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1.
新生物碱10-羟基脱氧喜树碱   总被引:4,自引:0,他引:4  
本文报道从羟基喜树碱的母液中分离剂, 新生物碱10-羟基脱氧喜树碱(1), 从园二色谱分析, 在天存在的A环氧取代喜树碱类化合物20-C具有和喜树碱一样的S构型, 而天然存在的脱氧喜树碱类化合物20C具有R构型, 即与喜树碱相反的绝对构型.  相似文献   

2.
喜树碱在弱碱性生理介质中主要以无生物活性的开环羧酸盐形式存在,肿瘤微环境具有弱酸性,而超分子有机框架可以富集和输送负离子药物至肿瘤微环境和肿瘤细胞内.为评估通过超分子有机框架富集和输送喜树碱类开环羧酸盐到肿瘤微环境及肿瘤细胞内,利用肿瘤弱酸性微环境驱动其内酯化,从而发展羧酸盐为前药的可能性,利用透析实验研究了两个超分子有机框架对喜树碱,SN-38和10-羟基喜树碱开环羧酸盐负离子的吸收和保留效应,利用吸收光谱研究了三个羧酸盐在弱酸性生理盐水介质中内酯化形成活性喜树碱分子的动力学.结果表明超分子有机框架对三个羧酸盐均具有显著的保留效应,在pH为6.5的弱酸性介质中,羧酸盐转化为相应内酯的(表观)半衰期分别为120, 22和31 h,远短于临床应用的喜树碱类药物伊立替康和拓扑替康重复用药间隔时间(14和21 d),为后续研究提供了依据.  相似文献   

3.
树脂吸附层析法分离喜树果中的喜果甙   总被引:3,自引:0,他引:3  
自 1 96 6年 Wall等 [1] 首次从喜树植物中分离出喜树碱后 ,至今已有 2 0多种化学成分从中分离出来 ,包括喜树碱 (Camptothecine,CPT)、 1 0 -羟基喜树碱、 1 1 -羟基喜树碱、 1 0 -甲氧基喜树碱、喜树次碱、白桦脂酸及喜果甙 (Vincoside- lactam,VCS- LT)等 [2 ] .研究表明 ,喜树碱类化合物和喜果甙均具有抗癌活性 [3~ 5] .从喜树果中分离喜果甙对充分利用我国丰富的喜树资源具有重要意义 .目前文献报道的分离提取喜果甙方法主要是溶剂萃取和氧化铝柱层析法 [6] ,过程复杂 ,收率很低 .本文采用树脂吸附法对喜果甙进行分离纯化 ,再经…  相似文献   

4.
采用比较分子相似性指数分析方法(CoMSIA)及比较分子场分析方法(CoMSIA)研究了两组CRH拮抗剂结构与活性的关系。在两种方法中,都考虑了静电场、立体场以及氢键场对构效关系的影响,结果表明采用CoMSIA得到构效关系模型要明显优于采用CoMFA得到的构效关系模型,在CoMSIA计算中,当引入疏水场时,三维构效关系模型能得到明显的改善,通过这个三维构效关系模型,可以较为精确地预测化合物的活性。通过分析分子场等值面图在空间的分布,可以观察到叠合分子周围的立体、静电以及疏水特征对化合物活性的影响。  相似文献   

5.
为了能更深入地认识含氟新化合物作为农药的生物活性和其结构间的关系,建立有意义的药物-受体作用模型,寻找同类化合物的药效团,对合成的含氟化合物在经典QSAR方法研究的基础上,又进一步运用DISCO,CoMFA和Leapfrog方法研究了它们的三维构效关系.首先根据化学结构,将分子进行了分类,然后再分别进行CoMFA计算,根据第I类分子的CoMFA结果,我们进行了含氯化合物的全新设计.根据各类中较好的构效关系模型,我们进行了分子的改造,预测了它们的活性.  相似文献   

6.
邓萍  蒋君好 《化学教育》2020,41(2):81-84
基于Discovery Studio软件高质量的分子三维结构可视化功能和分子对接模拟模块,设计了卡托普利与血管紧张素转化酶的分子对接实验,让学生通过分子对接模拟过程,掌握药物分子结构特征,理解构效关系特征,认识酶抑制剂和靶蛋白的作用机制,了解药物研究新手段。  相似文献   

7.
Combretastatins类微管蛋白抑制剂的定量构效关系与结合模式   总被引:1,自引:0,他引:1  
以Combretastatins的B环改造化合物为研究对象, 采用遗传函数分析方法进行了二维定量构效关系研究. 研究结果表明, Apol, PMI-mag, Dipole-mag, Hbond donor和RadOfGyration等描述符对该系列抑制剂活性的贡献最大. 采用比较分子场分析方法(CoMFA)和比较分子相似因子分析方法(CoMSIA)进行了三维定量构效关系研究, 建立的CoMFA和CoMSIA模型的交叉验证相关系数q2分别为0.630和0.634, 具有较强的预测能力. 利用CoMFA和CoMSIA模型的三维等势图解析了Combretastatins类化合物的构效关系, 阐明了B环上各取代基对抑制微管蛋白聚合活性的影响, 同时应用分子对接方法分析并验证了定量构效关系模型.  相似文献   

8.
喜树碱及其类似物结构修饰与构效关系研究进展   总被引:7,自引:2,他引:5  
本文对喜树碱“嵌入式”和“药物堆积”两种主要的药物作用模式,结构A、B、C、D、E环上优势位置及活性基团的取代和结构修饰,以及构效之间的关系进行综述,并提出今后结构修饰、定量构效关系及喜树碱的传输途径等研究方向。  相似文献   

9.
本研究通过分子模拟方法探究杜仲叶中安神活性成分。在TCMSP数据库中检索杜仲叶的化学成分,以“insomnia”和“anxiety”为关键词在GeneCards数据库中检索安神作用相关靶点。将检索得到的化学成分和靶点蛋白通过Schr?dinger软件进行分子对接,根据对接分数进行筛选,对筛选得到的配体-蛋白复合物进行结合自由能计算。与阳性对照组相比化合物儿茶素、桃叶珊瑚苷和槲皮素与靶点蛋白SLC6A4、SCNA、DRD2和HTR2A能够形成稳定的复合物体系。化合物儿茶素、桃叶珊瑚苷和槲皮素可能为杜仲叶中安神作用的活性成分。  相似文献   

10.
针对拓扑异构酶Ⅰ抑制剂高喜树碱类化合物,采用比较分子力场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)的方法对其进行三维定量构效关系的研究.构建CoMFA模型其q2=0.706,最佳主成分数n=6,非交叉验证系数r2=0.966,标准差S=0.277,F=117.613,立体场和静电场的贡献值分别为0.62和0.38.构建CoMSIA模型其q2=0.696,最佳主成分数n=7,非交叉验证系数r2=0.956,标准差S=0.320,F=74.374,其疏水场和立体场的贡献分别为0.75和0.25.结果显示疏水场和立体场对化合物的活性有较大影响.  相似文献   

11.
A series of novel phosphoramide mustard sophoridinic acid analogues, consisting of nitrogen mustard group and sophoridinic acid scaffold, have been designed, synthesized and evaluated for their topoisomerase inhibitory activity as well as cytotoxicity against six tumor cell lines (SMMC‐7721, LoVo, MCF‐7, K562, S180 and H22) and a normal cell line (L929). Among the compounds tested, five were found to be potent inhibitors and exhibited potent cytotoxicity against S180 and H22 cell lines with IC50 values of 1–4 μM. Further mechanistic studies showed that this class of compounds acted as novel topoisomerase I (Topo I) catalytic inhibitors by preventing the binding of Topo I to DNA and inhibiting the cleavage of DNA, and molecular docking studies revealed that the binding energy for these compounds was comparable to that for classic Topo I inhibitors CPT and HCPT, indicating that the compounds have an interaction with DNA and Topo I.  相似文献   

12.
In this paper, we present a strategy for screening drugs that bind to proteins by combining centrifugal filtration with desorption electrospray ionization mass spectrometry (DESI-MS). Membrane filtration was used to remove any unbound drugs. Then, drug–protein complexes deposited on the DESI substrate were dissociated during the DESI-MS analytical process, and the liberated drugs were measured. To validate the methodology, the screening of a series of drugs against two types of proteins was performed. Three DNA topoisomerase I (Topo I) inhibitors (camptothecin (CPT), hydroxycamptothecin (OHCPT) and 7-ethyl-10-hydroxycamptothecin (SN-38)) were screened against Topo I and the DNA-Topo I complex using DESI-MS. The results indicated that none of the inhibitors bound to Topo I, because the inhibitors had binding affinities only to the DNA-Topo I complex. Among the three drugs that bound to the DNA-Topo I complex, SN-38 had the strongest relative binding affinity, and CPT had the weakest relative binding affinity. The impact of the DESI spray solvent composition on the analysis of drug–protein complex binding was evaluated. Seven alkaloid drugs were also screened against Topo I using DESI-MS. Berberine and palmatine had good binding affinities. A screening of 21 types of drugs was carried out to determine whether the drugs bound to human serum albumin (HSA). The DESI-MS screening process could be achieved within 1.75 min. The study provides a method to qualitatively detect compounds that bind to proteins, showing great potential in drug design and screening.  相似文献   

13.
Camptothecin (CPT) is a natural topoisomerase I inhibitor with powerful antineoplastic activity against colorectal, breast, lung and ovarian cancers. To discover more potent antitumor agents, a series of new CPT derivatives were synthesized utilizing click chemistry. All compounds were assessed for cytotoxicity against A549, HCT‐116, HT‐29, LoVo, MDA‐MB‐231 cell lines, and some compounds exhibited good in vitro potency. Furthermore, all compounds kept or enhanced Topo I inhibition.  相似文献   

14.
A set of novel trans-tiliroside derivatives were synthesized. The structures of the derivatives were identified by their IR, 1H-NMR, and MS spectra analysis. Their anti-diabetic activities were evaluated on the insulin resistant (IR) HepG2 cell model. As a result, compounds 7a, 7c, 7h, and trans-tiliroside exhibited significant glucose consumption-enhancing effects in IR-HepG2 cells compared with the positive control (metformin). This research provides useful clues for further design and discovery of anti-diabetic agents.  相似文献   

15.
Visceral leishmaniasis, most lethal form of Leishmaniasis, is caused by Leishmania infantum in the Old world. Current therapeutics for the disease is associated with a risk of high toxicity and development of drug resistant strains. Thiol‐redox metabolism involving trypanothione and trypanothione reductase, key for survival of Leishmania, is a validated target for rational drug design. Recently published structure of trypanothione reductase (TryR) from L. infantum, in oxidized and reduced form along with Sb(III), provides vital clues on active site of the enzyme. In continuation with our attempts to identify potent inhibitors of TryR, we have modeled binding modes of selected tricyclic compounds and quinone derivatives, using AutoDock4. Here, we report a unique binding mode for quinone derivatives and 9‐aminoacridine derivatives, at the FAD binding domain. A conserved hydrogen bonding pattern was observed in all these compounds with residues Thr335, Lys60, His461. With the fact that these residues aid in the orientation of FAD towards the active site forming the core of the FAD binding domain, designing selective and potent compounds that could replace FAD in vivo during the synthesis of Trypanothione reductase can be deployed as an effective strategy in designing new drugs towards Leishmaniasis. We also report the binding of Phenothiazine and 9‐aminoacridine derivatives at the Z site of the protein. The biological significance and possible mode of inhibition by quinone derivatives, which binds to FAD binding domain, along with other compounds are discussed. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010  相似文献   

16.
Bcl-2蛋白是目前抗肿瘤药物研究很具前景的新靶点. Bcl-2蛋白与底物作用的活性腔生理情况下是蛋白与蛋白作用接触面大而平坦, 与底物结合时发生明显的诱导契合. 通过分析和比较Bcl-2蛋白和其高同源的Bcl-xL蛋白的自由状态及与底物复合时的9个相关三维结构模型, 明确了蛋白及活性腔的骨架结构特征, 活性腔内的重要位点和关键残基, 及它们结合底物时发生的诱导契合. 基于以上认识, 采用柔性对接的方法得到了高亲和力的小分子抑制剂与Bcl-2蛋白的合理结合模式, 为以后设计合成新型高效Bcl-2蛋白抑制剂打下了坚实基础.  相似文献   

17.
A single high‐affinity fatty acid binding site in the important human transport protein serum albumin (HSA) is identified and characterized using an NBD (7‐nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl)‐C12 fatty acid. This ligand exhibits a 1:1 binding stoichiometry in its HSA complex with high site‐specificity. The complex dissociation constant is determined by titration experiments as well as radioactive equilibrium dialysis. Competition experiments with the known HSA‐binding drugs warfarin and ibuprofen confirm the new binding site to be different from Sudlow‐sites I and II. These binding studies are extended to other albumin binders and fatty acid derivatives. Furthermore an X‐ray crystal structure allows locating the binding site in HSA subdomain IIA. The knowledge about this novel HSA site will be important for drug depot development and for understanding drug‐protein interaction, which are important prerequisites for modulation of drug pharmacokinetics.  相似文献   

18.
Several water-soluble derivatives (CPT3, CPT3a-d) of camptothecin (CPT) were synthesized, among which CPT3 bearing an N,N'-dimethyl-1-aminoethylcarbamate side-chain was further conjugated with reductively eliminating structural units of indolequinone, 4-nitrobenzyl alcohol and 4-nitrofuryl alcohol to produce novel prodrugs of camptothecin (CPT4-6). All CPT derivatives were of lower cytotoxicity than their parent compound of CPT. In contrast, CPT4 and CPT6 showed higher hypoxia selectivity of cytotoxicity towards tumor cells than CPT. A mechanism by which a representative prodrug CPT4 is activated in the presence of DT-diaphorase to release CPT was also discussed. The bioreduction activated CPT prodrugs including CPT4 and CPT6 are identified to be promising for application to the hypoxia targeting tumor chemotherapy.  相似文献   

19.
Abstract

Acinetobacter baumannii has emerged as an important pathogen for nosocomial infections having high morbidity and mortality. This pathogen is notorious for antimicrobial resistance to many common antimicrobial agents including fluoroquinolones, which have both intrinsic and acquired resistance mechanisms. Fluoroquinolones targeting the bacterial topoisomerase II (DNA gyrase and Topo IV) show potent broad-spectrum antibacterial activity by the stabilization of the covalent enzyme–DNA complex. However, their efficacy is now being threatened by an increasing prevalence of resistance. Fluoroquinolones cause stepwise mutations in DNA gyrase and Topo IV, having alterations of their binding sites. Furthermore, the water–Mg+2 bridge, which provides enzyme–fluoroquinolone interactions, has a significant role in resistance. In this study, 13 compounds were synthesized as 1,4-benzoxazine derivatives which act as bacterial topoisomerase II inhibitors and their antibacterial activities were determined against multi-drug resistant Acinetobacter strains which have ciprofloxacin (CIP) resistant and GyrA mutation. Afterwards we performed docking studies with Topo IV (pdb:2XKK) of these compounds to comprehend their binding properties in Discovery Studio 3.5. The results of this study show significant conclusions to elucidate the resistance mechanism and lead to the design of new antibacterial agents as bacterial topoisomerase II inhibitors.  相似文献   

20.
Selective topoisomerase II (Topo II) inhibitors have interested to a great extent for the design of new antitumoral compounds in recent years. Comparative molecular similarity indices analysis (CoMSIA) was performed on a series of previously synthesized benzoxazole, benzimidazole, and oxazolo(4,5-b)pyridine derivatives as eukaryotic Topo II inhibitors. A training set of 16 heterocyclic compounds was used to establish the CoMSIA model. They were constructed and geometrically optimized using SYBYL v7.0. The predictive ability of the model was assessed using a test set of 7 compounds. The best model has demonstrated a good fit having r2 value of 0.968 and cross-validated coefficient q2 value as 0.562 including steric and hydrophobic fields. The hydrophobic interactions showed a dominant role for increasing Topo II inhibitor activity and hydrophilic substituent was found more important than hydrophobic one on the 5 or 6 position of benzazole moiety. The model obtained from the present study can be useful for the modification and/or evaluation of the development of new Topo II inhibitors as potential antitumor compounds.  相似文献   

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