基于DPP4和EGFR靶点的药物设计、合成及相关药理活性研究
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摘要
本论文基于传统药物化学和计算机辅助药物设计思想及现代合成技术,针对抗糖尿病靶点二肽基肽酶IV (Dipeptidyl peptidase IV, DPP IV, DPP4)和抗肿瘤靶点表皮生长因子受体(Epidermal Growth Factor Receptor, EGFR)进行小分子化合物的设计、化学合成及进行相关的药理活性研究。同时,基于Au催化的级联反应构建具有潜在生物学活性的苯并咪唑并吡咯并喹唑啉酮类化合物。
首先,我们基于课题组已有研究工作基础,开展了具有α-氨基氟氰基吡咯烷类和β-氨基氰基吡咯烷类结构的DPP4抑制剂的设计、合成及抗糖尿病活性研究。基于先导化合物的药物代谢特点,我们一方面采用引入吸电子和供电子基团封闭代谢位点,芳香杂环替换苯环策略,另一方面采用延长小分子的链长策略来进行合理的药物设计,一共合成了47个结构新颖的化合物(A1-A22和B1-B25)。经药理活性测试,发现大部分化合物具有较好的DPP4抑制活性。其中,有11个化合物对DPP4的抑制活性<20nM,8个化合物(A1、A3、A7、A8、A9、A14、A15和A17)的DPP4抑制活性<10nM,IC50值分别为4.1nM、2.7nM、6.2nM、4.6nM、5.7nM、10.0nM、5.0nM、4.0nM。基于体外的DPP4抑制活性及选择性,我们选取化合物A14、A17、B12和B25进行了在ICR小鼠体内的急性降血糖活性研究,结果显示这四个化合物具有较好的体内降血糖作用,并具有较好的剂量依赖性。进一步的KBS db/db糖尿病小鼠体内的慢性降血糖研究表明,化合物A17和B25能有效降低体内血糖,并能提高血浆胰岛素含量。同时,化合物A14、A17和B25在SD大鼠体内具有良好的的药物代谢动力学性质,其口服生物利用度分别为16.8%、37.8%和22.8%。此外,还开展了化合物A14、A17和B25对hERG钾离子通道和肝代谢酶CYP450抑制作用以及化合物B25在ICR小鼠体内的急性毒性试验研究,均表明化合物具有良好的安全性。这些结果为后续进一步研究和药物开发奠定了良好的基础。
在EGFR抑制剂的设计、合成及抗肿瘤活性研究中,我们根据生物电子等排和拼合原理,设计并合成了56个结构新颖的化合物(C1-C30和D1-D26),并进行了相关的药理学评价。大部分化合物具有良好的EGFR野生型酶的抑制活性,其中有14个化合物对EGFR野生型酶的抑制活性<20nM,13个化合物对EGFR野生型酶的抑制活性<10nM,5个化合物对EGFR野生型酶的抑制活性<5nM。同时有10个化合物对EGFR T790M/L858双突变酶的抑制活性<10nM。基于此活性结果,我们又开展了化合物对A431细胞和NCI-H1975细胞的EGFR自动磷酸化抑制活性研究,结果表明在0.1μmol/L浓度下,化合物C4、D14、D15、D17和D22几乎完全阻断A431细胞的EGFR wt的自动磷酸化；在1.0μmol/L浓度下,化合物D14、D15、D17和D22几乎完全阻断NCI-H1975细胞的EGFR T790M/L858R的自动磷酸化。同时,我们还选择化合物D15进行了其它13种激酶的抑制活性研究,结果表明化合物D15不仅能抑制EGFR wt和EGFR T790M/L858R,而且对ErbB2和ErbB4具有较好的抑制活性。但对其它11种酪氨酸激酶的抑制作用较弱,这说明化合物D15具有良好的选择性,可以作为EGFR家族选择性抑制剂进行深入研究。
多环杂环化合物在药物化学研究中具有十分重要的作用。在本论文中,我们发展了一种简便有效的方法,即以两个简单的起始原料经Au(I)/Ag(I)共催化的级联反应一锅构建苯并[4,5]咪唑[1,2-c]吡咯[1,2-a]喹唑啉酮类化合物。该方法收率高、底物适用范围广,共设计合成了31个具有不同基团的化合物。该方法最大的特点在于采用“一锅串联”策略快速高效地构建三个C-N键,形成复杂的苯并咪唑并吡咯并喹唑啉酮类化合物；并且通过X-单晶衍射确证了化合物3Aa的结构。
综上所述,在DPP4抑制剂的研究中,一共合成47个活性较好的化合物。其中化合物A14、A17、B12和B25在ICR小鼠体内具有较好的体内降血糖作用；化合物A17和B25在KBS db/db糖尿病小鼠体内能有效降低体内血糖,并能提高血浆胰岛素含量；并且化合物A14、A17和B25在SD大鼠体内具有良好的的药物代谢动力学性质。此外化合物A14、A17和B25在hERG钾离子通道和肝代谢酶CYP450抑制作用以及化合物B25在ICR小鼠体内的急性毒性试验研究中,均表明化合物具有良好的安全性。在EGFR抑制剂研究中,一共合成56个具有较好活性的化合物。其中化合物C4、D14、D15、D17和D22在0.1μmol/L浓度下几乎完全阻断A431细胞的EGFR wt的自动磷酸化;化合物D14、D15、D17和D22在1.0μmol/L浓度下几乎完全阻断NCI-H1975细胞的EGFR T790M/L858R的自动磷酸化。并且化合物D15对其它13种激酶具有良好的选择性。在Au催化的方法学研究中,我们发展了一个简便有效的方法构建多环杂环化合物,该方法收率高、底物适用范围广。并通过X-单晶衍射确定化合物3Aa的结构。以上工作为我们开发具有自主知识产权的新药奠定了良好的基础。
Based on traditional medicinal chemistry, computer-aided drug design and modern synthetic technology, the dissertation for Ph.D. degree focused on design, synthesis and biological evaluation of Dipeptidyl peptidase IV inhibitors and Epidermal Growth Factor Receptor inhibitors and the methodology of Au(I)/Ag(I)-catalyzed cascade approach for the synthesis of polycyclic heterocyclic compounds.
Firstly, based on previous work in our group, we developed the work for the design, synthesis and biological evaluation of a-amino and (3-amino pyrrolidine-2-carbonitrile derivetives as DPP4inhibitors. Based on analysis of metabolites of lead compound, the rational design was carried out followed by introduction of different substituted group, displacement of aromatic ring with aromatic heterocyclic, and prolonging the side chains of lead compound. And47compounds (A1-A22and B1-B25) were designed, synthesized and evaluated to inhibit DPP4and other serine protein family activities. Among these compounds, the DPP4inhibitory activities of11compounds were less than20nM, the DPP4inhibitory activities of8compounds (A1, A3, A7, A8, A9, A14, A15and A17) were less than10nM. The IC50values were4.1nM,2.7nM,6.2nM,4.6nM,5.7nM,10.0nM,5.0nM and4.0nM, respectively. Moreover, most compounds showed good selectivity. Considering to DPP4inhibitory activities and selectivity in vitro, compounds A14, A17, B12and B25were selected for acute efficacy evaluation by the oral glucose tolerance test (OGTT) in ICR mice, and the results showed that compounds significantly reduced the blood glucose level after glucose challenge, and showed in dose-dependent manner. Moreover, compounds A17and B25were selected for the chronic effects experiment, and the results showed these two compounds increased the basal plasma insulin content significantly. Besides, compounds A14, A17and B25showed good pharmacokinetic in SD rats, and the oral bioavailability was16.8%、37.8%and22.8%, respectively. Besides, compound A17was selected for metabolite analysis in SD rats. Moreover, compounds A14, A17, B12and B25did not block hERG channel and showed no liver metabolic enzymes P450inhibition, such as CYP2C9, and compound B25showed good safety in acute toxicity study in ICR
In the research of design, synthesis and biological evaluation of EGFR inhibitors for treatment of non-small cell lunch cancer. Based on the bio-isosterism and pharmacophore combination principles,56compounds (C1-C30and D1-D26) were designed, synthesized and evaluated for inhibition of EGFR wt and EGFR T790M/L858R. Among these compounds, the EGFR wt inhibitory activities of14compounds were less than20nM, the EGFR wt inhibitory activities of13compounds were less than10nM, and the EGFR wt inhibitory activities of5compounds were less than5nM. Moreover, the EGFR T790M/L858R inhibitory activities of10compounds were less than10nM. Considering to the inhibitory activities of EGFR wt and EGFR T790M/L858R in vitro and anti-proliferative activities in A431and NCI-H1975cell lines, compounds C4, C18, D14, D15, D17and D22were selected for further study to attenuate EGFR activity and EGFR downstream signaling molecules in A431and NCI-H1975cancer cells. The results showed that compounds C4, D14, D15, D17and D22at0.1μmol/L almost completely blocked the autophosphorylation of EGFR wt in A431cells, and compounds D14, D15, D17and D22dose-dependently blocked EGFR T790M/L858R phosphorylation and downstream signaling in NCI-H1975cells. Moreover, compound D15was tested the activities on other members of the EGFR family ErbB2, ErbB4, as well as11types of tyrosine kinases using an in vitro kinase assay. These data demonstrated that compound D15was selective inhibitor of members of the EGFR family.
Polycyclic heterocyclic compounds had an important role in medicinal chemistry. In the methodology, we developed an efficient and facile Au(Ⅰ)/Ag(1)-catalyzed cascade method for one-pot synthesis of the complex polycyclic heterocycles through treatment of two simple starting materials. The strategy features Au(I)/Ag(I)-catalyzed one-pot cascade process involved in the formation of three new C-N bonds in high yields, and with broad substrate scope. Moreover, the structure of compound3Aa was characterized using X-ray crystallography.
In summary, based on traditional medicinal chemistry, computer-aided drug design and modern synthetic technology,103compounds (A1-A22, B1-B25, C1-C30and D1-D26) were designed and synthesized for evaluation of DPP4and EGFR. In the research of DPP4inhibitors, compounds A14, A17, B12and B25showed significantly reduced the blood glucose level after glucose challenge in ICR mice, and compounds A17and B25increased the basal plasma insulin content significantly in KBS dbldb mice. Moreover, compounds A14, A17and B25showed good pharmacokinetic in SD rats. And compounds A14, A17and B25did not block hERG channel and showed no liver metabolic enzymes P450inhibition, such as CYP2C9, and compound B25showed good safety in acute toxicity study in ICR mice. In the research of EGFR inhibitors, compounds C4, D14, D15, D17and D22at0.1μmol/L almost completely blocked the autophosphorylation of EGFR wt in A431cells, and compounds D14, D15, D17and D22dose-dependently blocked EGFR T790M/L858R phosphorylation and downstream signaling in NCI-H1975cells. Moreover, compound D15was a selective inhibitor of members of the EGFR family. In addition, Au-catalyzed cascade approach for synthesis of polycyclic heterocyclic compounds was developed. All the discussed works will be a good foundation for the developing new drugs with independent intellectual property rights.
首先,我们基于课题组已有研究工作基础,开展了具有α-氨基氟氰基吡咯烷类和β-氨基氰基吡咯烷类结构的DPP4抑制剂的设计、合成及抗糖尿病活性研究。基于先导化合物的药物代谢特点,我们一方面采用引入吸电子和供电子基团封闭代谢位点,芳香杂环替换苯环策略,另一方面采用延长小分子的链长策略来进行合理的药物设计,一共合成了47个结构新颖的化合物(A1-A22和B1-B25)。经药理活性测试,发现大部分化合物具有较好的DPP4抑制活性。其中,有11个化合物对DPP4的抑制活性<20nM,8个化合物(A1、A3、A7、A8、A9、A14、A15和A17)的DPP4抑制活性<10nM,IC50值分别为4.1nM、2.7nM、6.2nM、4.6nM、5.7nM、10.0nM、5.0nM、4.0nM。基于体外的DPP4抑制活性及选择性,我们选取化合物A14、A17、B12和B25进行了在ICR小鼠体内的急性降血糖活性研究,结果显示这四个化合物具有较好的体内降血糖作用,并具有较好的剂量依赖性。进一步的KBS db/db糖尿病小鼠体内的慢性降血糖研究表明,化合物A17和B25能有效降低体内血糖,并能提高血浆胰岛素含量。同时,化合物A14、A17和B25在SD大鼠体内具有良好的的药物代谢动力学性质,其口服生物利用度分别为16.8%、37.8%和22.8%。此外,还开展了化合物A14、A17和B25对hERG钾离子通道和肝代谢酶CYP450抑制作用以及化合物B25在ICR小鼠体内的急性毒性试验研究,均表明化合物具有良好的安全性。这些结果为后续进一步研究和药物开发奠定了良好的基础。
在EGFR抑制剂的设计、合成及抗肿瘤活性研究中,我们根据生物电子等排和拼合原理,设计并合成了56个结构新颖的化合物(C1-C30和D1-D26),并进行了相关的药理学评价。大部分化合物具有良好的EGFR野生型酶的抑制活性,其中有14个化合物对EGFR野生型酶的抑制活性<20nM,13个化合物对EGFR野生型酶的抑制活性<10nM,5个化合物对EGFR野生型酶的抑制活性<5nM。同时有10个化合物对EGFR T790M/L858双突变酶的抑制活性<10nM。基于此活性结果,我们又开展了化合物对A431细胞和NCI-H1975细胞的EGFR自动磷酸化抑制活性研究,结果表明在0.1μmol/L浓度下,化合物C4、D14、D15、D17和D22几乎完全阻断A431细胞的EGFR wt的自动磷酸化；在1.0μmol/L浓度下,化合物D14、D15、D17和D22几乎完全阻断NCI-H1975细胞的EGFR T790M/L858R的自动磷酸化。同时,我们还选择化合物D15进行了其它13种激酶的抑制活性研究,结果表明化合物D15不仅能抑制EGFR wt和EGFR T790M/L858R,而且对ErbB2和ErbB4具有较好的抑制活性。但对其它11种酪氨酸激酶的抑制作用较弱,这说明化合物D15具有良好的选择性,可以作为EGFR家族选择性抑制剂进行深入研究。
多环杂环化合物在药物化学研究中具有十分重要的作用。在本论文中,我们发展了一种简便有效的方法,即以两个简单的起始原料经Au(I)/Ag(I)共催化的级联反应一锅构建苯并[4,5]咪唑[1,2-c]吡咯[1,2-a]喹唑啉酮类化合物。该方法收率高、底物适用范围广,共设计合成了31个具有不同基团的化合物。该方法最大的特点在于采用“一锅串联”策略快速高效地构建三个C-N键,形成复杂的苯并咪唑并吡咯并喹唑啉酮类化合物；并且通过X-单晶衍射确证了化合物3Aa的结构。
综上所述,在DPP4抑制剂的研究中,一共合成47个活性较好的化合物。其中化合物A14、A17、B12和B25在ICR小鼠体内具有较好的体内降血糖作用；化合物A17和B25在KBS db/db糖尿病小鼠体内能有效降低体内血糖,并能提高血浆胰岛素含量；并且化合物A14、A17和B25在SD大鼠体内具有良好的的药物代谢动力学性质。此外化合物A14、A17和B25在hERG钾离子通道和肝代谢酶CYP450抑制作用以及化合物B25在ICR小鼠体内的急性毒性试验研究中,均表明化合物具有良好的安全性。在EGFR抑制剂研究中,一共合成56个具有较好活性的化合物。其中化合物C4、D14、D15、D17和D22在0.1μmol/L浓度下几乎完全阻断A431细胞的EGFR wt的自动磷酸化;化合物D14、D15、D17和D22在1.0μmol/L浓度下几乎完全阻断NCI-H1975细胞的EGFR T790M/L858R的自动磷酸化。并且化合物D15对其它13种激酶具有良好的选择性。在Au催化的方法学研究中,我们发展了一个简便有效的方法构建多环杂环化合物,该方法收率高、底物适用范围广。并通过X-单晶衍射确定化合物3Aa的结构。以上工作为我们开发具有自主知识产权的新药奠定了良好的基础。
Based on traditional medicinal chemistry, computer-aided drug design and modern synthetic technology, the dissertation for Ph.D. degree focused on design, synthesis and biological evaluation of Dipeptidyl peptidase IV inhibitors and Epidermal Growth Factor Receptor inhibitors and the methodology of Au(I)/Ag(I)-catalyzed cascade approach for the synthesis of polycyclic heterocyclic compounds.
Firstly, based on previous work in our group, we developed the work for the design, synthesis and biological evaluation of a-amino and (3-amino pyrrolidine-2-carbonitrile derivetives as DPP4inhibitors. Based on analysis of metabolites of lead compound, the rational design was carried out followed by introduction of different substituted group, displacement of aromatic ring with aromatic heterocyclic, and prolonging the side chains of lead compound. And47compounds (A1-A22and B1-B25) were designed, synthesized and evaluated to inhibit DPP4and other serine protein family activities. Among these compounds, the DPP4inhibitory activities of11compounds were less than20nM, the DPP4inhibitory activities of8compounds (A1, A3, A7, A8, A9, A14, A15and A17) were less than10nM. The IC50values were4.1nM,2.7nM,6.2nM,4.6nM,5.7nM,10.0nM,5.0nM and4.0nM, respectively. Moreover, most compounds showed good selectivity. Considering to DPP4inhibitory activities and selectivity in vitro, compounds A14, A17, B12and B25were selected for acute efficacy evaluation by the oral glucose tolerance test (OGTT) in ICR mice, and the results showed that compounds significantly reduced the blood glucose level after glucose challenge, and showed in dose-dependent manner. Moreover, compounds A17and B25were selected for the chronic effects experiment, and the results showed these two compounds increased the basal plasma insulin content significantly. Besides, compounds A14, A17and B25showed good pharmacokinetic in SD rats, and the oral bioavailability was16.8%、37.8%and22.8%, respectively. Besides, compound A17was selected for metabolite analysis in SD rats. Moreover, compounds A14, A17, B12and B25did not block hERG channel and showed no liver metabolic enzymes P450inhibition, such as CYP2C9, and compound B25showed good safety in acute toxicity study in ICR
In the research of design, synthesis and biological evaluation of EGFR inhibitors for treatment of non-small cell lunch cancer. Based on the bio-isosterism and pharmacophore combination principles,56compounds (C1-C30and D1-D26) were designed, synthesized and evaluated for inhibition of EGFR wt and EGFR T790M/L858R. Among these compounds, the EGFR wt inhibitory activities of14compounds were less than20nM, the EGFR wt inhibitory activities of13compounds were less than10nM, and the EGFR wt inhibitory activities of5compounds were less than5nM. Moreover, the EGFR T790M/L858R inhibitory activities of10compounds were less than10nM. Considering to the inhibitory activities of EGFR wt and EGFR T790M/L858R in vitro and anti-proliferative activities in A431and NCI-H1975cell lines, compounds C4, C18, D14, D15, D17and D22were selected for further study to attenuate EGFR activity and EGFR downstream signaling molecules in A431and NCI-H1975cancer cells. The results showed that compounds C4, D14, D15, D17and D22at0.1μmol/L almost completely blocked the autophosphorylation of EGFR wt in A431cells, and compounds D14, D15, D17and D22dose-dependently blocked EGFR T790M/L858R phosphorylation and downstream signaling in NCI-H1975cells. Moreover, compound D15was tested the activities on other members of the EGFR family ErbB2, ErbB4, as well as11types of tyrosine kinases using an in vitro kinase assay. These data demonstrated that compound D15was selective inhibitor of members of the EGFR family.
Polycyclic heterocyclic compounds had an important role in medicinal chemistry. In the methodology, we developed an efficient and facile Au(Ⅰ)/Ag(1)-catalyzed cascade method for one-pot synthesis of the complex polycyclic heterocycles through treatment of two simple starting materials. The strategy features Au(I)/Ag(I)-catalyzed one-pot cascade process involved in the formation of three new C-N bonds in high yields, and with broad substrate scope. Moreover, the structure of compound3Aa was characterized using X-ray crystallography.
In summary, based on traditional medicinal chemistry, computer-aided drug design and modern synthetic technology,103compounds (A1-A22, B1-B25, C1-C30and D1-D26) were designed and synthesized for evaluation of DPP4and EGFR. In the research of DPP4inhibitors, compounds A14, A17, B12and B25showed significantly reduced the blood glucose level after glucose challenge in ICR mice, and compounds A17and B25increased the basal plasma insulin content significantly in KBS dbldb mice. Moreover, compounds A14, A17and B25showed good pharmacokinetic in SD rats. And compounds A14, A17and B25did not block hERG channel and showed no liver metabolic enzymes P450inhibition, such as CYP2C9, and compound B25showed good safety in acute toxicity study in ICR mice. In the research of EGFR inhibitors, compounds C4, D14, D15, D17and D22at0.1μmol/L almost completely blocked the autophosphorylation of EGFR wt in A431cells, and compounds D14, D15, D17and D22dose-dependently blocked EGFR T790M/L858R phosphorylation and downstream signaling in NCI-H1975cells. Moreover, compound D15was a selective inhibitor of members of the EGFR family. In addition, Au-catalyzed cascade approach for synthesis of polycyclic heterocyclic compounds was developed. All the discussed works will be a good foundation for the developing new drugs with independent intellectual property rights.
引文
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