基于多肽模拟的小分子新型肽脱甲酰基酶抑制剂的设计与合成及构效关系研究
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摘要
病原菌感染严重危害人民健康,而抗生素是抵抗致病微生物的有效药物。随着抗生素的出现及其广泛应用,许多以往十分棘手的感染性疾病如天花、肺病、脑膜炎及伤寒病等,都遭遇“克星”,抗生素也因此被奉为“灵丹妙药”。然而随着抗生素的广泛应用甚至滥用,极大地锻炼了细菌的耐药能力。目前已经有相当多的细菌对抗生素产生了耐药性，耐药菌的发展速度也令人触目惊心。与此相对照,最近几年却没有新作用机制的抗生素问世,新型抗生素研发势在必行。
肽脱甲酰基酶(PDF)抑制剂则是一类新型的抗菌药物。PDF是一种脱甲酰基的金属蛋白酶,在细菌合成蛋白的过程中起着关键性的作用,而且不是人体正常细胞合成蛋白所必需,PDF抑制剂通过抑制PDF在这一过程中的脱甲酰基的作用,从而起到选择性抑制细菌合成蛋白的过程因此,这种全新作用机制的PDF抑制剂提供了一种全新的抗生素治疗可能。
到目前为止,已有两个化合物进入临床,分别是LBM415(由Vicuron和Novartis合作开发)和BB83698(由British Biotech和Genesoft合作开发),本论文基于多肽模拟的理论,设计了含3,4-脱氢脯氨酸和4-亚甲基脯氨酸结构的两类新型PDF抑制剂,提出了一种新的合成路线,通过对各关键位置的不同取代的体外抗菌活性进行了构效关系(SAR)的研究,并进行了广谱抗菌性,药代动力学,半数有效剂量(ED50),稳定性,溶解性,半致死量(LD50)等药物的体内研究,最后对合成PDF抑制剂的重要片段的新方法进行了研究。
论文的第一章绪论介绍了抗生素的发展历程,细菌的耐药现状,发展新作用机制抗生素的重要性,PDF抑制剂的作用机制和发展现状等研究背景,多肽模拟在药物研究中的作用。
论文的第二章的研究设计了一类含3,4-脱氢脯氨酸结构的新型PDF抑制剂,由于阳性对照LBM415的合成路线不能完成新型结构化合物的合成,本论文在LBM415的合成基础上提出了一条新的合成PDF抑制剂的路线,成功的合成了一系列的最终化合物,显示良好的体外抗菌活性,个别化合物对甲氧西林耐药金黄葡萄球菌ATCC43300的最低抑菌浓度(MIC)达到0.125μg/ml,优于已有抗生素。并通过P1’和P3’位置的取代研究了其抗菌构效关系。
论文的第三章的研究设计了含有4-亚甲基脯氨酸结构的PDF抑制剂,通过论文提出的新路线合成了一系列最终化合物,此类化合物同样显示出良好的体外抗菌活性,并通过阳性对照LBM415及3,4-脱氢脯氨酸结构的新型PDF抑制剂的体外抗菌活性研究了P1’,P2’,P3’的抗菌构效关系,结果显示4-亚甲基脯氨酸结构相对3,4-脱氢脯氨酸结构化合物在P3’位置显示不同的构效关系。
论文的第四章研究了两类新的PDF抑制剂的广谱抗菌性能,测试了敏感和耐药的临床分离的金黄葡萄球菌,表皮葡萄球菌,肺炎链球菌,流感嗜血杆菌,大肠杆菌,粪肠球菌,化脓性链球菌,卡他莫拉菌,对革兰氏阳性菌及部分革兰氏阴性菌显示了良好的体外抗菌活性；而其中代表性化合物SW1210的小鼠MRSA感染模型体内保护试验显示其ED5o为6.253mg/kg (95%可信限为4.307-9.077mg/kg);通过对六个体外抗菌活性较好的代表性化合物的药代动力学测试,研究了R1,R2,R3位置不同取代基对化合物的药代动力学参数的影响,其中化合物SW1201的绝对生物利用度高达88.76%；这六个化合物除SW2201在10μM浓度下对hERG钾通道抑制度为(15.86+1.27)%,其他五个化合物对hERG钾通道抑制较弱或无抑制；而急性毒性研究表明化合物SW2201的LD50>250mg/kg。
论文的第五章研究了PDF抑制剂的重要片段的合成,已有的合成方法是通过Evans手性配体进行手性诱导进行手性合成,此法虽能获得较高的ee值(ee值>99.3%),但步骤较多,总收率不高。本论文尝试了不对称拆分和不对称催化两种方式合成此片段。本论文以五步73%高收率获得消旋体,我们正在研究对消旋体的手性拆分。在不对称合成方面,论文尝试了亚胺对烯醇硅醚的不对称加成,不对称Michael反应,其中亚胺对烯醇硅醚的不对称加成在(S)-BINOL/Zr催化体系获得28%的ee值,此部分还在进行进一步研究。
People's life was severely threaten by pathogenic bacteria, and antibiotics were efficient therapeutic agents. Many infectious diseases such as smallpox, tuberculosis, meningitis, typhoid were cured by antibiotics. However, antibiotic-resistant bacteria was generated because the abuse of antibiotics and the situation of antibiotic-resistant bacteria was seriously worrisome until now. By contrast, there is no new antibiotics with novel mechanism in market during the last decade. This crisis has resulted in an intensive research effort to develop a new class of compounds that exhibit novel mechanisms of antibacterial activity.
Peptide deformylase (PDF) inhibitor was a kind of antibacterial drug with novel mechanism. PDF is iron(11) ion containing metalloprotease, which play critical role in bacterial protein synthesis while it does not share close homology with any mammalian cell equivalent. PDF inhibitor prevent PDF from catalyzing the deformyl process during bacterial protein synthesis.Therefore, PDF inhibitor with novel mechanism might become a new therapeutic agent against bacterial infections.
Thus far, two PDF inhibitors that underwent human clinical trials are BB83698(discovered by British Biotech, in collaboration with Genesoft) and LBM415(discovered by Vicuron pharmaceuticals, in collaboration with Novartis). In this dissertation, we designed two novel PDF inhibitors bearing3,4-dehydroproline or4-methyleneproline structure, and promoted a new route for PDF inhibitor synthesis. Screening antibacterial activities of serials of compounds to study structure-activity relationship(SAR) at different position. Preclinical study including broad-spectrum antibacterial activities, pharmacokinetics,50%effective dose(ED50), stability, solubility, lethal median dose(LD50) were evaluated in this dissertation. At last, we do the research on developing new method for synthesis of important fragment of PDF inhibitor.
Chapter1is the short review of the research background including the development of antibiotics, the situation of drug-resistant bacteria, the importance of developing antibiotic with new mechanism, mechanism of PDF inhibitor and the current situation of PDF inhibitor, and the important role of peptidomimetics in the research of development of drugs.
Chapter2is about the design and synthesis of novel PDF inhibitor containing3,4-dehydroproline motif. Because we can not get the novel compounds by the route which was used for synthesis of positive control LBM415, we promoted a new method based on the one used for synthesis LBM415, and obtain the final products successfully. Good to excellent antibacterial activities of these compounds were observed, minimum inhibit concentration(MIC) of the best one is0.125μg/ml against methicillin-resistant staphylococcus aureus ATCC43300, and it is better than most existing drugs such as Penicillin, Ciprofloxacin, Linezolid, Vancomycin. And we replaced motif at P1' and P3'position to discovery the SAR of these compounds.
In chapter3, we designed a serial of compounds bearing3-methylene pyrrolidine motif as novel PDF inhibitors, and synthesized these compounds by using the new route promoted by us. They also show good in vitro antibacterial activity against Gram-positive test strains. The SAR at P1', P2' and P3'position were explored by contrasting LBM415and novel PDF inhibitors we developed, and different SAR of antibacterial activity at P3' position was observed between PDF inhibitors containing3,4-dehydroproline motif and the ones bearing3-methylene pyrrolidine motif.
In chapter4, we test the good ones of the two novel PDF inhibitors for broad-spectrum antibacterial activities against the clinical isolated susceptive and resistant strains including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Haemophilus influenzae, Enterococcus faecalis, Enterococcus faecium, Moraxella catarrhalis, Escherichia coli, Streptococcus pyogenes, and they show good to excellent antibacterial activities against Gram-positive strains and moderate activities against Gram-negative strains. And we test ED50of the representative compound SW1210using the murine models of MRSA, and ED50of SW1210is6.253mg/kg (95%confidence limit is4.307-9.077mg/kg). To find the relation between the groups in R1, R2and R3position and pharmacokinetic parameters, we have six representative compounds to be tested, and find the absolute bioavailability of SW1201up to88.76%. Although SW2201shows (15.86±1.27)%inhibition against hERG potassium channel in10μM concentration, the rest of these six compounds show less to no inhibition. We do research on study of actue toxicity of SW2201, and find the LD50>250mg/kg.
We study on developing new method for synthesis of important fragment of PDF inhibitor in chapter5. The method for construction of chiral center has been reported was inducing by Evans'auxiliary, even high ee value was obtained with this method, it has some disadvantages such as too much steps, low overall yield. We get the racemic product with5steps and about73%yield, and we are doing further study on chemical resolution. We also attempt to synthesis the fragment by catalytic asymmetric reaction such as asymmetric Mannich addition reaction between imine and silyl enol ether, Michael reaction, the first reaction obtain28%ee value catalyzed by (S)-BINOL/Zr. Further studies on the asymmetric synthesis are currently in progress.
肽脱甲酰基酶(PDF)抑制剂则是一类新型的抗菌药物。PDF是一种脱甲酰基的金属蛋白酶,在细菌合成蛋白的过程中起着关键性的作用,而且不是人体正常细胞合成蛋白所必需,PDF抑制剂通过抑制PDF在这一过程中的脱甲酰基的作用,从而起到选择性抑制细菌合成蛋白的过程因此,这种全新作用机制的PDF抑制剂提供了一种全新的抗生素治疗可能。
到目前为止,已有两个化合物进入临床,分别是LBM415(由Vicuron和Novartis合作开发)和BB83698(由British Biotech和Genesoft合作开发),本论文基于多肽模拟的理论,设计了含3,4-脱氢脯氨酸和4-亚甲基脯氨酸结构的两类新型PDF抑制剂,提出了一种新的合成路线,通过对各关键位置的不同取代的体外抗菌活性进行了构效关系(SAR)的研究,并进行了广谱抗菌性,药代动力学,半数有效剂量(ED50),稳定性,溶解性,半致死量(LD50)等药物的体内研究,最后对合成PDF抑制剂的重要片段的新方法进行了研究。
论文的第一章绪论介绍了抗生素的发展历程,细菌的耐药现状,发展新作用机制抗生素的重要性,PDF抑制剂的作用机制和发展现状等研究背景,多肽模拟在药物研究中的作用。
论文的第二章的研究设计了一类含3,4-脱氢脯氨酸结构的新型PDF抑制剂,由于阳性对照LBM415的合成路线不能完成新型结构化合物的合成,本论文在LBM415的合成基础上提出了一条新的合成PDF抑制剂的路线,成功的合成了一系列的最终化合物,显示良好的体外抗菌活性,个别化合物对甲氧西林耐药金黄葡萄球菌ATCC43300的最低抑菌浓度(MIC)达到0.125μg/ml,优于已有抗生素。并通过P1’和P3’位置的取代研究了其抗菌构效关系。
论文的第三章的研究设计了含有4-亚甲基脯氨酸结构的PDF抑制剂,通过论文提出的新路线合成了一系列最终化合物,此类化合物同样显示出良好的体外抗菌活性,并通过阳性对照LBM415及3,4-脱氢脯氨酸结构的新型PDF抑制剂的体外抗菌活性研究了P1’,P2’,P3’的抗菌构效关系,结果显示4-亚甲基脯氨酸结构相对3,4-脱氢脯氨酸结构化合物在P3’位置显示不同的构效关系。
论文的第四章研究了两类新的PDF抑制剂的广谱抗菌性能,测试了敏感和耐药的临床分离的金黄葡萄球菌,表皮葡萄球菌,肺炎链球菌,流感嗜血杆菌,大肠杆菌,粪肠球菌,化脓性链球菌,卡他莫拉菌,对革兰氏阳性菌及部分革兰氏阴性菌显示了良好的体外抗菌活性；而其中代表性化合物SW1210的小鼠MRSA感染模型体内保护试验显示其ED5o为6.253mg/kg (95%可信限为4.307-9.077mg/kg);通过对六个体外抗菌活性较好的代表性化合物的药代动力学测试,研究了R1,R2,R3位置不同取代基对化合物的药代动力学参数的影响,其中化合物SW1201的绝对生物利用度高达88.76%；这六个化合物除SW2201在10μM浓度下对hERG钾通道抑制度为(15.86+1.27)%,其他五个化合物对hERG钾通道抑制较弱或无抑制；而急性毒性研究表明化合物SW2201的LD50>250mg/kg。
论文的第五章研究了PDF抑制剂的重要片段的合成,已有的合成方法是通过Evans手性配体进行手性诱导进行手性合成,此法虽能获得较高的ee值(ee值>99.3%),但步骤较多,总收率不高。本论文尝试了不对称拆分和不对称催化两种方式合成此片段。本论文以五步73%高收率获得消旋体,我们正在研究对消旋体的手性拆分。在不对称合成方面,论文尝试了亚胺对烯醇硅醚的不对称加成,不对称Michael反应,其中亚胺对烯醇硅醚的不对称加成在(S)-BINOL/Zr催化体系获得28%的ee值,此部分还在进行进一步研究。
People's life was severely threaten by pathogenic bacteria, and antibiotics were efficient therapeutic agents. Many infectious diseases such as smallpox, tuberculosis, meningitis, typhoid were cured by antibiotics. However, antibiotic-resistant bacteria was generated because the abuse of antibiotics and the situation of antibiotic-resistant bacteria was seriously worrisome until now. By contrast, there is no new antibiotics with novel mechanism in market during the last decade. This crisis has resulted in an intensive research effort to develop a new class of compounds that exhibit novel mechanisms of antibacterial activity.
Peptide deformylase (PDF) inhibitor was a kind of antibacterial drug with novel mechanism. PDF is iron(11) ion containing metalloprotease, which play critical role in bacterial protein synthesis while it does not share close homology with any mammalian cell equivalent. PDF inhibitor prevent PDF from catalyzing the deformyl process during bacterial protein synthesis.Therefore, PDF inhibitor with novel mechanism might become a new therapeutic agent against bacterial infections.
Thus far, two PDF inhibitors that underwent human clinical trials are BB83698(discovered by British Biotech, in collaboration with Genesoft) and LBM415(discovered by Vicuron pharmaceuticals, in collaboration with Novartis). In this dissertation, we designed two novel PDF inhibitors bearing3,4-dehydroproline or4-methyleneproline structure, and promoted a new route for PDF inhibitor synthesis. Screening antibacterial activities of serials of compounds to study structure-activity relationship(SAR) at different position. Preclinical study including broad-spectrum antibacterial activities, pharmacokinetics,50%effective dose(ED50), stability, solubility, lethal median dose(LD50) were evaluated in this dissertation. At last, we do the research on developing new method for synthesis of important fragment of PDF inhibitor.
Chapter1is the short review of the research background including the development of antibiotics, the situation of drug-resistant bacteria, the importance of developing antibiotic with new mechanism, mechanism of PDF inhibitor and the current situation of PDF inhibitor, and the important role of peptidomimetics in the research of development of drugs.
Chapter2is about the design and synthesis of novel PDF inhibitor containing3,4-dehydroproline motif. Because we can not get the novel compounds by the route which was used for synthesis of positive control LBM415, we promoted a new method based on the one used for synthesis LBM415, and obtain the final products successfully. Good to excellent antibacterial activities of these compounds were observed, minimum inhibit concentration(MIC) of the best one is0.125μg/ml against methicillin-resistant staphylococcus aureus ATCC43300, and it is better than most existing drugs such as Penicillin, Ciprofloxacin, Linezolid, Vancomycin. And we replaced motif at P1' and P3'position to discovery the SAR of these compounds.
In chapter3, we designed a serial of compounds bearing3-methylene pyrrolidine motif as novel PDF inhibitors, and synthesized these compounds by using the new route promoted by us. They also show good in vitro antibacterial activity against Gram-positive test strains. The SAR at P1', P2' and P3'position were explored by contrasting LBM415and novel PDF inhibitors we developed, and different SAR of antibacterial activity at P3' position was observed between PDF inhibitors containing3,4-dehydroproline motif and the ones bearing3-methylene pyrrolidine motif.
In chapter4, we test the good ones of the two novel PDF inhibitors for broad-spectrum antibacterial activities against the clinical isolated susceptive and resistant strains including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Haemophilus influenzae, Enterococcus faecalis, Enterococcus faecium, Moraxella catarrhalis, Escherichia coli, Streptococcus pyogenes, and they show good to excellent antibacterial activities against Gram-positive strains and moderate activities against Gram-negative strains. And we test ED50of the representative compound SW1210using the murine models of MRSA, and ED50of SW1210is6.253mg/kg (95%confidence limit is4.307-9.077mg/kg). To find the relation between the groups in R1, R2and R3position and pharmacokinetic parameters, we have six representative compounds to be tested, and find the absolute bioavailability of SW1201up to88.76%. Although SW2201shows (15.86±1.27)%inhibition against hERG potassium channel in10μM concentration, the rest of these six compounds show less to no inhibition. We do research on study of actue toxicity of SW2201, and find the LD50>250mg/kg.
We study on developing new method for synthesis of important fragment of PDF inhibitor in chapter5. The method for construction of chiral center has been reported was inducing by Evans'auxiliary, even high ee value was obtained with this method, it has some disadvantages such as too much steps, low overall yield. We get the racemic product with5steps and about73%yield, and we are doing further study on chemical resolution. We also attempt to synthesis the fragment by catalytic asymmetric reaction such as asymmetric Mannich addition reaction between imine and silyl enol ether, Michael reaction, the first reaction obtain28%ee value catalyzed by (S)-BINOL/Zr. Further studies on the asymmetric synthesis are currently in progress.
引文
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