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CN113087658B - 具有热休克热蛋白70抑制活性的化合物及其应用 - Google Patents

具有热休克热蛋白70抑制活性的化合物及其应用 Download PDF

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CN113087658B
CN113087658B CN202110365441.1A CN202110365441A CN113087658B CN 113087658 B CN113087658 B CN 113087658B CN 202110365441 A CN202110365441 A CN 202110365441A CN 113087658 B CN113087658 B CN 113087658B
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潘峥婴
杨杰
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Peking University Shenzhen Graduate School
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Abstract

本发明属于医药技术领域，具体提供具有热休克蛋白70抑制活性的化合物及其应用。所述化合物包括说明书中三种化合物中的至少一种。本发明的化合物对谷胱甘肽反应能力弱且对热休克蛋白70具有较强结合能力，在复杂的生物体系中具有较高活性和较低的副作用，因此可以作为抑制剂。

Description

具有热休克热蛋白70抑制活性的化合物及其应用
技术领域
本发明属于医药技术领域，尤其涉及具有热休克蛋白70抑制活性的化合物及其应用。
背景技术
热休克蛋白70(Hsp70)广泛分布于各个生物体，其序列和结构从低等细菌到高等哺乳动物均具有高度的保守性。Hsp70由氨基端的核苷酸结合域、羧基端的底物结合域(SBD)以及连接于核苷酸结合域和底物结合域之间的约十个氨基酸残基的疏水柔性链组成。其中，底物结合域SBD又可分为富含β折叠的SBDβ亚结构域和富含α螺旋的SBDα亚结构域。
有文献报道，
Figure BDA0003007097500000011
(PES)是Hsp70的抑制剂，并被认为可能是结合在Hsp70的SBD上。PES能对肿瘤细胞进行选择性杀伤，而同等浓度下对正常细胞基本没有毒性，能抑制白血病、淋巴瘤、膀胱癌、胰腺癌、非小细胞肺癌、宫颈癌等肿瘤细胞的活性，但是PES对于体内大量存在的谷胱甘肽(GSH)也有较强的反应能力，因此需要发展对GSH反应性能较弱，而保持或者提高对Hsp70结合能力的抑制剂，以便提高化合物在复杂生物体系中的活性和降低可能的副作用。
发明内容
本发明实施例提供具有热休克蛋白70抑制活性的化合物及其应用，旨在提供对谷胱甘肽反应能力弱且对热休克蛋白70具有较强结合能力的化合物。
本发明是这样实现的：
具有热休克蛋白70抑制活性的化合物，所述化合物包括如下三种化合物中的至少一种：
Figure BDA0003007097500000021
相应地，上述具有热休克蛋白70抑制活性的化合物在作为抑制剂的应用。
可选地，所述应用为将所述具有热休克蛋白70抑制活性的化合物作为热休克蛋白70的抑制剂。
本发明的有益效果如下：
相对于现有技术，本发明提供的具有热休克蛋白70抑制活性的化合物，对谷胱甘肽反应能力弱且对热休克蛋白70具有较强结合能力，在复杂的生物体系中具有较高活性和较低副作用，因此可以作为热休克蛋白70抑制剂。
具体实施方式
为了使本发明要解决的技术问题、技术方案及有益效果更加清楚明白，以下结合实施例，对本发明做进一步的详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。
本发明实施例提供的具有热休克蛋白70抑制活性的化合物具有如下所示的结构：
Figure BDA0003007097500000031
本发明的化合物，可以通过下面反应式得到。
反应式：
Figure BDA0003007097500000032
反应式从苯乙炔及其衍生物出发，在低温下加入双三甲基硅基胺基锂(LiHMDS)，而后加入氯磺酰胺，获得目标产物。
为更好的说明本发明的技术方案，下面举例做进一步的说明。
实施例1
一种具有热休克蛋白70抑制活性的化合物，该化合物的化学结构式如下所示：
Figure BDA0003007097500000041
本实施例的化合物采用上述反应式的路线制备得到。
实施例2
一种具有热休克蛋白70抑制活性的化合物，该化合物的化学结构式如下所示：
Figure BDA0003007097500000042
本实施例的化合物采用上述反应式的路线制备得到。
实施例3
一种具有热休克蛋白70抑制活性的化合物，该化合物的化学结构式如下所示：
Figure BDA0003007097500000043
本实施例的化合物采用上述反应式的路线制备得到。
性能测试：
对实施例1至3得到的化合物进行了相应的性能验证分析，并以文献化合物PES为对比例，具体验证过程如下：
(1)紫外-可见分光光度法检测化合物与GSH反应的t1/2：
在缓冲液(50mM Tris-HCl,pH 7.5,100mM KCl,5mM MgCl2)中将1mM GSH与50μM实施例1至3及对比例中的任一种化合物进行混合，在SHIMADZU UV-2600仪器上进行紫外-可见光谱扫描(240nm至340nm)，每5分钟在25℃下记录一次光谱，直到UV-Vis信号达到平稳为止。最后，通过记录在280nm处的吸收来监测、拟合出伴随反应产物增加的浓度变化的时间过程，结果记录于表1中。
(2)荧光密度中心法检测化合物与Hsp70反应的t1/2：
在缓冲液中将1mM实施例1至3及对比例中的任一种化合物与10μMWT-hHsp70快速混合，在Hitachi F-4500仪器上进行hHsp70内源荧光扫描，其中激发光295nm，记录310nm至380nm处发射光强度，每5分钟在25℃下记录一次光谱，直到内源荧光信号达到平稳为止。使用该公式
Figure BDA0003007097500000051
计算内源荧光的荧光密度中心(CSM)，拟合出荧光密度中心随反应变化的时间过程，结果记录于表1中。
(3)检测化合物抑制癌细胞DoHH2增殖实验步骤：
将DOHH2细胞在补充有10％胎牛血清(FBS，Gibco)的RMPI-1640(Gibco)中培养。将细胞接种到96孔板中(3000个细胞/孔)，用不同浓度的实施例1至3及对比例中的任一种化合物处理72小时，而后用Cell Titer-Glo发光细胞活力测定法(Promega)进行测量，结果记录于表1中。
表1
Figure BDA0003007097500000052
Figure BDA0003007097500000061
从表1可知，实施例1至3的化合物有效地降低了与GSH的反应能力，表现在第3列的t1/2明显大于(甚至未检出)对比例(PES)的t1/2；但仍有效保持与Hsp70的反应活性，表现在第4列的t1/2小于或相当于对比例(PES)的t1/2；此外，实施例1至实施例3还具有有效的肿瘤细胞抑制活性，表现在第5列的GI50低于对比例(PES)的GI50。这些数据表明相比于对比例PES，实施例1至3化合物在复杂生物体内可以更好的保持靶向Hsp70的效率，降低脱靶的可能性。
综上可见，本发明设计合成的具有热休克蛋白70抑制活性的化合物，对谷胱甘肽反应能力弱且对热休克蛋白70具有较强结合能力的化合物，可以作为热休克蛋白70的抑制剂。
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、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (2)

1.具有热休克蛋白70抑制活性的化合物，其特征在于，所述化合物选自如下两种化合物中的至少一种：
Figure FDA0003576499010000011
2.如权利要求1所述的具有热休克蛋白70抑制活性的化合物在制备抑制热休克蛋白70药物中的应用。
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CN105439972A (zh) * 2015-07-17 2016-03-30 中国科学院广州生物医药与健康研究院 热休克蛋白抑制剂及其制备方法和应用
US20170014434A1 (en) * 2014-02-26 2017-01-19 The Trustees Of The University Of Pennsylvania Small Molecule HSP70 Inhibitors
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CN109364045A (zh) * 2018-10-21 2019-02-22 郑州大学第附属医院 一种热休克蛋白90抑制剂及在肝癌治疗方面的应用

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* Cited by examiner, † Cited by third party
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US20110189125A1 (en) * 2008-09-19 2011-08-04 Trustees Of The University Of Pennsylvania Modulators of HSP70/DnaK Function and Methods of Use Thereof
US20170014434A1 (en) * 2014-02-26 2017-01-19 The Trustees Of The University Of Pennsylvania Small Molecule HSP70 Inhibitors
CN105439972A (zh) * 2015-07-17 2016-03-30 中国科学院广州生物医药与健康研究院 热休克蛋白抑制剂及其制备方法和应用
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CN109364045A (zh) * 2018-10-21 2019-02-22 郑州大学第附属医院 一种热休克蛋白90抑制剂及在肝癌治疗方面的应用

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