对神经退行性疾病具有多靶点治疗作用的药物研究
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摘要
神经退行性疾病如老年痴呆(Alzheimer's disease, AD)、帕金森病(Parkinson's disease, PD)、和中风(Stroke)等均是由多病因引起的,造成神经细胞死亡的过程也是多因素的。因此基于单个治疗靶点设计的药物并未在治疗中枢神经系统紊乱疾病上达到令人满意的疗效。随着中枢神经系统紊乱疾病的致病因素和发病机制不断的被发现和阐明,具有多靶点治疗作用的药物研究开始出现,为治疗神经退行性疾病药物的研究开辟了一个崭新的领域。
本文选择作用于AD不同致病环节的关键靶点,对其配体结构进行研究,利用药效团模型设计软件Catalyst中的HypoGen模块分别建立了Acetylcholinesterase (AChE)、Beta-site APP cleaving enzymes 1 (BACE-1)、Poly(ADP-ribose)polymerase-1 (PARP-1).与Cysteine Asp-specific proteases-3 (Caspase-3)抑制剂的药效团模型。以已知的具有神经保护作用的2-氨基噻唑衍生物为先导化合物,结合药效团模型进行结构优化,设计出具有多功能神经保护作用的PARP-1抑制剂(1-7)。在所设计的单靶点神经保护剂的基础上,利用药效团模型叠合比对法,找到与PARP-1具有最大配体结构相似性的作用靶点AChE,设计出符合PARP-1抑制剂药效团模型和AChE抑制剂药效团模型的多靶点配体化合物(8-10)。经药效团预测化合物1-10具有较好的PARP-1抑制活性和AChE抑制活性。目标化合物经过合成后将进行相关生物活性筛选试验,以验证所提出的基于药效团的多靶点配体药物设计方法的可靠性,为进一步设计多靶点神经保护剂提供理论指导与实验数据。
目标化合物的合成过程中,首先采用微波辐射方法合成4,5取代-2-氨基噻唑化合物,将其作为母体结构进行进一步的合成,得到10个4,5取代-2-氨基噻唑酰胺和Schiff碱衍生物。化合物的结构经过UV、IR、1H-NMR、13C-NMR、EI-MS、与HPLC等方法得到了确证。
将得到的目标化合物进行相关的生物活性筛选,结果如下：
1.酶抑制活性筛选
PARP-1抑制活性实验结果显示化合物1-3和7在1μM时对PARP-1均产生大于50%的抑制活性,IC50值分别为240,753,224,和682 nM。
AChE抑制活性实验结果显示化合物10具有较好的抑制活性作用,IC50值为2511nM。
Caspase-3抑制活性初筛实验结果表明化合物3在65.3μM时对Caspase-3具有54.99±2.42%的抑制活性。蛋白酪氨酸磷酸酯酶(PTP-SIGMA)抑制活性初筛实验结果表明化合物4在272.9μM浓度下能抑制93.22±3.08%的PTP-SIGMA活性。
2.PC12细胞保护活性筛选
H2O2诱导的PC12细胞损伤模型：采用MTT法检测细胞存活率,结果表明化合物3和7对H2O2诱导的PC12细胞损伤具有较高细胞保护作用,EC50值分别为129和324nM。
氧糖剥夺(OGD)诱导的PC12细胞损伤模型：首先采用MTT法检测细胞存活率,化合物1、2和7表现出较好的细胞保护作用,EC5o值分别为143、191和361 nM。然后利用另一种细胞活性检测方法LDH法进行验证,实验结果显示化合物1-4和7在3μM浓度下能分别减少34.6%,20.1%,33.1%,24.0%,和28.4%OGD损伤导致的细胞LDH释放。最后考察了化合物1-3对OGD导致的PC12细胞凋亡的抑制作用,在浓度3μM下它们分别产生了70.7%,45.1%,和64.4%的抑制细胞凋亡作用。
3.SH-SY5Y细胞保护活性初筛
β-淀粉样蛋白(Aβ)诱导神经母细胞瘤细胞(SH-SY5Y细胞)损伤的保护作用的初筛结果表明化合物1在32.9μM浓度下能减少45.54%的细胞死亡,具有明显的抗Aβ细胞毒性作用。
目标化合物的生物活性筛选结果验证了基于药效团的单靶点与多靶点化合物的设计方法的可靠性,筛选得到了对H2O2,OGD与Aβ毒性均具有较好神经细胞保护作用的PARP-1抑制剂(化合物1-3),以及潜在的具有PARP-1与AChE双重抑制活性的多靶点配体化合物(化合物10)。
本论文的研究特点和创新之处：
1.本文的多靶点配体药物设计思路合理,以AD各个致病环节的关键靶点为研究对象,选择具有配体结构相似性的靶点进行多靶点配体药物的设计,得到具有潜在PARP-1和AChE双重抑制活性的多靶点配体化合物。
2.本文利用药效团模型叠合比对进行多靶点配体药物设计的方法具有创新性。
3.所设计合成的目标化合物经过生物活性筛选,实验结果验证了化合物设计思路的可行性与设计方法的可靠性。
The pathogenic mechanism of neurodegenerative diseases are poly-etiological in origin and the processes leading to neuronal death are multifactorial, as indicated by transcriptomics and proteomic. The pathology of many disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and stroke, includes an array of different pathways, and many of pathways involved in etiology of these diseases overlap. The traditional drug design "one-target, one-disease" in earlier and in many current researches has not met with the expected success for Central Nervous System (CNS) disorders. As increasing understanding of the entire complex pharmacological picture associated with the disease, a concept the multi-target-directed ligands that are rationally designed to modulate multiple mechanisms of a specific disease emerges. It will broaden our outlook in the treatment of neurodegenerative diseases.
The ligands of some key targets related to the pathogenic mechanism of AD were chosen to be research objects. The pharmacophore models of Acetylcholinesterase (AChE) inhibitors、Beta-site APP cleaving enzymes 1 (BACE-1) inhibitors、Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors、and Cysteine Asp-specific proteases-3 (Caspase-3) inhibitors were respectively established by using the HypoGen module of catalyst software. Firstly, molecules with 2-aminothiazole framework were chosen as a scaffold for further chemical modification by phamacophore model to explore PARP-1 inhibitors with multi-function neuroprotection (1-7). Secondary, because targets which resemble in ligands will exhibit similarity in pharmacophore models, on the basis of the designed PARP-1 inhibitors, multi-target-directed compounds (8-10) were designed by overlapping pharmacophores. As pharmacophore model predicted, compounds 1-10 with drug-likeness had good estimate activity to inhibit AChE and PARP-1. After synthesis, the biological activity screening was carried to validate the design method of multi-target-directed drugs based on the pharmacophore models. This work will provide theory guidance and experimental data for further design of multi-target neuroprotective agents.
In this study, we prepared 2-aminothiazole analogs in which the application of microwave technology was used.The cyclization step, carried by microwave, was performed in only a few minutes compared to the conventional thermal heating for 12h. Then they were reacted with different acid or acyl chloride respectively at RT. Finally, ten 4, 5-substituted-2-aminothiazole derivatives were synthesized. They were all characterized and analyzed by UV、IR、1H-NMR、13C-NMR、EI-MS、and HPLC.
After biological activity screening, the results included as follows:
1. Enzyme inhibition screening
Assay for PARP-1 inhibition in vitro:Compounds 1-3 and 7 almost showed more than 50% PARP-1 inhibition at a concentration of 1μM. They were more potent (IC50 240,753, 224, and 682 nM, respectively).
Assay for AChE inhibition in vitro:Compound 10 show potent AChE inhibition (IC50=2511nM).
Preliminary screening for Caspase-3 inhibitory activity in vitro:Compound 3 showed 54.99±2.42% inhibitory activity of Caspase-3 in the concentration of 65.3μM.
Preliminary screening for PTP-sigma inhibitory activity in vitro:In the concertration of 272.9μM, compound 4 showed 93.22±3.08%inhibitory activity.
2. Assays for cytoprotective action in PC12 cell
H2O2-induced PC12 cell injury model:In MTT assay, compounds 3 and 7 were highly protective (EC50 129, and 324 nM, respectively), and compounds 1,2, and 4 were moderately protective.
oxygen-glucose deprivation (OGD) induced PC12 cell death model:In MTT assay, compounds 1,2, and 7 were more protective (EC50 143,191, and 361 nM, respectively). In LDH release assay, compounds 1-4 and 7 (3μM) significantly reduced the OGD-induced LDH release by 34.6%,20.1%,33.1%,24.0%, and 28.4% respectively. We also performed a biparametric cytofluorimetric analysis using fluorescein isothiocyanate (FITC)-conjugated annexin V and propidium iodide (PI) double staining. A concentration of 3μM of compounds 1-3 significantly reduced OGD-induced total apoptotic cells (early and late apoptotic cells) by 70.7%,45.1%, and 64.4% respectively.
3. Preliminary screening for cytoprotective action in SH-SY5Y cell
Preliminary screening of cytoprotection against Aβinduced SH-SY5Y cell death: Compound 1 had 45.54% protection in the concentration of 32.9μM.
In conclusion, compounds 1-3 possessed expecting neuroprotection against H2O2, OGD, and Aβinduced cell death, and compounds 10 had potent multi-target-directed activities with both PARP-1 and AChE inhibiton, which validated method of muliti-target-directed ligands design.
The characters and innovation points:
1. The muliti-target-directed ligands design is reasonable. The key targets related to the pathogenic mechanism of AD were chosen to be research objects, and targets which resemble in ligands were selected to use to multi-target-directed ligands design. A series of compounds that have potent multi-target-directed activities with both PARP-1 and AChE inhibiton were designed.
2. The method of overlapping pharmacophores used to multi-target-directed ligands design is original.
3. The results of biological activity screening validated the feasibility of the concept and method of muliti-target-directed ligands design.
本文选择作用于AD不同致病环节的关键靶点,对其配体结构进行研究,利用药效团模型设计软件Catalyst中的HypoGen模块分别建立了Acetylcholinesterase (AChE)、Beta-site APP cleaving enzymes 1 (BACE-1)、Poly(ADP-ribose)polymerase-1 (PARP-1).与Cysteine Asp-specific proteases-3 (Caspase-3)抑制剂的药效团模型。以已知的具有神经保护作用的2-氨基噻唑衍生物为先导化合物,结合药效团模型进行结构优化,设计出具有多功能神经保护作用的PARP-1抑制剂(1-7)。在所设计的单靶点神经保护剂的基础上,利用药效团模型叠合比对法,找到与PARP-1具有最大配体结构相似性的作用靶点AChE,设计出符合PARP-1抑制剂药效团模型和AChE抑制剂药效团模型的多靶点配体化合物(8-10)。经药效团预测化合物1-10具有较好的PARP-1抑制活性和AChE抑制活性。目标化合物经过合成后将进行相关生物活性筛选试验,以验证所提出的基于药效团的多靶点配体药物设计方法的可靠性,为进一步设计多靶点神经保护剂提供理论指导与实验数据。
目标化合物的合成过程中,首先采用微波辐射方法合成4,5取代-2-氨基噻唑化合物,将其作为母体结构进行进一步的合成,得到10个4,5取代-2-氨基噻唑酰胺和Schiff碱衍生物。化合物的结构经过UV、IR、1H-NMR、13C-NMR、EI-MS、与HPLC等方法得到了确证。
将得到的目标化合物进行相关的生物活性筛选,结果如下：
1.酶抑制活性筛选
PARP-1抑制活性实验结果显示化合物1-3和7在1μM时对PARP-1均产生大于50%的抑制活性,IC50值分别为240,753,224,和682 nM。
AChE抑制活性实验结果显示化合物10具有较好的抑制活性作用,IC50值为2511nM。
Caspase-3抑制活性初筛实验结果表明化合物3在65.3μM时对Caspase-3具有54.99±2.42%的抑制活性。蛋白酪氨酸磷酸酯酶(PTP-SIGMA)抑制活性初筛实验结果表明化合物4在272.9μM浓度下能抑制93.22±3.08%的PTP-SIGMA活性。
2.PC12细胞保护活性筛选
H2O2诱导的PC12细胞损伤模型：采用MTT法检测细胞存活率,结果表明化合物3和7对H2O2诱导的PC12细胞损伤具有较高细胞保护作用,EC50值分别为129和324nM。
氧糖剥夺(OGD)诱导的PC12细胞损伤模型：首先采用MTT法检测细胞存活率,化合物1、2和7表现出较好的细胞保护作用,EC5o值分别为143、191和361 nM。然后利用另一种细胞活性检测方法LDH法进行验证,实验结果显示化合物1-4和7在3μM浓度下能分别减少34.6%,20.1%,33.1%,24.0%,和28.4%OGD损伤导致的细胞LDH释放。最后考察了化合物1-3对OGD导致的PC12细胞凋亡的抑制作用,在浓度3μM下它们分别产生了70.7%,45.1%,和64.4%的抑制细胞凋亡作用。
3.SH-SY5Y细胞保护活性初筛
β-淀粉样蛋白(Aβ)诱导神经母细胞瘤细胞(SH-SY5Y细胞)损伤的保护作用的初筛结果表明化合物1在32.9μM浓度下能减少45.54%的细胞死亡,具有明显的抗Aβ细胞毒性作用。
目标化合物的生物活性筛选结果验证了基于药效团的单靶点与多靶点化合物的设计方法的可靠性,筛选得到了对H2O2,OGD与Aβ毒性均具有较好神经细胞保护作用的PARP-1抑制剂(化合物1-3),以及潜在的具有PARP-1与AChE双重抑制活性的多靶点配体化合物(化合物10)。
本论文的研究特点和创新之处：
1.本文的多靶点配体药物设计思路合理,以AD各个致病环节的关键靶点为研究对象,选择具有配体结构相似性的靶点进行多靶点配体药物的设计,得到具有潜在PARP-1和AChE双重抑制活性的多靶点配体化合物。
2.本文利用药效团模型叠合比对进行多靶点配体药物设计的方法具有创新性。
3.所设计合成的目标化合物经过生物活性筛选,实验结果验证了化合物设计思路的可行性与设计方法的可靠性。
The pathogenic mechanism of neurodegenerative diseases are poly-etiological in origin and the processes leading to neuronal death are multifactorial, as indicated by transcriptomics and proteomic. The pathology of many disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and stroke, includes an array of different pathways, and many of pathways involved in etiology of these diseases overlap. The traditional drug design "one-target, one-disease" in earlier and in many current researches has not met with the expected success for Central Nervous System (CNS) disorders. As increasing understanding of the entire complex pharmacological picture associated with the disease, a concept the multi-target-directed ligands that are rationally designed to modulate multiple mechanisms of a specific disease emerges. It will broaden our outlook in the treatment of neurodegenerative diseases.
The ligands of some key targets related to the pathogenic mechanism of AD were chosen to be research objects. The pharmacophore models of Acetylcholinesterase (AChE) inhibitors、Beta-site APP cleaving enzymes 1 (BACE-1) inhibitors、Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors、and Cysteine Asp-specific proteases-3 (Caspase-3) inhibitors were respectively established by using the HypoGen module of catalyst software. Firstly, molecules with 2-aminothiazole framework were chosen as a scaffold for further chemical modification by phamacophore model to explore PARP-1 inhibitors with multi-function neuroprotection (1-7). Secondary, because targets which resemble in ligands will exhibit similarity in pharmacophore models, on the basis of the designed PARP-1 inhibitors, multi-target-directed compounds (8-10) were designed by overlapping pharmacophores. As pharmacophore model predicted, compounds 1-10 with drug-likeness had good estimate activity to inhibit AChE and PARP-1. After synthesis, the biological activity screening was carried to validate the design method of multi-target-directed drugs based on the pharmacophore models. This work will provide theory guidance and experimental data for further design of multi-target neuroprotective agents.
In this study, we prepared 2-aminothiazole analogs in which the application of microwave technology was used.The cyclization step, carried by microwave, was performed in only a few minutes compared to the conventional thermal heating for 12h. Then they were reacted with different acid or acyl chloride respectively at RT. Finally, ten 4, 5-substituted-2-aminothiazole derivatives were synthesized. They were all characterized and analyzed by UV、IR、1H-NMR、13C-NMR、EI-MS、and HPLC.
After biological activity screening, the results included as follows:
1. Enzyme inhibition screening
Assay for PARP-1 inhibition in vitro:Compounds 1-3 and 7 almost showed more than 50% PARP-1 inhibition at a concentration of 1μM. They were more potent (IC50 240,753, 224, and 682 nM, respectively).
Assay for AChE inhibition in vitro:Compound 10 show potent AChE inhibition (IC50=2511nM).
Preliminary screening for Caspase-3 inhibitory activity in vitro:Compound 3 showed 54.99±2.42% inhibitory activity of Caspase-3 in the concentration of 65.3μM.
Preliminary screening for PTP-sigma inhibitory activity in vitro:In the concertration of 272.9μM, compound 4 showed 93.22±3.08%inhibitory activity.
2. Assays for cytoprotective action in PC12 cell
H2O2-induced PC12 cell injury model:In MTT assay, compounds 3 and 7 were highly protective (EC50 129, and 324 nM, respectively), and compounds 1,2, and 4 were moderately protective.
oxygen-glucose deprivation (OGD) induced PC12 cell death model:In MTT assay, compounds 1,2, and 7 were more protective (EC50 143,191, and 361 nM, respectively). In LDH release assay, compounds 1-4 and 7 (3μM) significantly reduced the OGD-induced LDH release by 34.6%,20.1%,33.1%,24.0%, and 28.4% respectively. We also performed a biparametric cytofluorimetric analysis using fluorescein isothiocyanate (FITC)-conjugated annexin V and propidium iodide (PI) double staining. A concentration of 3μM of compounds 1-3 significantly reduced OGD-induced total apoptotic cells (early and late apoptotic cells) by 70.7%,45.1%, and 64.4% respectively.
3. Preliminary screening for cytoprotective action in SH-SY5Y cell
Preliminary screening of cytoprotection against Aβinduced SH-SY5Y cell death: Compound 1 had 45.54% protection in the concentration of 32.9μM.
In conclusion, compounds 1-3 possessed expecting neuroprotection against H2O2, OGD, and Aβinduced cell death, and compounds 10 had potent multi-target-directed activities with both PARP-1 and AChE inhibiton, which validated method of muliti-target-directed ligands design.
The characters and innovation points:
1. The muliti-target-directed ligands design is reasonable. The key targets related to the pathogenic mechanism of AD were chosen to be research objects, and targets which resemble in ligands were selected to use to multi-target-directed ligands design. A series of compounds that have potent multi-target-directed activities with both PARP-1 and AChE inhibiton were designed.
2. The method of overlapping pharmacophores used to multi-target-directed ligands design is original.
3. The results of biological activity screening validated the feasibility of the concept and method of muliti-target-directed ligands design.
引文
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