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。     

20S蛋白酶体抑制剂吡咯啉酮类似物的设计、合成及活性测试(英文)

本文设计并合成了一系列吡咯啉酮类似物,这些化合物可能作为Michael受体与蛋白酶体活性位点Thr1O~γ不可逆结合,从而抑制蛋白酶体的活性。虽然活性测试结果显示这些化合物对蛋白酶体的抑制活性很弱,但是可以通过吡咯啉酮类化合物进一步的结构优化来提高对蛋白酶体的抑制活性。     

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。     

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。     

新型β-肽环氧酮类蛋白酶体抑制剂的合成与活性评价

目的 设计合成新型的β-肽类蛋白酶体抑制剂,并对其活性进行评价。方法 根据先导化合物Carfilzomib与蛋白酶体的作用方式,保留其与蛋白酶体结合的关键环氧酮片段,并结合β-氨基酸的特点,采用氨基酸替换、生物电子等排等药物设计的方法,设计一类结构新颖的蛋白酶体抑制剂;采用缩合、氧化、还原等反应,合成系列目标化合物;通过体外酶抑制活性实验检验化合物活性。结果 合成了8个结构新颖的β-肽环氧酮类衍生物,化合物结构经1H-NMR、ESI-MS确证,部分化合物体现了一定的蛋白酶体抑制活性。结论 β-氨基酸作为一种重要的α-氨基酸替换结构,有望能够丰富短肽类蛋白酶体抑制剂的结构类型。     

20S蛋白酶体表达与类风湿关节炎的关系探讨

目的 探讨类风湿关节炎（RA）患者20S蛋白酶体表达水平的变化及其与RA疾病活动性的关系.方法 测定RA患者及正常对照外周血单个核细胞20S蛋白酶体蛋白表达水平.结果 与正常对照相比,RA患者20S蛋白酶体表达升高[（2.92±1.41VS（0.65±0.42）,P＜0.01].20S蛋白酶本表达水平与DAS28、CRP、ERS之间无显著相关性.结论 RA患者PBMC中20S蛋白酶体表达升高,其水平与疾病活动无显著相关性.     

针对20S蛋白酶体的抗肿瘤药物研究进展

20S蛋白酶体在生物体内的功能主要是水解蛋白,其与许多疾病如阿尔斯海默症、癌症等有密切的相关性,已经成为抗肿瘤药物研发的新靶点。本文对已经上市的硼替佐米、卡非佐米及正在临床研究阶段的Marizomib的结构及应用特点进行综述。     

肽醛类前药衍生物作为蛋白酶体抑制剂的研究(英文)

为了提高经典的肽醛类蛋白酶体抑制剂的稳定性和生物利用度,我们设计合成了4个肽缩醛和2个肽杂缩醛衍生物,并对其进行了酶水平和体外抗肿瘤实验。结果显示,4个肽缩醛化合物几乎没有显示任何活性,表明此类化合物有用作前药的潜质。而2个肽杂缩醛化合物在酶水平和细胞水平均表现出明显的活性,则表明此类化合物可能不是通过前药的形式而发挥作用,进一步优化杂环的结构,有可能发现更好的蛋白酶体抑制剂。     

环肽类蛋白酶体抑制剂TMC-95的研究进展

环肽类化合物TMC-95是以蛋白酶体为靶点的新型抗肿瘤先导化合物,目前受到越来越多药物化学家的关注.本文通过收集近年来国内外的相关文献对环肽类蛋白酶体抑制剂TMC-95的作用机制、构效关系等方面研究进行综述,为进一步研究此类化合物提供参考.     

Discovery and synthesis of hydronaphthoquinones as novel proteasome inhibitors

Screening efforts led to the identification of PI-8182 (1), an inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome. Compound 1 contains a hydronaphthoquinone pharmacophore with a thioglycolic acid side chain at position 2 and thiophene sulfonamide at position 4. An efficient synthetic route to the hydronaphthoquinone sulfonamide scaffold was developed, and compound 1 was synthesized in-house to confirm the structure and activity (IC(50) = 3.0 ± 1.6 μM [n = 25]). Novel hydronaphthoquinone derivatives of 1 were designed, synthesized, and evaluated as proteasome inhibitors. The structure-activity relationship (SAR) guided synthesis of more than 170 derivatives revealed that the thioglycolic acid side chain is required and the carboxylic acid group of this side chain is critical to the CT-L inhibitory activity of compound 1. Furthermore, replacement of the carboxylic acid with carboxylic acid isosteres such as tetrazole or triazole greatly improves potency. Compounds with a thio-tetrazole or thio-triazole side chain in position 2, where the thiophene was replaced by hydrophobic aryl moieties, were the most active compounds with up to 20-fold greater CT-L inhibition than compound 1 (compounds 15e, 15f, 15h, 15j, IC(50) values around 200 nM, and compound 29, IC(50) = 150 nM). The synthetic iterations described here not only led to improving potency in vitro but also resulted in the identification of compounds that are more active such as 39 (IC(50) = 0.44 to 1.01 μM) than 1 (IC(50) = 3.54 to 7.22 μM) at inhibiting the proteasome CT-L activity in intact breast cancer cells. Treatment with 39 also resulted in the accumulation of ubiquitinated cellular proteins and inhibition of tumor cell proliferation of breast cancer cells. The hit 1 and its analogue 39 inhibited proteasome CT-L activity irreversibly.     

Design, synthesis, and biological evaluation of novel carbohydrate-based sulfamates as carbonic anhydrase inhibitors

Carbonic anhydrases (CAs) IX and XII are enzymes with newly validated potential for the development of personalized, first-in-class cancer chemotherapies. Here we present the design and synthesis of novel carbohydrate-based CA inhibitors, several of which were very efficient inhibitors (K(i)<10 nM) with good selectivity for cancer-associated CA isozymes over off-target CA isozymes. All inhibitors comprised a carbohydrate core with one hydroxyl group derivatized as a sulfamate. Five different carbohydrates were chosen to present a selection of molecular shapes with subtle stereochemical differences to the CA enzymes active site. Variable modifications of the remaining sugar hydroxyl groups were incorporated to provide an incremental coverage of chemical property parameters that are associated with biopharmaceutical performance. All sulfamate inhibitors displayed ligand efficiencies that are consistent with those reported for good drug lead candidates.     

Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants

Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade. To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selective peptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed low nanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and >100-fold thrombin selectivity. The X-ray structure of one of these inhibitors, 36, demonstrates its unique binding interactions with FXIa. Compound 32 caused a doubling of the activated partial thromboplastin time in human plasma at 2.4 microM and was efficacious in a rat model of venous thrombosis. These data suggest that factor XIa plays a significant role in venous thrombosis and may be a suitable target for the development of antithrombotic therapy.     

新型吲哚类胆固醇酯转运蛋白抑制剂的设计、合成及生物活性研究

目的设计并合成一系列以吲哚为母核的新型小分子胆固醇酯转运蛋白(CETP)抑制剂,并初步评价其体外抑制活性。方法以实验室前期获得的化合物Ⅰ为先导化合物,主要对其吲哚母环的2,3,5位进行修饰改造。以吲哚-2-羧酸乙酯衍生物为原料,通过还原、氧化、还原胺化、取代、Suzuki偶联、亲核取代反应制备得到8个目标化合物;以吲哚或吲哚-2-羧酸乙酯为原料,经Vilsmeier反应在3位引入醛基,再经过还原胺化、取代、Suzuki偶联、亲核取代得到7个目标化合物;进一步通过对2位酯基水解或经还原、烷基化得到另外2个目标化合物。采用BODIPY-CE荧光分析法,以anacetrapib为阳性对照药,测试目标化合物体外对CETP的抑制活性。结果与结论合成了17个未见报道的新化合物,结构经~1H-NM R、M S、~(13)C-NM R谱确证;活性测试表明该类化合物具有中等强度的CETP抑制活性,其中化合物10h的活性较先导化合物有接近10倍的提高,为今后该类化合物的结构优化提供了重要指导。     

Design,synthesis, biological evaluation,and molecular docking of novel flavones as H3R inhibitors

A series of novel flavone derivatives were designed, synthesized, and evaluated for their H₃R inhibitory activity. The results showed that four compounds exhibited significant anti‐H₃R activity. Molecular docking experiments indicated that a salt bridge, hydrogen‐bonding, and hydrophobic interactions all contributed to interactions between inhibitors and H₃R.     

新型吲哚胺-2,3-双加氧酶1抑制剂的设计及生物活性研究

目的 吲哚胺2,3-双加氧酶1（Indoleamine-2,3-dioxygenase 1,IDO1）催化色氨酸的氧化裂解,是色氨酸-犬尿氨酸途径中的关键限速步骤。在肿瘤组织中,肿瘤细胞高表达吲哚胺2,3-双加氧酶1,因此设计其小分子抑制剂有望成为有效的肿瘤免疫治疗药物。方法 本研究在前期高通量筛选发现的先导化合物LVS-19的基础上,通过分子对接模型,设计合成新型吲哚胺-2,3-双加氧酶1抑制剂。结果 设计并合成5个衍生物。其中最优化合物6e测得的IC₅₀值为2.61 μmol·L^-1,相较于苗头化合物活性提高约3倍的。结论 本研究能为吲哚胺2,3-双加氧酶1抑制剂的结构修饰与改造提供理论依据。     

Design and synthesis of novel 1,4-benzodiazepine derivatives and their biological evaluation as cholinesterase inhibitors

A new series of 1,4-benzodiazepine-2,5-dione structurally related to cyclopenin has been synthesized. The new compounds were assayed in vivo and in vitro for their ability to inhibit acetylcholinesterase enzyme and were found to have potent reversible anticholinesterase activity when tested in vitro for isolated frog rectus abdominis and guinea pig ileum in addition to increasing brain cholinesterase level in rats when percentage inhibition were tested in vivo, moreover compounds 5a, 5b, 5c and 5g were the most active. LD(50) was performed for these derivatives and they displayed high safety margin.