小分子CCR4拮抗剂的设计、合成与筛选
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摘要
CCR4(chemokine receptor 4)属于CC类趋化因子受体(CCR)家族成员之一,在自身免疫性疾病、过敏性炎症、血栓性疾病等过程中发挥重要作用。研究选择性的活性小分子化合物不仅有利于研究CCR4的生物功能,而且还可为以CCR4作为潜在的药物靶标发展新型药物进行有益的探索,尤其是在抗哮喘药物方面,具有广阔的研究、开发与应用前景。本课题基于同源模建方法构建了CCR4的三维结构,分析其结构特征及与配体的相互作用特点,采用Me Too的策略,利用计算机药物辅助设计的手段,设计并合成了30个全新结构化合物,建立了化合物绝对构型的确证方法。在活性筛选中,通过毛细管电泳结果表明有9个化合物与CCR4受体N端有较强的结合作用;其中有6个化合物有较强的抑制MDC介导CCR4转染的HEK293细胞的趋化运动。化合物N8的趋化抑制作用与阳性对照化合物的趋化抑制作用相当,具有进一步的研究价值。在所合成的酯类化合物中,化合物N29表现出良好的抑制MDC介导CCR4转染的HEK293细胞的趋化运动作用,说明酯类化合物有进一步研究与开发的价值。MTT法实验结果表明,优选化合物的细胞毒性低于阳性对照化合物或与之相当。根据得到的活性数据对已合成的化合物进行了构效关系的分析,为下一步的工作提供了理论依据。
Chemokines and their receptors play an important role in inflammation, tumor, autoimmune diseases, allergy and HIV infection. So far, about 50 species of human chemokines and about 20 kinds of chemokine receptors has been obtained by cloning. With the completion of the Human Genome Project and the development of orphan receptor program, the amount of chemokines and their receptors will continue to increase, therefore the research on this field research has great theoretical significance and application value. Some of the reorganized chemokines, chemokines and their receptor antagonists which have entered the clinical research have become new biological treatment hot spots.
CC chemokine receptor 4 (CCR4) is a kind of G-protein-coupled receptors with a characteristic seven-transmembrane structure and selectively expressed on Th2-type CD41 T cells, which was found in 1995. It has 3 natural-specific ligands, among which Thymus and activation regulated chemokines (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) positioned on the 16q13 region of 16th human chromosome have a high affinity to CCR4, and their Kd values were 0.5nm and 0.18nM separately. The third natural CCR4 ligand, Chemokine-like factor 1(CKLF1), a new cytokine which was found in July 2001, positioned on the 16q22 region of 16th chromosome has very different structure and expression from TARC and MDC and its in-depth study is now in progress.
CCR4 plays an important role in autoimmune diseases, allergic inflammation, thrombotic diseases etc.. The small molecule CCR4 antagonists synthesized by now are: flavanone thiazole compounds, lactam compounds, 2 - aminothiazoles compounds, sulfonyl aryl amines, diamino-pyrimidine, as well as cyclic amine. At present, Chemokine receptor antagonists in Phase I Clinical Trial Service are CXCR2, CXCR4, CCR1 and CCR5 antagonists, but not CCR4 antagonists. Therefore the research of activie and selective small molecule CCR4 antagonists is conducive not only to study CCR4 biological function, but also beneficial to explore the development of new drugs with CCR4 as a potential drug target, especially in the anti-asthma drugs, and has broad research, development and application prospects.
Since no experimentally determined three-dimensional CCR4 structure is currently available, we modeled the structure of CCR4 based on the structure of 1U19A protein of bovine rhodopsin. By analysis of its structural characteristics and the characteristics of ligand interaction, using Me Too strategy and computer- assisted drug design methods; we designed and synthesized 30 compounds, among which 22 are lactam compounds and 8 ester compounds. All the compounds synthesized have two chiral carbon atoms. We have used Chiral Synthesisl method, directly obtaied the R, R configuration of the enantiomers, thus avoided separation of chiral compounds and the use of chiral separation column. At the same time, by the use of 2D 1H-1H COSY spectra and 1D-NOESY spectrum the absolute configurations of these compounds have been determined. This method is convenient, easy, economic and efficient.
Capillary Electrophoresis results showed that 9 compounds have strong combination with the receptor, among which 6 compounds have strong MDC- mediated inhibition of CCR4-transfected HEK293 cells chemotaxis.1 compound has an significant inhibitory effect similar to that of the positive compound. It has the value for further research. There is an ester compounds showed good activity. This indicates that the esters have the value of research and development. MTT results show that the toxicity of optimization compounds lower than positive compound or equivalent. We analyzed the structure-activity relationship of compounds. This provides a theoretical basis for the next work.
Chemokines and their receptors play an important role in inflammation, tumor, autoimmune diseases, allergy and HIV infection. So far, about 50 species of human chemokines and about 20 kinds of chemokine receptors has been obtained by cloning. With the completion of the Human Genome Project and the development of orphan receptor program, the amount of chemokines and their receptors will continue to increase, therefore the research on this field research has great theoretical significance and application value. Some of the reorganized chemokines, chemokines and their receptor antagonists which have entered the clinical research have become new biological treatment hot spots.
CC chemokine receptor 4 (CCR4) is a kind of G-protein-coupled receptors with a characteristic seven-transmembrane structure and selectively expressed on Th2-type CD41 T cells, which was found in 1995. It has 3 natural-specific ligands, among which Thymus and activation regulated chemokines (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) positioned on the 16q13 region of 16th human chromosome have a high affinity to CCR4, and their Kd values were 0.5nm and 0.18nM separately. The third natural CCR4 ligand, Chemokine-like factor 1(CKLF1), a new cytokine which was found in July 2001, positioned on the 16q22 region of 16th chromosome has very different structure and expression from TARC and MDC and its in-depth study is now in progress.
CCR4 plays an important role in autoimmune diseases, allergic inflammation, thrombotic diseases etc.. The small molecule CCR4 antagonists synthesized by now are: flavanone thiazole compounds, lactam compounds, 2 - aminothiazoles compounds, sulfonyl aryl amines, diamino-pyrimidine, as well as cyclic amine. At present, Chemokine receptor antagonists in Phase I Clinical Trial Service are CXCR2, CXCR4, CCR1 and CCR5 antagonists, but not CCR4 antagonists. Therefore the research of activie and selective small molecule CCR4 antagonists is conducive not only to study CCR4 biological function, but also beneficial to explore the development of new drugs with CCR4 as a potential drug target, especially in the anti-asthma drugs, and has broad research, development and application prospects.
Since no experimentally determined three-dimensional CCR4 structure is currently available, we modeled the structure of CCR4 based on the structure of 1U19A protein of bovine rhodopsin. By analysis of its structural characteristics and the characteristics of ligand interaction, using Me Too strategy and computer- assisted drug design methods; we designed and synthesized 30 compounds, among which 22 are lactam compounds and 8 ester compounds. All the compounds synthesized have two chiral carbon atoms. We have used Chiral Synthesisl method, directly obtaied the R, R configuration of the enantiomers, thus avoided separation of chiral compounds and the use of chiral separation column. At the same time, by the use of 2D 1H-1H COSY spectra and 1D-NOESY spectrum the absolute configurations of these compounds have been determined. This method is convenient, easy, economic and efficient.
Capillary Electrophoresis results showed that 9 compounds have strong combination with the receptor, among which 6 compounds have strong MDC- mediated inhibition of CCR4-transfected HEK293 cells chemotaxis.1 compound has an significant inhibitory effect similar to that of the positive compound. It has the value for further research. There is an ester compounds showed good activity. This indicates that the esters have the value of research and development. MTT results show that the toxicity of optimization compounds lower than positive compound or equivalent. We analyzed the structure-activity relationship of compounds. This provides a theoretical basis for the next work.
引文
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