1，3，4-噻二唑类氨肽酶N抑制剂的设计、合成及活性研究
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摘要
第一部分氨肽酶N研究进展
氨肽酶N(APN)是一类膜型锌离子依赖性的外肽酶,主要富集在小肠,参与食物的消化,将其分解为氨基酸;在肾中,APN参与肾素.血管紧张素系统,降解血管紧张素Ⅲ,降低Na~+K~+-ATP酶的水平,调节近曲小管对钠的吸收;在脑组织参与内源性镇痛物质脑啡肽、内啡肽在中枢神经系统的代谢
APN在肿瘤细胞表面高水平表达,通过降解细胞外基质,促进多种生长因子的释放、刺激血管内皮细胞释放肿瘤微血管形成相关因子,促进肿瘤新生血管的形成、加速肿瘤细胞增殖、增强肿瘤细胞粘附性、促进肿瘤细胞侵袭与转移。APN在粒细胞及淋巴细胞表面大量表达,参与T淋巴细胞依赖的炎症反应;在抗原递呈细胞表面大量表达,降解趋化因子(如fMLP)、抗原递呈分子以及多种免疫活性物质(如:IL-8),抑制巨噬细胞和自然杀伤细胞对肿瘤细胞表面抗原的识别和直接杀伤细胞的能力,使机体免疫力下降。APN降解能够使HIV-1辅助受体CCR5脱敏的趋化因子fMLP,降低细胞的天然免疫功能,并使CCR5增敏,促进HIV病毒进入宿主细胞。APN作为人冠状病毒HCoV-229E和传染性胃肠炎病毒(TGEV)表面的受体,在上呼吸道感染(如:SARS)和急性肠炎中扮演重要角色。因此,APN抑制剂有望发展成为一类新型的治疗药物,用于治疗如肿瘤、白血病、风湿性关节炎、糖尿病肾病和阿尔茨海默病。
APN抑制剂主要用于预防和治疗肿瘤,分为天然产物抑制剂和小分子合成抑制剂,迄今报道的多数抑制剂包含锌离子螯合基。研究较为成熟的抑制剂是从网状橄榄链霉菌培养液中发现的Bestatin,已作为免疫增强剂于1987年在日本上市。
第二部分基于靶点结构的合理药物设计
本研究利用基于结构(Structure-Based)的药物设计思想进行全新药物设计,利用计算机辅助药物设计软件的优势,通过深入研究E.Coli APN的三维结构以及酶-抑制剂复合物的结合模式,用柔性对接来模拟目标化合物与靶酶的相互作用。APN水解底物时具有专属性,优先水解的氨基酸残基为丙氨酸,而金属蛋白酶(包括基质金属蛋白酶MMP和氨肽酶N/CD13)的天然作用底物胶原蛋白的主要成分是脯氨酸-甘氨酸残基。因而我们以丙氨酸和甘氨酸为先导化合物,并在分子中引入能与靶酶的疏水性口袋相互作用且具有抗癌活性的1,3,4-噻二唑和肉桂酸骨架,对目标化合物进行了如下修饰:(ⅰ)在分子中引入不同的吸电子基和推电子基,考察不同电性效应对靶酶的作用;(ⅱ)在分子中引入能与靶酶形成氢键的基团,以增强化合物与靶酶的亲和力;(ⅲ)在分子中引入体积不等的取代基,考察不同立体效应对靶酶的作用。
此外,本文不仅从整体上考虑化合物结构与酶活性中心的匹配性,而且组成化合物的各结构片段均选择了具有抗癌活性的片段或组织相容性较好氨基酸残基。在对结构进行优化设计时预先充分考虑到了药物在体内的ADME等动力学特性,化合物的分子量、脂水分配系数、氢键受体数和氢键供体数均符合Lipinski规则,从而提高化合物的中标率。
第三部分目标化合物的合成
在基于靶点结构的合理药物设计的基础上,本着结构多样性的原则,合成了42个结构确定的目标化合物。将不同取代的苯甲酸和氨基硫脲在三氯氧磷中缩合得到5-取代苯基-1,3,4-噻二唑-2-胺;不同取代的肉桂酸和氨基酸用DCC法缩合得到肉桂酰胺:最后将两种中间体用DCC法缩合得到终产物。DCC法的优点是反应条件温和,操作简便。对所合成的化合物,通过红外光谱、核磁共振氢谱、核磁共振碳谱、电喷雾质谱等方法进行结构确证。经查阅文献证实,所合成的目标化合物为新型化合物,未见文献报道。
第四部分目标化合物的活性评价
本研究设计合成了3个系列共42个1,3,4-噻二唑类的目标化合物,并对其活性进行了初步筛选。由于APN和MMP都属于锌离子依赖性金属蛋白酶,并且在肿瘤细胞的侵袭与转移过程中发挥重要的作用,体外抑酶筛选时同时针对两种酶进行活性评价,体外细胞测试时采用了特异性表达APN的白血病细胞(HL-60),观察化合物对HL-60细胞的生长抑制作用。初步的测试表明多数化合物都有抑制APN的活性,其中化合物A7、A8、B4、B14、C5和C9显示了较好的APN抑制活性,IC_(50)分别是31.4μM、68.7μM、35.3μM、27.1μM、44.6μM、41.1μM,这些化合物可被用作研究新的APN抑制剂的先导物。研究发现:含丙氨酸残基的化合物对APN的活性优于对MMP的活性,而含甘氨酸残基的化合物对APN和MMP都表现出相应的活性,说明含丙氨酸残基的化合物对APN有较好的选择性。体外白血病细胞生长抑制实验发现对APN抑酶活性较好的6个化合物除A8和B4外,均对HL-60细胞显示了中等程度的抑制作用。所得的部分量化参数(如FlexX对接结果)与体外活性试验具有一定相关性,说明设计思路合理。
结论:我们设计、合成了一系列结构新颖的1,3,4-噻二唑类衍生物,并对这些化合物进行了初步活性评价,通过体外活性筛选发现了有开发潜力的化合物,为发现活性更好的新型抗肿瘤药物打下坚实的基础。
PartⅠ.Recent Progress in Aminopeptidase N
Aminopeptidases N,one of membrane-bound zinc-dependent exopeptidase expressed mostly in intestine,is involved in the final hydrolysis of nutrients to amino acid,in the degradation of angiotensinⅢ,in the decrease Na~+-K~+-ATP level,in the regulation absorption sodium in kidney,in the metabolism endogenous enkephalin and endorphin in the the central nervous system.
APN,over-expressed on the surface of tumor cells,promots the invasion and metastasis of tumor cells via degrading extracellular matrix,promoting the release of most growth factor,stimulating the release of cellular factors associated with the neovascularization by vascular endotheilal cells,promoting the angiogenesis of tumor, speeding up the proliferation of tumor cells,enhancing the adhesiveness of tumor cells.APN is over-expressed on the surface of granulocyte and lymphocyte and participates the T-lymphocyte dependent inflammatory reaction.The enzyme is also over-expressed on the surface of antigen presenting cells,which degrades chemokines, antigen presenting molecule and lots of immunoactive substances,depresses the recognization of macrophage and NK cells to surface antigen on tumor cells and the ability to kill tumor cells directly,impairs the immunological functions.APN play a role in the entry of HIV-1 into host cells by degrading chemokine fMLP associated with the desensitization of the co-receptor CCR5 for HIV-1.APN serves as a receptor for human corona viruses HCoV-229E which causes upper respiratory infections and transmissible gastroenteritis viruses(TGEV) which causes a severe gastroenteritis in newborn pigs.Therefore,APN will be a good target for the design of novel therapeutic agents for the treatment of diseases,such as cancer,leukemia,rheumatoid arthritis,diabetic nephropathy and central nervous system diseases,such as Alzheimer's disease.
APN inhibitors were designed to prevent and treat tumor,divided into two types, natural inhibitors and synthetic inhibitors.Most APN inhibitors thus far reported contain zinc binding group.Bestatin,firstly isolated from a culture filtrate of Streptomyces olivoreticuli,has been used in clinics as an immunoenhancer in Japan in 1987.
PartⅡ.Structure-based Rational Target Compounds Design
The characteristics of this study are the utilization of structure-based drug design comprehensively.The structure information of the active site of E.Coli APN and enzyme-inhibitor complex was thorough studied with advantages of computer-aided drug design software.Flexsible Docking was used for modeling the interaction between target compounds and enzyme.APN exhibits a broad specificity for peptides with a N-terminal neutral or basic amino acid.The favored substrate of APN is alanine.On the other hand,the major components of ECM are Pro-Gly residues.So the alanine and the glycine were considered as the lead compounds.The 1,3,4-thiadiazole and the cinnamic acid which can interact with hydrophobic site of APN and has the property of anticancer was introduced into the target compounds. This scaffold is optimized with following chemical modification:(ⅰ) Various electron-attracting groups and electron-pushting groups was linked to target compounds so as to investigate the interaction of electric effect with APN;(ⅱ) The group which can form hydrogen bond with the enzyme was introduced to enhace affinity;(ⅲ) The group with various space volume was connected to target compounds to investigate the interaction of stereoscopic effect.
Additionally,the matching of target compounds with the active site of enzyme is not only considered overall in this study,the fragments used in the target compounds also apply the fragments with anticancer activity and amino acid residual which can be compatible with tissues.The ADME and pharmacokinetics properties of the target compounds have also been considered in advance.Molecular weight, lipid-water partition,the number of hydrogen bond receptor and hydrogen bond donor fit the Lipinski rule and so increasing the hit rate.
PartⅢ.Synthesis and discussion of targeted compounds
On the basis of structure-based drug design,we obtained 42 structural confirmed target compounds.The various substituted carboxylic acid was condensed with N-aminothiourea in presence of Phosphorus oxychloride,yielding 5-substituted-1,3,4-thiadiazol-2-amine.The coupling of amino acid with various substituted cinnamic acid led to amide using DCC.Finally,the intermediate 5-substituted-1,3,4-thiadiazol-2-amine and amide were reacted using DCC to give target compounds.The advantage of DCC method is mild reaction conditions and simple operation.All the targeted compounds are novel without any report by now, and the structures of new compounds are identified by IR,~1H-NMR,~(13)C-NMR and ESI-MS.
PartⅣ.The Biological Evaluation
We design and synthesis 42 novel 1,3,4-thiadiazole derivatives which were performed the in vitro preliminary activity evaluations.APN and MMP are zinc-dependent metalloproteinase and closely associated with the invasion and metastasis of tumor cells.So the in vitro enzyme inhibitory activity was determined against APN and MMP.The cells assay is performed toward leukemia cells(HL-60) which express APN.The preliminary test results showed that most of compounds have ability to inhibit APN.Six compounds,A7、A8、B4、B14、C5、C9 displayed good ability to inhibit APN with IC_(50) values 31.4μM、68.7μM、35.3μM、27.1μM、44.6μM、41.1μM respectively.These compounds could be used as lead compounds for exploring novel APN inhibitors in the future.The results show that APN inhibition activity of compounds containing alanine acid residues is superior to MMP inhibition activity, while compounds containing glycine acid residues exhibited both APN and MMP inhibition activity.So the compounds containing alanine acid residues displayed selectivity toward APN.In in vitro growth inhibition against leukemia cells,the results indicated that most potent APN inhibitor(A7、B14、C5、C9) displayed good inhibitory effect against the growth of HL-60 cells.It is discovered that there is some relevance between part of the quantitative parameters(such as FlexX Docking score) and the in vitro activity of compounds.It shows that the study idea is rational.
In conclusion,a series of novel 1,3,4- thiadiazole derivatives have been designed and synthesized.The preliminary inhibitory activities of target compounds were evaluated in this thesis.All of these discoveries provide a beneficial theoretical basis for the optimization of lead structure and lay a solid foundation for the discovery of novel more potent anticancer agents in future.
氨肽酶N(APN)是一类膜型锌离子依赖性的外肽酶,主要富集在小肠,参与食物的消化,将其分解为氨基酸;在肾中,APN参与肾素.血管紧张素系统,降解血管紧张素Ⅲ,降低Na~+K~+-ATP酶的水平,调节近曲小管对钠的吸收;在脑组织参与内源性镇痛物质脑啡肽、内啡肽在中枢神经系统的代谢
APN在肿瘤细胞表面高水平表达,通过降解细胞外基质,促进多种生长因子的释放、刺激血管内皮细胞释放肿瘤微血管形成相关因子,促进肿瘤新生血管的形成、加速肿瘤细胞增殖、增强肿瘤细胞粘附性、促进肿瘤细胞侵袭与转移。APN在粒细胞及淋巴细胞表面大量表达,参与T淋巴细胞依赖的炎症反应;在抗原递呈细胞表面大量表达,降解趋化因子(如fMLP)、抗原递呈分子以及多种免疫活性物质(如:IL-8),抑制巨噬细胞和自然杀伤细胞对肿瘤细胞表面抗原的识别和直接杀伤细胞的能力,使机体免疫力下降。APN降解能够使HIV-1辅助受体CCR5脱敏的趋化因子fMLP,降低细胞的天然免疫功能,并使CCR5增敏,促进HIV病毒进入宿主细胞。APN作为人冠状病毒HCoV-229E和传染性胃肠炎病毒(TGEV)表面的受体,在上呼吸道感染(如:SARS)和急性肠炎中扮演重要角色。因此,APN抑制剂有望发展成为一类新型的治疗药物,用于治疗如肿瘤、白血病、风湿性关节炎、糖尿病肾病和阿尔茨海默病。
APN抑制剂主要用于预防和治疗肿瘤,分为天然产物抑制剂和小分子合成抑制剂,迄今报道的多数抑制剂包含锌离子螯合基。研究较为成熟的抑制剂是从网状橄榄链霉菌培养液中发现的Bestatin,已作为免疫增强剂于1987年在日本上市。
第二部分基于靶点结构的合理药物设计
本研究利用基于结构(Structure-Based)的药物设计思想进行全新药物设计,利用计算机辅助药物设计软件的优势,通过深入研究E.Coli APN的三维结构以及酶-抑制剂复合物的结合模式,用柔性对接来模拟目标化合物与靶酶的相互作用。APN水解底物时具有专属性,优先水解的氨基酸残基为丙氨酸,而金属蛋白酶(包括基质金属蛋白酶MMP和氨肽酶N/CD13)的天然作用底物胶原蛋白的主要成分是脯氨酸-甘氨酸残基。因而我们以丙氨酸和甘氨酸为先导化合物,并在分子中引入能与靶酶的疏水性口袋相互作用且具有抗癌活性的1,3,4-噻二唑和肉桂酸骨架,对目标化合物进行了如下修饰:(ⅰ)在分子中引入不同的吸电子基和推电子基,考察不同电性效应对靶酶的作用;(ⅱ)在分子中引入能与靶酶形成氢键的基团,以增强化合物与靶酶的亲和力;(ⅲ)在分子中引入体积不等的取代基,考察不同立体效应对靶酶的作用。
此外,本文不仅从整体上考虑化合物结构与酶活性中心的匹配性,而且组成化合物的各结构片段均选择了具有抗癌活性的片段或组织相容性较好氨基酸残基。在对结构进行优化设计时预先充分考虑到了药物在体内的ADME等动力学特性,化合物的分子量、脂水分配系数、氢键受体数和氢键供体数均符合Lipinski规则,从而提高化合物的中标率。
第三部分目标化合物的合成
在基于靶点结构的合理药物设计的基础上,本着结构多样性的原则,合成了42个结构确定的目标化合物。将不同取代的苯甲酸和氨基硫脲在三氯氧磷中缩合得到5-取代苯基-1,3,4-噻二唑-2-胺;不同取代的肉桂酸和氨基酸用DCC法缩合得到肉桂酰胺:最后将两种中间体用DCC法缩合得到终产物。DCC法的优点是反应条件温和,操作简便。对所合成的化合物,通过红外光谱、核磁共振氢谱、核磁共振碳谱、电喷雾质谱等方法进行结构确证。经查阅文献证实,所合成的目标化合物为新型化合物,未见文献报道。
第四部分目标化合物的活性评价
本研究设计合成了3个系列共42个1,3,4-噻二唑类的目标化合物,并对其活性进行了初步筛选。由于APN和MMP都属于锌离子依赖性金属蛋白酶,并且在肿瘤细胞的侵袭与转移过程中发挥重要的作用,体外抑酶筛选时同时针对两种酶进行活性评价,体外细胞测试时采用了特异性表达APN的白血病细胞(HL-60),观察化合物对HL-60细胞的生长抑制作用。初步的测试表明多数化合物都有抑制APN的活性,其中化合物A7、A8、B4、B14、C5和C9显示了较好的APN抑制活性,IC_(50)分别是31.4μM、68.7μM、35.3μM、27.1μM、44.6μM、41.1μM,这些化合物可被用作研究新的APN抑制剂的先导物。研究发现:含丙氨酸残基的化合物对APN的活性优于对MMP的活性,而含甘氨酸残基的化合物对APN和MMP都表现出相应的活性,说明含丙氨酸残基的化合物对APN有较好的选择性。体外白血病细胞生长抑制实验发现对APN抑酶活性较好的6个化合物除A8和B4外,均对HL-60细胞显示了中等程度的抑制作用。所得的部分量化参数(如FlexX对接结果)与体外活性试验具有一定相关性,说明设计思路合理。
结论:我们设计、合成了一系列结构新颖的1,3,4-噻二唑类衍生物,并对这些化合物进行了初步活性评价,通过体外活性筛选发现了有开发潜力的化合物,为发现活性更好的新型抗肿瘤药物打下坚实的基础。
PartⅠ.Recent Progress in Aminopeptidase N
Aminopeptidases N,one of membrane-bound zinc-dependent exopeptidase expressed mostly in intestine,is involved in the final hydrolysis of nutrients to amino acid,in the degradation of angiotensinⅢ,in the decrease Na~+-K~+-ATP level,in the regulation absorption sodium in kidney,in the metabolism endogenous enkephalin and endorphin in the the central nervous system.
APN,over-expressed on the surface of tumor cells,promots the invasion and metastasis of tumor cells via degrading extracellular matrix,promoting the release of most growth factor,stimulating the release of cellular factors associated with the neovascularization by vascular endotheilal cells,promoting the angiogenesis of tumor, speeding up the proliferation of tumor cells,enhancing the adhesiveness of tumor cells.APN is over-expressed on the surface of granulocyte and lymphocyte and participates the T-lymphocyte dependent inflammatory reaction.The enzyme is also over-expressed on the surface of antigen presenting cells,which degrades chemokines, antigen presenting molecule and lots of immunoactive substances,depresses the recognization of macrophage and NK cells to surface antigen on tumor cells and the ability to kill tumor cells directly,impairs the immunological functions.APN play a role in the entry of HIV-1 into host cells by degrading chemokine fMLP associated with the desensitization of the co-receptor CCR5 for HIV-1.APN serves as a receptor for human corona viruses HCoV-229E which causes upper respiratory infections and transmissible gastroenteritis viruses(TGEV) which causes a severe gastroenteritis in newborn pigs.Therefore,APN will be a good target for the design of novel therapeutic agents for the treatment of diseases,such as cancer,leukemia,rheumatoid arthritis,diabetic nephropathy and central nervous system diseases,such as Alzheimer's disease.
APN inhibitors were designed to prevent and treat tumor,divided into two types, natural inhibitors and synthetic inhibitors.Most APN inhibitors thus far reported contain zinc binding group.Bestatin,firstly isolated from a culture filtrate of Streptomyces olivoreticuli,has been used in clinics as an immunoenhancer in Japan in 1987.
PartⅡ.Structure-based Rational Target Compounds Design
The characteristics of this study are the utilization of structure-based drug design comprehensively.The structure information of the active site of E.Coli APN and enzyme-inhibitor complex was thorough studied with advantages of computer-aided drug design software.Flexsible Docking was used for modeling the interaction between target compounds and enzyme.APN exhibits a broad specificity for peptides with a N-terminal neutral or basic amino acid.The favored substrate of APN is alanine.On the other hand,the major components of ECM are Pro-Gly residues.So the alanine and the glycine were considered as the lead compounds.The 1,3,4-thiadiazole and the cinnamic acid which can interact with hydrophobic site of APN and has the property of anticancer was introduced into the target compounds. This scaffold is optimized with following chemical modification:(ⅰ) Various electron-attracting groups and electron-pushting groups was linked to target compounds so as to investigate the interaction of electric effect with APN;(ⅱ) The group which can form hydrogen bond with the enzyme was introduced to enhace affinity;(ⅲ) The group with various space volume was connected to target compounds to investigate the interaction of stereoscopic effect.
Additionally,the matching of target compounds with the active site of enzyme is not only considered overall in this study,the fragments used in the target compounds also apply the fragments with anticancer activity and amino acid residual which can be compatible with tissues.The ADME and pharmacokinetics properties of the target compounds have also been considered in advance.Molecular weight, lipid-water partition,the number of hydrogen bond receptor and hydrogen bond donor fit the Lipinski rule and so increasing the hit rate.
PartⅢ.Synthesis and discussion of targeted compounds
On the basis of structure-based drug design,we obtained 42 structural confirmed target compounds.The various substituted carboxylic acid was condensed with N-aminothiourea in presence of Phosphorus oxychloride,yielding 5-substituted-1,3,4-thiadiazol-2-amine.The coupling of amino acid with various substituted cinnamic acid led to amide using DCC.Finally,the intermediate 5-substituted-1,3,4-thiadiazol-2-amine and amide were reacted using DCC to give target compounds.The advantage of DCC method is mild reaction conditions and simple operation.All the targeted compounds are novel without any report by now, and the structures of new compounds are identified by IR,~1H-NMR,~(13)C-NMR and ESI-MS.
PartⅣ.The Biological Evaluation
We design and synthesis 42 novel 1,3,4-thiadiazole derivatives which were performed the in vitro preliminary activity evaluations.APN and MMP are zinc-dependent metalloproteinase and closely associated with the invasion and metastasis of tumor cells.So the in vitro enzyme inhibitory activity was determined against APN and MMP.The cells assay is performed toward leukemia cells(HL-60) which express APN.The preliminary test results showed that most of compounds have ability to inhibit APN.Six compounds,A7、A8、B4、B14、C5、C9 displayed good ability to inhibit APN with IC_(50) values 31.4μM、68.7μM、35.3μM、27.1μM、44.6μM、41.1μM respectively.These compounds could be used as lead compounds for exploring novel APN inhibitors in the future.The results show that APN inhibition activity of compounds containing alanine acid residues is superior to MMP inhibition activity, while compounds containing glycine acid residues exhibited both APN and MMP inhibition activity.So the compounds containing alanine acid residues displayed selectivity toward APN.In in vitro growth inhibition against leukemia cells,the results indicated that most potent APN inhibitor(A7、B14、C5、C9) displayed good inhibitory effect against the growth of HL-60 cells.It is discovered that there is some relevance between part of the quantitative parameters(such as FlexX Docking score) and the in vitro activity of compounds.It shows that the study idea is rational.
In conclusion,a series of novel 1,3,4- thiadiazole derivatives have been designed and synthesized.The preliminary inhibitory activities of target compounds were evaluated in this thesis.All of these discoveries provide a beneficial theoretical basis for the optimization of lead structure and lay a solid foundation for the discovery of novel more potent anticancer agents in future.
引文
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