CN109761961A - 一种苯并三氮唑衍生物作为Sirtuin抑制剂及其应用 - Google Patents
一种苯并三氮唑衍生物作为Sirtuin抑制剂及其应用 Download PDFInfo
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Abstract
本发明公开了一种苯并三氮唑衍生物作为Sirtuin抑制剂及其应用,其方案在于苯并三氮唑衍生物作为Sirtuin抑制剂的结构式及在制备抗肿瘤药物中的应用。该抑制剂对Sirtuin有抑制剂效果,并且本发明合成原料便宜、成本较低、选择性高,抗肿瘤活性明显,可用于选择性强、高效低毒的新型Sirtuin抑制剂类抗肿瘤药物。
Description
技术领域
本发明属于药物化学领域,具体涉及苯并三氮唑衍生物作为Sirtuin抑制剂及其应用。
背景技术
Sirtuin是组蛋白去乙酰化酶HDACs的一种亚型,它属于NAD+依赖的去赖氨酸酰化酶(NAD-dependent lysine deacylase),另一种则是Zn2+依赖的组蛋白去乙酰化酶,亦称为HDAC。人类Sirtuin家族中公认的成员有7个:SIRT1~SIRT7,其细胞定位和功能上各有不同,例如:SIRT3、SIRT4和SIRT5位于线粒体,可以调节多种线粒体能量代谢通路;SIRT2位于细胞质,可以去乙酰化酶活性;SIRT1、SIRT6和SIRT7位于细胞核,能够影响染色质稳定性及基因转录。
SIRT1虽然位于细胞核,但也可以转移到细胞质中发挥作用,例如参与胰岛素信号通路的抑制过程。每个Sirtuins亚型均有其各自的酶促反应特点。SIRT1~3具有很强的去乙酰化酶活性,而SIRT4~7则只能检测到很弱的去乙酰化酶活性,后经研究发现,SIRT5还具有去琥珀酰基化和去丙二酰基化酶活性,而SIRT4和SIRT6还具有ADP核糖转移酶活性,SIRT6还具有较强的去长链脂肪酰化酶活性。目前报道的Sirtuins抑制剂大多是通过高通量筛选后经过结构优化而得,但存在选择性较低、成本高的问题。
Sirtuin在细胞凋亡、DNA损伤修复、基因沉默等多个方面发挥着重要的作用,与多种疾病的发生发展有着密切关系。近年来,Sirtuin已成为肿瘤治疗的热门靶点之一。虽然Sirtuin抑制剂还没有被成功开发上市,但是寻找具有新骨架或新官能团、高抑制活性和选择性的Sirtuin抑制剂越来越成为当前靶向药物研发的热点。
发明内容
本发明的目的,其一在于提供一种苯并三氮唑衍生物作为Sirtuin抑制剂,该Sirtuin抑制剂可以抑制Sirtuin活性。
本发明的目的,其二在于提供前述Sirtuin抑制剂可作为新型Sirtuin抑制剂在制备抗肿瘤药物中的应用。
本发明的技术方案:一种苯并三氮唑衍生物作为Sirtuin抑制剂,所述抑制剂的结构式为:
前述的苯并三氮唑衍生物作为Sirtuin抑制剂中,所述的R:是芳环基、杂环基、环烷基或烷基;
前述的苯并三氮唑衍生物作为Sirtuin抑制剂中,所述的X:是O、NH或CH2;
前述的苯并三氮唑衍生物作为Sirtuin抑制剂中,所述的Y:是O、S、Se、NH或CH。
本发明的优点,在于苯并三氮唑衍生物作为Sirtuin抑制剂,所述的抑制剂对Sirtuin有抑制剂效果,并且本发明合成原料便宜、成本较低、选择性高,抗肿瘤活性明显,可用于选择性强、高效低毒的新型Sirtuin抑制剂类抗肿瘤药物。
具体实施方式
下面结合具体实施方式对本发明的技术方案作进一步说明。下面所描述的本发明各个实施方式中所涉及的技术特征只要彼此之间未构成冲突就可以相互组合。下述方法中所涉及配料或材料,如无特殊说明,均为商业途径可获得。相关实验方法中如无特殊说明的均为本技术领域现有常规方法。其中的数值或数值比例,如无标注,均指质量数值或质量比例。
实施例1:
苯并三氮唑衍生物作为Sirtuin抑制剂的合成,具体合成路线为:
其中R的定义见表1:
表1
化合物1-6的13C-NMR、1H-NMR和HR-MS数据
化合物1:1H-NMR(400MHz,DMSO-d)δ(ppm):8.40(s,1H),8.27(s,1H),7.95(d,2H),7.51(d,3H),7.21(d,2H).13C-NMR(100MHz,DMSO-d):161.39,145.52,138.21,136.72,132.41,130.69,127.85,126.61–126.05,124.32–123.64,123.08,121.48,120.34,114.98,113.35,106.61.HR-MS(ESI)m/z calculated for C30H21N8O4 +[2M+H]+557.1680,found557.1712.
化合物2:1H-NMR(400MHz,CDCl3)δ(ppm):9.60(s,1H),8.14–8.02(m,1H),7.47(qdd,3H),7.37(ddd,1H),7.24–7.18(m,1H),6.45(dt,1H).13C-NMR(100MHz,CDCl3):145.46,136.72,126.46,124.44,121.23,121.05,119.03–118.59,118.15,116.19,112.08,109.58.HR-MS(ESI)m/z calculated for C11H9N4O2[M+H]+229.0647,found 229.0670.
化合物3:1H-NMR(400MHz,CDCl3)δ(ppm):9.43(s,1H),9.42(d,1H),8.14(d,2H),7.91(d,2H),7.81(ddd,2H),7.60(ddd,2H).13C-NMR(100MHz,CDCl3):166.63,154.00,153.51,149.82,145.74,138.21,134.27,132.28,131.49,130.79,129.82,128.91,127.76,127.32,122.93,120.63.HR-MS(ESI)m/z calculated for C16H11N4O2[M+H]+291.0804,found 291.0816.
化合物4:1H-NMR(400MHz,CDCl3)δ(ppm):9.06(s,1H),8.98(dd,1H),8.83(d,1H),8.30(dd,2H),8.19(d,1H),8.06(d,1H),7.85–7.77(m,1H),7.70–7.63(m,2H).13C-NMR(100MHz,CDCl3):159.02,151.78,150.51,147.12,145.27,139.73,134.27,132.79,129.53,127.32,123.19,122.03,115.23.HR-MS(ESI)m/z calculated C16H11N4O2[M+H]+for291.0804,found 291.0824.
化合物5:1H-NMR(400MHz,CDCl3)δ(ppm):8.84–8.80(m,1H),8.37(dtd,1H),8.13(ddq,1H),7.71–7.61(m,1H),7.56–7.54(m,1H),7.54–7.46(m,1H),7.19(ddq,1H).13C-NMR(100MHz,CDCl3):151.64,145.89,144.01,132.07,130.85,127.59,121.80,119.73,115.07,115.99,112.33.HR-MS(ESI)m/z calculated C11H8N3O3[M+H]+230.0487,found230.0509.
化合物6:1H-NMR(400MHz,CDCl3)δ(ppm):8.96–8.90(m,1H),8.43–8.36(m,1H),8.41–8.36(m,1H),8.19–8.11(m,1H),8.02–7.97(m,1H),7.73–7.63(m,1H),7.58–7.48(m,1H),7.46–7.40(m,1H).13C-NMR(100MHz,CDCl3):145.70,142.06,137.92,133.17,130.51,130.51,130.17,126.40,125.96,120.28,115.05.HR-MS(ESI)m/z calculated C11H8N3O2S[M+H]+246.0259,found 246.0281.
实施例2:
苯并三氮唑衍生物作为Sirtuin抑制剂在体外的Sirtuin抑制活性和选择性
1.活性筛选
已有的Sirtuins亚型为1、2、3、5、6,相对应的1、2、3亚型的底物多肽H3K9AcWW(200μM)及其辅酶NAD(1mM);5的底物多肽H3K9SuWW(200μM)及其辅酶NAD(1mM);6的底物多肽H3K9MyWW(200μM)及其辅酶NAD(1mM)。
1.1Sirt1、2、3酶反应
底物多肽H3K9AcWW(200μM)及其辅酶NAD(1mM),与Sirt1、2、3(1μM)含有DTT(1mM)的Tris pH7.4(20mM)溶液中,加入系列浓度的待测药物,37℃反应60min后,用盐酸/醋酸溶液进行淬灭反应。高速离心后,送HPLC待测,并计算IC50值。
1.2Sirt5酶反应
底物多肽H3K9SuWW(200μM)及其辅酶NAD(1mM),与Sirt5(1μM)在含有DTT(1mM)的Tris pH7.4(20mM)溶液中,加入系列浓度的待测药物,37℃反应60min后,用盐酸/醋酸溶液进行淬灭反应。高速离心后,送HPLC待测,并计算IC50值。
1.3Sirt6酶反应
底物多肽H3K9MyWW(200μM)及其辅酶NAD(1mM),与Sirt6(1μM)含有DTT(1mM)的Tris pH7.4(20mM)溶液中,加入系列浓度的待测药物,37℃反应60min后,用盐酸/醋酸溶液进行淬灭反应。高速离心后,送HPLC待测,并计算IC50值。
化合物1~6的Sirtuin抑制活性结果如表2:
表2对Sirtuin不同亚型的IC50值
实施例3:
苯并三氮唑衍生物作为Sirtuin抑制剂对不同肿瘤细胞的抗肿瘤活性
采用公认的可用于大规模抗肿瘤药物筛选、细胞毒性试验测定的四甲基氮唑蓝比色法(MTT)评价候选化合物对5种人癌细胞株的抗细胞增殖活性。测试化合物为化合物1~2;阴性对照组为不加药组;阳性对照药为临床上使用的抗肿瘤药物Vorinostat(SAHA)。
细胞株:人乳腺癌细胞MCF-7、人肝癌细胞HepG2、人肺癌细胞A549、人结肠癌细胞SW480、宫颈癌细胞Hela。
细胞增殖抑制率=(阴性对照组0D值-药物组0D值)*100%/阴性对照组0D值。通过化合物系列浓度的抑制率计算得到IC50值(单位为μM),结果见表3。
表3 MTT法测定化合物1和2对不同肿瘤细胞的IC50值(单位为μM)
以上对本发明的实施方式作了详细说明,但本发明不限于所描述的实施方式。对于本领域的技术人员而言,在不脱离本发明原理和精神的情况下,对这些实施方式进行多种变化、修改、替换和变型,仍落入本发明的保护范围内。
Claims (2)
1.一种苯并三氮唑衍生物作为Sirtuin抑制剂,其特征在于:所述抑制剂的结构式为:
所述的R:是芳基、杂环基、环烷基或烷基;
所述的X:是O、NH或CH2;
所述的Y:是O、S、Se、NH或CH。
2.权利要求1中所述的苯并三氮唑衍生物作为Sirtuin抑制剂在制备抗肿瘤药物中的应用。
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Citations (3)
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US20050038069A1 (en) * | 1996-06-19 | 2005-02-17 | Aventis Pharma Limited | Substituted azabicyclic compounds |
WO2008026704A1 (fr) * | 2006-08-31 | 2008-03-06 | Kyowa Hakko Kogyo Co., Ltd. | Dérivé d'isoquinoline |
CN101928254A (zh) * | 2010-07-09 | 2010-12-29 | 南京大学 | 苯并三唑衍生物及其制法与用途 |
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Patent Citations (3)
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US20050038069A1 (en) * | 1996-06-19 | 2005-02-17 | Aventis Pharma Limited | Substituted azabicyclic compounds |
WO2008026704A1 (fr) * | 2006-08-31 | 2008-03-06 | Kyowa Hakko Kogyo Co., Ltd. | Dérivé d'isoquinoline |
CN101928254A (zh) * | 2010-07-09 | 2010-12-29 | 南京大学 | 苯并三唑衍生物及其制法与用途 |
Non-Patent Citations (3)
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CHUNG-YI WU等: "Stable Benzotriazole Esters as Mechanism-Based Inactivators of the Severe Acute Respiratory Syndrome 3CL Protease", 《CHEMISTRY & BIOLOGY》 * |
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