多取代氨基噻吩类/吡咯羧酸类p53-MDM2结合抑制剂的设计、合成及生物活性评价
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摘要
恶性肿瘤是严重威胁人类健康的重大疾病之一,并已成为我国城市居民的第一死因。研究表明,p53基因是与人类恶性肿瘤相关性最高的肿瘤抑制因子之一可通过DNA修复、细胞周期阻滞和凋亡等方式发挥抑制肿瘤作用。而癌基因MDM2的表达产物MDM2蛋白可与p53蛋白结合,调控p53的转录活性和稳定性,抑制p53正常的生物学功能,从而促进肿瘤的发生和发展。大量研究表明,阻断p53-MDM2相互作用可引起p53的聚集和激活,促使肿瘤细胞生长阻滞或凋亡,是一种有效的癌症治疗策略。近年来,小分子p53-MDM2结合抑制剂由于其在肿瘤治疗方面的潜在应用前景而备受关注。
为寻找全新母核结构的p53-MDM2结合抑制剂,本论文利用计算机辅助药物设计方法构建了p53-MDM2结合抑制剂的三维药效团和分子对接模型,利用此模型对Maybridge数据库和本实验室化合物库进行虚拟筛选,获得了具良好生物活性的3,4,5-三取代氨基噻吩衍生物MCL0527。在此基础上,根据其结构特征,结合骨架迁越、电子等排等理性药物设计方法对MCL0527进行结构优化,设计合成了76个3,4,5-三取代氨基噻吩类衍生物和类似物。所得化合物的p53-MDM2结合抑制活性及体外肿瘤细胞增殖抑制活性测试结果表明：大部分化合物表现出中等到强的p53-MDM2结合抑制活性(ki:0.086～17.66μM)；多数化合物同时对表达野生型p53的A549和HCT116细胞具有中等到强的增殖抑制活性(A549IC50:0.25～22.05μM; HCT116IC50:0.24～35.54μM),并对表达野生型p53的细胞株具有良好的选择性,部分化合物的增殖抑制活性和选择性优于阳性对照Nutlin-3.根据活性测试结果,进行了初步构效关系讨论。代表性化合物(1-55)的体内抗肿瘤活性测试(300mg/kg, ig,qd,21天)结果显示,其对裸小鼠人肺癌A549移植瘤有显著的生长抑制作用,抑制率为59.7%,受试动物体重未见明显下降,提示该化合物具有进一步研究的价值,有成为新型抗肿瘤化合物的潜力。化合物1-51的小鼠全血中代谢稳定性测试结果表明,其在血液中稳定,为该类化合物的后续深入代谢研究奠定了基础。
以前一章节研究过程中发现的活性较好的3,4,5-三取代氨基吡咯类衍生物为基础,根据最低能量构象叠合分析、合理药物设计原理及初步生物活性评价,获得并确定了先导分子1,2,5-三芳基吡咯羧酸类化合物2-39。在此基础上,采用生物电子等排和类似物设计等方法,进而设计合成了26个1,2,5-三芳基吡咯羧酸衍生物。p53-MDM2结合抑制活性测试结果显示,大部分化合物表现出纳摩尔数量级的抑制活性,4个化合物的结合抑制活性优于阳性对照Nutlin-3。其中,化合物2-53(Ki=0.019μM)的活性较Nutlin-3(Ki=0.055μM)提高了2倍,较先导化合物2-39(Ki=1.48μM)提高了77倍。总结初步构效关系：①吡咯环1-苯基上取代基及取代位置的影响：间位取代者的活性总体优于对位取代；取代基为氯、溴或三氟甲基时活性基本相当；邻位引入氟原子有利于提高活性；②吡咯环2-苯基上取代基及取代位置的影响：间氯取代者的活性优于对氯取代；对位引入氟原子可保持或提高活性；③以其它芳环替代5位苯环活性基本保持；④3-羧基衍生化对活性影响较大,可导致活性降低甚至消失。体外肿瘤细胞增殖抑制活性测试结果表明,大部分化合物对表达野生型p53的A549和HCT166细胞具有中等的增殖抑制活性,部分化合物对野生型p53细胞株具有一定的选择性,与Nutlin-3基本相当。在活性筛选的基础上,开展代表性化合物2-53与MDM2的分子对接研究,阐明该类化合物与MDM2蛋白可能的相互作用模式；采用最低能量构象比较分析方法解释了2-53具有强p53-MDM2结合抑制活性的原因,为进一步药物设计提供有利依据。此外,计算机辅助的1,2,5-三芳基吡咯羧酸类衍生物类药性质评价结果表明,该类化合物在体内具有较好的ADME'性质,为后续深入的ADMET'性质研究奠定了基础。
Malignant tumor is one of the major diseases threatening human health worldwide. It has become the number-one cause of death for city dwellers in China. The tumor suppressor p53, key node of the p53pathway, plays essential roles in various cellular activities, such as cell cycle, apoptosis and DNA repair. However, aberrations in p53regulation and/or defective signaling in the p53pathway result in many cases of inadequate tumor suppression. One important cause of p53function deficiency involves MDM2, the negative regulator of the activity and stability of p53. Extensive studies have established that reactivation of p53by utilizing p53-MDM2binding inhibitors is a promising strategy for cancer therapy. Consequently, the research on small-molecule p53-MDM2binding inhibitors has attracted considerable attention in recent years.
In order to discover novel scaffolds, a3D pharmacophore model (Hypol) of p53-MDM2binding inhibitors was established. Combining with docking studies, the Hypol-based virtual screening led to the identification of compound MCL0527(1-49) as a novel lead. Then series of763,4,5-trisubstituted aminothiophene derivatives and analogues were designed and synthesized based on the structural features of MCL0527according to principles of bioisosterism and design of analogues. MDM2binding assay results showed that most target compounds exhibited moderate to potent affinities towards MDM2. In vitro evaluation against human cancer cell lines showed that most compounds displayed not only moderate to potent tumor cell anti-proliferation activities on wild-type p53expressing cell lines A549and HCT116but also good selective profile for p53status. Preliminary SARs were disclosed. In vivo anti-tumor activity evaluation showed that1-55could significantly inhibit the tumor growth (59.7%) in human lung adenocarcinoma A549xenograft in nude mice. A metabolic stability assay showed that 1-51exhibited good stability in mice whole blood, which laid a foundation for further metabolism studies.
Based on the structural features of3,4,5-trisubstituted aminopyrroles obtained in previous study, a series of261,2,5-triaryl carboxypyrrole derivatives were designed and synthesized according to the molecular alignment analysis and rational drug design theory. MDM2binding assay showed that most target compounds exhibited potent affinities towards MDM2. Five compounds exhibited improved potency compared to Nutlin-3. Particularly, compound2-53(Ki-0.019μM) is2times more potent than Nutlin-3(Ki=0.055uM). Preliminary SARs were revealed as followed. For the1-phenyl ring of pyrrole, meta-substituted compounds were more potent than para position. Cl, Br and CF3substituents imparted equally positive effect to the binding affinities. Introducing an F atom at meta position was beneficial for potency. Referring to the2-phenyl ring of pyrrole,m-chloro substituted compounds exhibited better activities than that of p-chloro. Introducing an F atom at para position was beneficial for potency. In the case of5-phenyl ring of pyrrole, using other aryl rings to replace phenyl moiety could retain the binding affinities. Derivatization at3-carboxy group caused a loss of potency in varying degrees. In vitro evaluation against human cancer cell lines showed that most compounds displayed moderate tumor cell anti-proliferation activities on wild-type p53expressing cell lines A549and HCT116. Molecular docking analysis was performed to predict the binding mode of MDM2and2-53. Besides, Compared analysis of minimized conformers explained the possible reason that2-53showed potent p53-MDM2binding affinities, which provided useful information for further drug design. In addition, predicted ADME drug-like properties showed that the1,2,5-triaryl carboxypyrroles possessed moderate to good ADME properties. The above results provide new insights for the development of1,2,5-triaryl carboxypyrroles as anti-cancer agents.
为寻找全新母核结构的p53-MDM2结合抑制剂,本论文利用计算机辅助药物设计方法构建了p53-MDM2结合抑制剂的三维药效团和分子对接模型,利用此模型对Maybridge数据库和本实验室化合物库进行虚拟筛选,获得了具良好生物活性的3,4,5-三取代氨基噻吩衍生物MCL0527。在此基础上,根据其结构特征,结合骨架迁越、电子等排等理性药物设计方法对MCL0527进行结构优化,设计合成了76个3,4,5-三取代氨基噻吩类衍生物和类似物。所得化合物的p53-MDM2结合抑制活性及体外肿瘤细胞增殖抑制活性测试结果表明：大部分化合物表现出中等到强的p53-MDM2结合抑制活性(ki:0.086～17.66μM)；多数化合物同时对表达野生型p53的A549和HCT116细胞具有中等到强的增殖抑制活性(A549IC50:0.25～22.05μM; HCT116IC50:0.24～35.54μM),并对表达野生型p53的细胞株具有良好的选择性,部分化合物的增殖抑制活性和选择性优于阳性对照Nutlin-3.根据活性测试结果,进行了初步构效关系讨论。代表性化合物(1-55)的体内抗肿瘤活性测试(300mg/kg, ig,qd,21天)结果显示,其对裸小鼠人肺癌A549移植瘤有显著的生长抑制作用,抑制率为59.7%,受试动物体重未见明显下降,提示该化合物具有进一步研究的价值,有成为新型抗肿瘤化合物的潜力。化合物1-51的小鼠全血中代谢稳定性测试结果表明,其在血液中稳定,为该类化合物的后续深入代谢研究奠定了基础。
以前一章节研究过程中发现的活性较好的3,4,5-三取代氨基吡咯类衍生物为基础,根据最低能量构象叠合分析、合理药物设计原理及初步生物活性评价,获得并确定了先导分子1,2,5-三芳基吡咯羧酸类化合物2-39。在此基础上,采用生物电子等排和类似物设计等方法,进而设计合成了26个1,2,5-三芳基吡咯羧酸衍生物。p53-MDM2结合抑制活性测试结果显示,大部分化合物表现出纳摩尔数量级的抑制活性,4个化合物的结合抑制活性优于阳性对照Nutlin-3。其中,化合物2-53(Ki=0.019μM)的活性较Nutlin-3(Ki=0.055μM)提高了2倍,较先导化合物2-39(Ki=1.48μM)提高了77倍。总结初步构效关系：①吡咯环1-苯基上取代基及取代位置的影响：间位取代者的活性总体优于对位取代；取代基为氯、溴或三氟甲基时活性基本相当；邻位引入氟原子有利于提高活性；②吡咯环2-苯基上取代基及取代位置的影响：间氯取代者的活性优于对氯取代；对位引入氟原子可保持或提高活性；③以其它芳环替代5位苯环活性基本保持；④3-羧基衍生化对活性影响较大,可导致活性降低甚至消失。体外肿瘤细胞增殖抑制活性测试结果表明,大部分化合物对表达野生型p53的A549和HCT166细胞具有中等的增殖抑制活性,部分化合物对野生型p53细胞株具有一定的选择性,与Nutlin-3基本相当。在活性筛选的基础上,开展代表性化合物2-53与MDM2的分子对接研究,阐明该类化合物与MDM2蛋白可能的相互作用模式；采用最低能量构象比较分析方法解释了2-53具有强p53-MDM2结合抑制活性的原因,为进一步药物设计提供有利依据。此外,计算机辅助的1,2,5-三芳基吡咯羧酸类衍生物类药性质评价结果表明,该类化合物在体内具有较好的ADME'性质,为后续深入的ADMET'性质研究奠定了基础。
Malignant tumor is one of the major diseases threatening human health worldwide. It has become the number-one cause of death for city dwellers in China. The tumor suppressor p53, key node of the p53pathway, plays essential roles in various cellular activities, such as cell cycle, apoptosis and DNA repair. However, aberrations in p53regulation and/or defective signaling in the p53pathway result in many cases of inadequate tumor suppression. One important cause of p53function deficiency involves MDM2, the negative regulator of the activity and stability of p53. Extensive studies have established that reactivation of p53by utilizing p53-MDM2binding inhibitors is a promising strategy for cancer therapy. Consequently, the research on small-molecule p53-MDM2binding inhibitors has attracted considerable attention in recent years.
In order to discover novel scaffolds, a3D pharmacophore model (Hypol) of p53-MDM2binding inhibitors was established. Combining with docking studies, the Hypol-based virtual screening led to the identification of compound MCL0527(1-49) as a novel lead. Then series of763,4,5-trisubstituted aminothiophene derivatives and analogues were designed and synthesized based on the structural features of MCL0527according to principles of bioisosterism and design of analogues. MDM2binding assay results showed that most target compounds exhibited moderate to potent affinities towards MDM2. In vitro evaluation against human cancer cell lines showed that most compounds displayed not only moderate to potent tumor cell anti-proliferation activities on wild-type p53expressing cell lines A549and HCT116but also good selective profile for p53status. Preliminary SARs were disclosed. In vivo anti-tumor activity evaluation showed that1-55could significantly inhibit the tumor growth (59.7%) in human lung adenocarcinoma A549xenograft in nude mice. A metabolic stability assay showed that 1-51exhibited good stability in mice whole blood, which laid a foundation for further metabolism studies.
Based on the structural features of3,4,5-trisubstituted aminopyrroles obtained in previous study, a series of261,2,5-triaryl carboxypyrrole derivatives were designed and synthesized according to the molecular alignment analysis and rational drug design theory. MDM2binding assay showed that most target compounds exhibited potent affinities towards MDM2. Five compounds exhibited improved potency compared to Nutlin-3. Particularly, compound2-53(Ki-0.019μM) is2times more potent than Nutlin-3(Ki=0.055uM). Preliminary SARs were revealed as followed. For the1-phenyl ring of pyrrole, meta-substituted compounds were more potent than para position. Cl, Br and CF3substituents imparted equally positive effect to the binding affinities. Introducing an F atom at meta position was beneficial for potency. Referring to the2-phenyl ring of pyrrole,m-chloro substituted compounds exhibited better activities than that of p-chloro. Introducing an F atom at para position was beneficial for potency. In the case of5-phenyl ring of pyrrole, using other aryl rings to replace phenyl moiety could retain the binding affinities. Derivatization at3-carboxy group caused a loss of potency in varying degrees. In vitro evaluation against human cancer cell lines showed that most compounds displayed moderate tumor cell anti-proliferation activities on wild-type p53expressing cell lines A549and HCT116. Molecular docking analysis was performed to predict the binding mode of MDM2and2-53. Besides, Compared analysis of minimized conformers explained the possible reason that2-53showed potent p53-MDM2binding affinities, which provided useful information for further drug design. In addition, predicted ADME drug-like properties showed that the1,2,5-triaryl carboxypyrroles possessed moderate to good ADME properties. The above results provide new insights for the development of1,2,5-triaryl carboxypyrroles as anti-cancer agents.
引文
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