四氢异喹啉-噁二唑类非共价型蛋白酶体抑制剂研究初探

目的探索四氢异喹啉-噁二唑类非共价型蛋白酶体抑制剂的可行性。方法基于拼合原理,将新型非共价型蛋白酶体抑制剂PI-1833(5)的1,2,4-噁二唑靶头与本研究组发现的四氢异喹啉脲拟肽骨架相拼合,设计了四氢异喹啉-噁二唑类非共价型蛋白酶体抑制剂,合成了N-((3-苯基-1,2,4-噁二唑-5-基)甲基)-3,4-二氢异喹啉-2(1H)-甲酰异丙胺(8),并采用MTT法评价其对人胃癌细胞MGC-803的生长抑制活性;利用分子对接的方法分析化合物与20S蛋白酶体的结合状态。结果与结论化合物8在10μmol·L~(-1)浓度下没有显示出抗肿瘤活性;通过比较化合物5和8与20S蛋白酶体的对接结果,发现化合物8不产生活性的主要原因可能是噁二唑和四氢异喹啉之间的连接臂柔性不够,提示进一步研究的重点应该是对连接臂的优化。     

新型非共价结合拟肽类蛋白酶体抑制剂的合成及活性评价

目的 设计、合成系列非共价结合拟肽类蛋白酶体抑制剂,并对其进行活性评价。方法 根据非共价结合蛋白酶体抑制剂与蛋白酶体的结合特点,采用氨基酸替换、生物电子等排等经典的药物设计方法,选取邻氯苄胺作为化合物的羧基末端基团,同时在肽骨架结构中引入六元环以增强肽类化合物的稳定性,设计并合成了一系列短肽非共价结合类蛋白酶体抑制剂,并通过体外蛋白酶体活性抑制实验评价该类化合物的活性。结果 共合成了8个具有全新结构的二肽和三肽化合物,其结构经¹H-NMR、ESI-MS确证,该类化合物对蛋白酶体具有中等的抑制活性。结论 肽链的长短及氨基末端不同的取代基对化合物的蛋白酶体抑制活性都有影响,8个化合物在体外对蛋白酶体都具有不同程度的抑制活性。本研究丰富了蛋白酶体抑制剂的结构类型,为该类化合物的深入研究奠定了基础。     

磺胺类黄酮衍生物20S蛋白酶体抑制剂的设计、合成与活性评价

本文通过计算机辅助设计,设计并合成了一系列磺胺类黄酮衍生物作为非共价20S蛋白酶体抑制剂,并对其生物活性进行了测试。与先导化合物相比（β5亚基的IC50值为14.0μM）,化合物仅表现出局部的改善,但仍可作为一类潜在的20S蛋白酶体抑制剂。     

环氧酮肽类蛋白酶体抑制剂的研究进展

随着硼替佐米和卡非佐米被FDA批准用于多发性骨髓瘤患者的治疗,蛋白酶体已成为一种越来越热门的抗肿瘤药物的靶点。环氧酮肽类化合物由于其良好的选择性和较低的不良反应已成为蛋白酶体抑制剂的研究热点。本文主要综述蛋白酶体的结构和功能、环氧酮肽类蛋白酶体抑制剂的作用机制及发展现状。     

蛋白酶体抑制剂筛选模型的建立

蛋白酶体对肿瘤生长相关蛋白的降解起十分重要的调控作用,能够通过多种机制抑制肿瘤生长和扩散,已成为一个新的抗癌靶点[1].特异性蛋白酶体抑制剂PS-341在体外和小鼠肿瘤模型中表现出明显的抗肿瘤活性,目前已在进行Ⅱ～Ⅲ期临床试验[1].寻找特异的蛋白酶体抑制剂,关键是建立特异、简便的筛选模型.我们根据荧光底物Suc-Leu-Leu-Val-Tyr-AMC在SDS活化的蛋白酶体作用下发生水解,释放出具有荧光的AMC(7-氨基-4-甲基香豆素)的原理,建立了蛋白酶体抑制剂的筛选模型.本文就该模型的建立作一介绍.     

蛋白酶体抑制剂的研究进展

作为体内蛋白质降解的途径之一,蛋白酶体具有非常重要的生理作用,并与多种疾病密切相关。抑制蛋白酶体的功能已经成为肿瘤治疗的叉一有前景的新途径,并受到越来越多的关注。本文对蛋白酶体的组成结构、病理生理作用和现有抑制剂进行归纳总结。     

去泛素化酶小分子抑制剂抗肿瘤作用研究:新进展和新思路

泛素-蛋白酶体通路异常是导致蛋白质内稳态失控的重要因素。而在该过程中,负责移除蛋白底物泛素链的去泛素化酶至关重要,其活性或表达异常可造成关键致癌/抑癌蛋白的功能变化,直接或间接导致肿瘤发生发展和恶性演进。基于此,靶向去泛素化酶的小分子抑制剂发现及研究已经成为抗肿瘤候选药物的热点领域之一。本综述将重点介绍泛素-蛋白酶体通路、尤其是去泛素化酶对肿瘤的调控作用和机制,介绍去泛素化酶小分子抑制剂在肿瘤治疗研究中的应用,并针对小分子抑制剂的研究现状和最新进展展开讨论,为基于去泛素化酶的抗肿瘤新策略研究提供思路。     

Carfilzomib:从天然产物到药物的研发历程

天然产物及其衍生物是药物的重要来源。Carfilzomib是一个以天然产物为先导通过结构优化得到的用于治疗多发性骨髓瘤的药物,其先导化合物Epoxomicin是从微生物中发现的具有抗癌活性的环氧酮肽类天然产物,能够选择性地抑制蛋白酶体,其环氧酮结构以独特的两步反应和蛋白酶体共价结合,因此克服了同类药物的脱靶缺点。以Epoxomicin为先导,通过结构优化得到活性更强、成药性性更好的Carfilzomib,作为新一代蛋白酶体抑制剂于2012年上市。     

三肽四氮唑类20S蛋白酶体抑制剂的设计、合成与活性研究

泛素-蛋白酶体途径是细胞内降解蛋白质的一种主要方式,由20S蛋白酶体来完成蛋白质的降解。本文在已经报道的肽类抑制剂的基础上,设计合成了一类三肽四氮唑化合物,通过1H NMR、MS以及元素分析对化合物结构进行了表征。活性评价结果表明,有3个目标化合物(6b、6d和6h)具有较好的抑制20S蛋白酶体类胰凝乳蛋白酶的活性。分子对接研究显示,这类新型C端基肽类化合物能通过与活性位点非共价相互作用而与蛋白酶体结合。     

芹黄素、白杨黄素和木犀草素选择性抑制肿瘤细胞胰凝乳蛋白酶样和胰蛋白酶样蛋白酶体催化活性

<正>泛素-蛋白酶体途径在调节细胞凋亡和细胞周期中起重要作用。蛋白酶体功能由3种主要的催化活性介导,即胰凝乳蛋白酶样(CT-L)、胰蛋白酶样(T-L)和肽基谷氨酰肽水解样(PGPH)活性。近期研究显示,蛋白酶体抑制剂具抗肿瘤活性并已用于肿瘤(如     

Potential for proteasome inhibition in the treatment of cancer

Proteasome inhibition is a new approach to treating cancer. Proteasome inhibitors specifically induce apoptosis in cancer cells, but most proteasome inhibitors are not suitable for clinical development. Peptide boronates overcome the shortcomings of earlier generation proteasome inhibitors, and bortezomib (VELCADE; formerly PS-341) is the first peptide boronate to enter clinical trials. Preclinical studies of bortezomib have demonstrated antitumor activity in a variety of tumor types. Phase I trials provided evidence of manageable toxicities and support a twice-weekly dosing regimen now being examined in a Phase III study.     

Macrocyclic proteasome inhibitors

Proteasome inhibitors have proven to be effective anticancer agents. Despite the success of the first on the market proteasome inhibitor bortezomib in chemotherapy, alternative clinically useful proteasome inhibitors are still urgently needed as bortezomib therapy causes severe side effects and is limited by arising drug resistance. Experience from previous proteasome inhibitor studies has thereby demonstrated that the identification of proteasome inhibitor structures with suitable pharmacological properties is a key factor for a successful development of clinically useful proteasome inhibitors. Macrocycles often show distinct and in comparison to linear small molecules superior pharmacological properties. Consequently, macrocyclic proteasome inhibitors might represent promising small molecules for drug development. Here, we want to highlight the current state of the art of macrocyclic proteasome inhibitor research. To this end, we give an overview and critically discuss currently known classes of macrocyclic proteasome inhibitors.     

蛋白酶体与蛋白酶体抑制剂

蛋白酶体是一种存在于细胞质和细胞核内的蛋白水解酶复合物,是降解细胞内蛋白质的主要酶系统。蛋白酶体涉及机体的多种生理功能和许多疾病的发病机制,近年来已成为基础和临床研究的热点之一。在此对蛋白酶体的结构、功能及其抑制剂的研究进展进行综述。     

The therapeutic potential of microbial proteasome inhibitors

The proteasome influences cellular homeostasis through the degradation of regulatory proteins, many of which are also involved in disease pathogenesis. In particular, numerous regulatory proteins associated with tumor growth, such as cyclins, cyclin-dependent kinase inhibitors, tumor suppressors, and NF-κB inhibitors are degraded by the proteasome. Proteasome inhibitors can stabilize these regulatory proteins, resulting in the suppression of tumor development and the regulation of immune responses. Thus, proteasome inhibitors are promising candidate antitumor agents and immune-regulatory agents. Bortezomib is the first-in-class proteasome inhibitor approved for the treatment of multiple myeloma. Despite its high efficiency, however, a large proportion of patients do not attain sufficient clinical response due to toxicity and drug resistance. Therefore, the development of new proteasome inhibitors with improved pharmacological properties is needed. Natural products produced by microorganisms are a promising source of such compounds. This review provides an overview of proteasome inhibitors produced by microorganisms, with special focus on inhibitors isolated from actinomycetes.     

蛋白酶体抑制剂的抗肿瘤作用及其临床应用

泛素．蛋白酶体通路介导细胞蛋白质的降解，在细胞周期、基因转录及表达、抗厚提呈和炎症演进等方面发挥调控作用。蛋白质酶体抑制剂可抑制肿瘤细胞的生长和增殖，诱导凋亡，逆转肿揎细胞的多药耐药性，增加其他化疗药物和放疗的敏感性，具有良好的抗肿瘤作用，是一个极有前是的抗肿瘤药物。现综述其作用机制、分类、抗肿瘤作用及临床应用进展。     

Entry into a new class of potent proteasome inhibitors having high antiproliferative activity by structure-based design

Proteasome inhibition is a therapeutic concept of current interest in anticancer research. We report here the design, synthesis, and biological characterization of prototypes of a new class of noncovalent proteasome inhibitors showing high activity in biochemical and cellular assays.     

Leaving groups prolong the duration of 20S proteasome inhibition and enhance the potency of salinosporamides

Salinosporamide A ( 1 (NPI-0052)) is a potent, monochlorinated 20S proteasome inhibitor in clinical trials for the treatment of cancer. To elucidate the role of the chlorine leaving group (LG), we synthesized analogues with a range of LG potentials and determined their IC 50 values for inhibition of chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-like (C-L) activities of 20S proteasomes. Proteasome activity was also determined before and after attempted removal of the inhibitors by dialysis. Analogues bearing substituents with good LG potential exhibited the greatest potency and prolonged duration of proteasome inhibition, with no recovery after 24 h of dialysis. In contrast, activity was restored after 相似文献   

Proteasome inhibition and multiple myeloma

A greater understanding of the biology of myeloma has focused research on the identification of novel target-based treatment strategies. Proteasome inhibition represents one such approach and the introduction of bortezomib, the first-in-class proteasome inhibitor, has been a major breakthrough in the treatment of multiple myeloma. As a result of its novel mechanism of action, bortezomib has been shown to induce responses in patients previously refractory to treatment, and results in increased progression-free and overall survival rates. The current understanding of the biology of the proteasome and the mechanism by which proteasome inhibition leads to myeloma cell death is described in this review. The role of proteasome inhibitors in the management of myeloma is also discussed.