),8.213(d,J=8.2Hz,1H),7.846(t,J=8.0Hz,1H),7.352(t,J=8.0Hz,2H),7.210(t,J=7.4Hz,1H),7.051(d,J=8.4Hz,2H),6.963(d,J=8.4Hz,1H),3.721(s,3H),3.113(m,2H),1.568(dd,J=5.6Hz,2H),1.421(m,J=5.7Hz,2H),0.968(t,J=6.2Hz,3H)。
实施例12
通过荧光偏振分析法检测化合物的BH3类似程度
合成一个带有21个氨基酸的Bid BH3肽段(氨基酸:79-99:QEDIIRNIARHLAQVGDSMDR),并在N端标记上6-羧基荧光素琥珀酰亚胺酯(FAM)作为荧光标签(FAM-Bid)。竞争结合实验中所用的反应体系为GST-Bcl-2蛋白(40nM)或Mcl-1蛋白,和FAM-Bid多肽(5nM)溶于反应缓冲液中(100mM K3PO4,pH7.5;100μg/ml牛γ白蛋白;0.02%叠氮化钠)。在96孔板中,每孔加入100μL反应体系,然后加入1μL不同浓度的溶于DMSO的待检测化合物(3-硫吗啉8-氧-8H-苊并[1,2-b]吡咯-9-腈)母液至实验设计所需终浓度。同时设立两个对照组,一个对照组为反应体系中只含有Bcl-2或Mcl-1和FAM-Bid(相当于0%抑制率),另一对照组中的反应体系只含有FAM-Bid肽段。96孔板经过4个小时的避光孵育后,进行酶标仪上检测。荧光极化值(mP)在由530nm波长激发产生的485nm发射波长下测量。Ki值根计算公式推导得出。试验结果如附图1所示。该化合物与Bcl-2蛋白的竞争结合常数为310nM。
按照上述相同的试验方法检测其他6个化合物(如下结构式所示)的BH3类似程度,它们与Bcl-2和Mcl-1蛋白的结合常数在也是nM级,分别为:600nM,890nM,560nM,790nM,510nM,710nM。
实施例13
活细胞内荧光偏振能量转移(FRET)检测化合物的BH3类似性
利用磷酸钙共沉淀的方法将2μgBcl-2-CFP和Bax-YFP质粒分别或同时转染至Hela细胞中,转染24小时后,将细胞接种于6孔培养板(2×105个/孔),加入溶于DMSO的待检测化合物(3-硫吗啉8-氧-8H-苊并[1,2-b]吡咯-9-腈)至终浓度(2,5,10和15μM),药物作用24小时后(如附图2a),PBS清洗细胞3次,用GENIOS荧光酶标仪(TECAN,Swiss)检测荧光值。在时间依赖的实验中,转染后的细胞接种于6孔板后,加入40μM化合物,药物作用3、6和24小时(附图2b),读板检测荧光。在只转染Bcl-2-CFP质粒的细胞组中记录475nm发射波长值,激发波长为433nm。在只转染Bax-YFP质粒的细胞组中记录527nm发射波长值,激发波长为505nm。对共转染Bcl-2-CFP和Bax-YFP质粒的细胞实验组记录527nm和475nm发射波长值,激发波长为433nm。527nm发射荧光与475nm发射荧光相比值即为FRET,将单独转染对照组的FRET值设为1.0,表示两蛋白未发生荧光偏振能量转移。在共转染的细胞中,由于Bcl-2蛋白和Bax蛋白的相互作用使得FRET值增加至2.0,而随着加药浓度和时间的增加,对两蛋白相互作用的干扰增强,FRET随之减弱。细胞活力由MTT法进行测定。试验结果如附图2和附图3所示,该化合物在2μM,作用3h即可干扰Bcl-2/Bax之间的相互作用,呈浓度时间依赖趋势。
按照上述相同的试验方法检测其他7个化合物(如下结构式所示),试验证明这些化合物均具有细胞内模拟BH3-only蛋白的作用。
实施例14
通过Bax蛋白与线粒体共定位检测化合物的BH3类似度
利用磷酸钙共沉淀方法将5μg Bax-YFP质粒转染至MCF-7细胞中,转染24小时后,将细胞接种于6孔培养板(0.2×106个/孔),加入10μM待检测化合物(3-硫吗啉8-氧-8H-苊并[1,2-b]吡咯-9-腈),作用6小时后,PBS清洗并同50nMMito Tracker Red CMXRos(线粒体特异探针;红色)避光孵育10min,PBS清洗三次后,Radiance2000激光共聚焦显微镜(Bio-Rad,USA)扫描荧光图像。同时进行双通道扫描,一个通道扫描Bax-YFP的绿色荧光,另一通道扫描指示线粒体的CMXRos探针红色荧光,两通道图像相互叠加显示共定位情况。当Bax蛋白定位于线粒体上,绿色荧光与红色荧光叠加成橘色,如附图4所示;对照附图5显示不能驱动BAX向线粒体移位,共定位失败的试验结果。
按照上述相同的试验方法检测其他5个化合物(如下结构式所示),结果显示他们均具有驱动BAX向线粒体移位的作用,说明具有细胞内模拟BH3-only蛋白的作用。
实施例15
化合物依赖BAX/BAK的细胞毒性实验验证其BH3类似物的特性
磷酸钙共沉淀转染3μg BAX/BAK干扰质粒至MCF-7细胞中,转染24小时后,收集细胞,Western检测RNA干扰后BAX和BAK蛋白表达情况,相同处理无质粒转染的细胞组设为对照组。转染后的细胞接种于96孔板中(1×105个/孔),平行进行未转染质粒细胞组的对照实验,按实验设计浓度梯度加入待检测化合物(3-硫吗啉8-氧-8H-苊并[1,2-b]吡咯-9-腈),作用48小时后,MTT检测细胞活力,结果如附图6所示,Gossypol作为非特异性BH3类似物与本发明的化合物对比平行处理,可见3-硫吗啉8-氧-8H-苊并[1,2-b]吡咯-9-腈具有绝对依赖BAX/BAK的细胞毒性。
按照上述相同的试验方法检测其他6个化合物(如下结构式所示),结果显示下述化合物具有绝对依赖BAX/BAK的作用特点。
实施例16
Western印记检测化合物对Mcl-1和Bcl-2的抑制作用
收集细胞样品后,以1×106/50μl细胞裂解液(62.5mM Tris-HCL pH6.8;2%SDS;10%甘;50mM DTT;0.01%溴酚蓝)低温裂解,离心,取蛋白上清,100℃煮沸样品5分钟,12%SDS-PAGE电泳并转膜,相应抗体检测目的蛋白,辣根过氧化酶标记二抗并结合ECL显色法检测目的蛋白在细胞中的表达量。附图7和附图8分别显示待检测化合物(3-硫吗啉8-氧-8H-苊并[1,2-b]吡咯-9-腈)对Mcl-1和Bcl-2的抑制作用。
经同样方法对检测6个化合物(如下结构式所示),它们均具有抑制Mcl-2蛋白的作用。
Claims (2)
1、一类苊并杂环类化合物,其分子结构通式为:
其中:
(I)R1=XR5、噻吩甲氧基、噻吩甲氨基、硫吗啉基,R2=H,R3=H,R4=CN、COOH、COOR6或CONHR7;
(II)R1=H,R2=XR5、噻吩甲氧基、噻吩甲氨基、硫吗啉基,R3=H,R4=CN、COOH、COOR6或CONHR7;
(III)R1=H,R2=H,R3=四氢吡喃-4-氧基、四氢噻喃-4-氧基、噻吩甲氧基、噻吩甲氨基、硫吗啉基,R4=CN;
其中:X=O、S、羰基、酯基、酰胺;
R5=a、(CH2)nAr-(o,m,p)Y,Y=CH3、NO2、Ph、F,Cl、Br、CF3、OCH3、SCH3、NH2(n=0-4);
b、四氢吡喃基、四氢噻喃基;
R6=CH3或C2H5;
R7=CH3、C2H5或Ar。
2、权利要求1所述的苊并杂环类化合物在制备BH3类似物类Bcl-2家族蛋白抑制剂中的应用。
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US13/128,381 US20110251188A1 (en) | 2008-11-11 | 2009-10-25 | Acenaphtho heterocycle compounds, cyclodextrin inclusion compounds and complexes, and uses in the manufactures of bh3 protein analogue, bcl-2 family protein inhibitors thereof |
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CN2009102099612A CN101928243B (zh) | 2008-11-11 | 2009-10-25 | 苊并杂环类化合物,其环糊精包合物、配结物及其在制备Bcl-2家族蛋白抑制剂中的应用 |
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JP2011534990A JP2012508194A (ja) | 2008-11-11 | 2009-10-25 | アセナフトヘテロ環式化合物、そのシクロデキストリン包接化合物及びシクロデキストリン複合体、並びにそれらがBH3タンパク質類似体、Bcl−2ファミリータンパク質の阻害剤の製造における使用 |
BRPI0921044A BRPI0921044A2 (pt) | 2008-11-11 | 2009-10-25 | composto heterocíclico de acenafto, composto de inclusão de ciclodextrina do composto heterocíclico de acenafto, complexo de ciclodextrina do composto heterocíclico de acenafto, uso do composto heterocíclico de acenafto, uso do composto de inclusão de ciclodextrina do composto heterocíclico de acenafto e uso do complexo de ciclodextrina |
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KR1020117013490A KR20110086848A (ko) | 2008-11-11 | 2009-10-25 | 아세나프토 헤테로시클릭 화합물, 사이클로덱스트린을 포함하는 화합물 및 복합체, 및 이의 BH3 단백질 유사체, Bcl-2 패밀리 단백질 억제제 제조용도 |
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Cited By (8)
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WO2010054575A1 (zh) * | 2008-11-11 | 2010-05-20 | 大连理工大学 | 苊并杂环类化合物、其环糊精包合物和环糊精配结物以及它们在制备BH3类似物Bcl-2家族蛋白抑制剂中的应用 |
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CN1304370C (zh) * | 2004-09-15 | 2007-03-14 | 大连理工大学 | 苊并杂环类化合物及其诱导细胞凋亡和抗肿瘤的应用 |
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CN101423491A (zh) * | 2008-11-11 | 2009-05-06 | 大连理工大学 | 苊并杂环类化合物及其在制备BH3类似物类Bcl-2家族蛋白抑制剂中的应用 |
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2008
- 2008-11-11 CN CNA2008102287462A patent/CN101423491A/zh active Pending
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WO2010054575A1 (zh) * | 2008-11-11 | 2010-05-20 | 大连理工大学 | 苊并杂环类化合物、其环糊精包合物和环糊精配结物以及它们在制备BH3类似物Bcl-2家族蛋白抑制剂中的应用 |
CN101723907B (zh) * | 2009-07-25 | 2011-09-14 | 大连理工大学 | 一类邻二氰基苊并吡嗪化合物及其抗肿瘤应用 |
CN101633637B (zh) * | 2009-08-18 | 2011-09-28 | 华东理工大学 | 8-氧-8H-苊并[1,2-b]吡咯衍生物 |
CN102321012A (zh) * | 2010-07-28 | 2012-01-18 | 大连理工大学 | 一类苊并杂环类化合物及其应用 |
CN102336700A (zh) * | 2010-07-28 | 2012-02-01 | 大连理工大学 | 一类氨基取代苊并杂环类化合物及其应用 |
WO2012013147A1 (zh) * | 2010-07-28 | 2012-02-02 | 大连理工大学 | 苊并杂环类化合物及其应用 |
CN102321012B (zh) * | 2010-07-28 | 2013-08-21 | 大连理工大学 | 一类苊并杂环类化合物及其应用 |
CN102336700B (zh) * | 2010-07-28 | 2013-11-06 | 大连理工大学 | 一类氨基取代苊并杂环类化合物及其应用 |
US8614333B2 (en) | 2010-07-28 | 2013-12-24 | Dalian University Of Technology | Acenaphtho heterocyclic compound and application thereof |
WO2012100368A1 (zh) * | 2011-01-25 | 2012-08-02 | 大连理工大学 | 筛选肿瘤细胞的方法及其用途 |
CN103435574A (zh) * | 2013-08-15 | 2013-12-11 | 大连理工大学 | 一种巯基苯并噻唑取代的苊并杂环类化合物及其应用 |
CN103435574B (zh) * | 2013-08-15 | 2014-10-29 | 大连理工大学 | 一种巯基苯并噻唑取代的苊并杂环类化合物及其应用 |
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MX2011004643A (es) | 2011-10-28 |
CN101928243A (zh) | 2010-12-29 |
CA2742856A1 (en) | 2010-05-20 |
US20110251188A1 (en) | 2011-10-13 |
JP2012508194A (ja) | 2012-04-05 |
RU2011118591A (ru) | 2012-12-20 |
IL212393A0 (en) | 2011-06-30 |
EP2366701A1 (en) | 2011-09-21 |
AU2009316152A1 (en) | 2010-05-20 |
BRPI0921044A2 (pt) | 2019-09-24 |
WO2010054575A1 (zh) | 2010-05-20 |
ZA201103355B (en) | 2012-01-25 |
KR20110086848A (ko) | 2011-08-01 |
CN101928243B (zh) | 2012-09-05 |
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