Thermodynamic Parameters for the Association of Fluorinated Benzenesulfonamides with Bovine Carbonic Anhydrase II

This paper describes a calorimetric study of the association of a series of seven fluorinated benzenesulfonamide ligands (C₆H_nF_5?nSO₂NH₂) with bovine carbonic anhydrase II (BCA). Quantitative structure–activity relationships between the free energy, enthalpy, and entropy of binding and pK_a and log P of the ligands allowed the evaluation of the thermodynamic parameters in terms of the two independent effects of fluorination on the ligand: its electrostatic potential and its hydrophobicity. The parameters were partitioned to the three different structural interactions between the ligand and BCA: the Zn^II cofactor–sulfonamide bond (≈65 % of the free energy of binding), the hydrogen bonds between the ligand and BCA (≈10 %), and the contacts between the phenyl ring of the ligand and BCA (≈25 %). Calorimetry revealed that all of the ligands studied bind in a 1:1 stoichiometry with BCA; this result was confirmed by ¹⁹F NMR spectroscopy and X‐ray crystallography (for complexes with human carbonic anhydrase II).     

pH/光热双重响应的纳米递送系统构建及对耐药膀胱癌细胞的联合治疗

以介孔聚多巴胺(MPDA)的制备为出发点,通过搭载化疗药物阿霉素(DOX)和包覆相变材料 1-十四醇(PCM),构建了 pH/光热双重响应的 MPDA-DOX@PCM 纳米递送系统,实现了对耐药膀胱癌细胞(BIU-87/ADR)的光热治疗(PTT)和化疗。结果表明,MPDA-DOX@PCM 尺寸约为 179 nm,DOX的最大搭载率为 22%,光热转换效率高达 49.1%。在 pH=7.4和温度为 25 ℃的条件下,DOX的累积释放率为4.57%;当pH值降为5.5和温度升高到45 ℃时,DOX的累积释放率可提高到60.13%。在808 nm激光辐照下,MPDA-DOX@PCM孵育的BIU-87/ADR细胞存活率降低至9.5%,证明了其优异的PTT/化疗联合治疗性能。     

OJ手性柱分离芳基烷酸类非甾体解热镇痛药的色谱保留特性和拆分机理

使用纤维素类手性柱OJ柱, 分离布洛芬、依托度酸、非诺洛芬钙、酮洛芬、洛索洛芬等5个芳基烷酸类非甾体解热镇痛药对映体, 并通过溶质计量置换保留模型和热力学研究对OJ手性柱手性分离机理进行探讨. 结果表明, OJ手性柱可在正相条件下分离系列芳基烷酸类非甾体解热镇痛药, 对映体的色谱保留和分离度可以通过改变流动相中醇类置换剂和浓度、有机酸性改性剂和浓度、柱温等因素调节.     

抗抑郁药帕罗西汀的合成研究进展

本文综述了抗抑郁药帕罗西汀及其中间体的合成研究进展．     

基于石墨烯独特生物界面效应的功能化载体研究进展

二维石墨烯及其衍生物与生物界面的相互作用,展现出相比于传统维度粒子截然不同的特性,为功能化医药载体的设计开发提供了潜力策略.除了优异的电学、热学、光学等性能外,石墨烯的独特的二维性质,可以引起细胞更强的应激反应,包括与细胞膜发生水平摩擦/竖直嵌入/三明治超级结构、选择性被细胞内吞、胞内限域折叠、引发细胞自噬以及隐形活化效应.基于上述独特界面效应以及理论模拟机制,对石墨烯进行合理设计,可在保障安全性的前提下,满足药物递送、疫苗佐剂、成像传感、光热治疗等需求.本综述结合课题组近10年在(氧化)石墨烯与生物界面效应、微观作用机理及应用开发方面的系统研究工作,同时涵盖了国际最新进展,以期为石墨烯高效、安全体系的设计、构建和应用,提供理论依据和前瞻性预测.     

活性氧响应型抗肿瘤前药研究进展

活性氧(ROS)在机体信号转导和代谢中起着至关重要的作用,而ROS水平的升高与多种病变(癌症和炎症等)息息相关,基于肿瘤组织高水平ROS开发的肿瘤特异杀伤性前药策略,在增强药效和药物选择性方面提供了一种新颖的方法.本综述介绍了目前用于构建抗肿瘤前药的ROS敏感键:芳基硼酸/酯、烷基硫/硒醚、硫缩酮、过氧草酸酯、氨基丙烯酸酯、噻唑烷酮和α-酮酰胺等,并且详叙了基于这些敏感键设计的前药在抗肿瘤方向上的应用,同时探讨了现有ROS响应型前药系统的研究进展和局限性,并对未来的研究方向进行了展望.     

Anticancer Drugs: Recent Strategies to Improve Stability Profile,Pharmacokinetic and Pharmacodynamic Properties

In past decades, anticancer research has led to remarkable results despite many of the approved drugs still being characterized by high systemic toxicity mainly due to the lack of tumor selectivity and present pharmacokinetic drawbacks, including low water solubility, that negatively affect the drug circulation time and bioavailability. The stability studies, performed in mild conditions during their development or under stressing exposure to high temperature, hydrolytic medium or light source, have demonstrated the sensitivity of anticancer drugs to many parameters. For this reason, the formation of degradation products is assessed both in pharmaceutical formulations and in the environment as hospital waste. To date, numerous formulations have been developed for achieving tissue-specific drug targeting and reducing toxic side effects, as well as for improving drug stability. The development of prodrugs represents a promising strategy in targeted cancer therapy for improving the selectivity, efficacy and stability of active compounds. Recent studies show that the incorporation of anticancer drugs into vesicular systems, such as polymeric micelles or cyclodextrins, or the use of nanocarriers containing chemotherapeutics that conjugate to monoclonal antibodies can improve solubility, pharmacokinetics, cellular absorption and stability. In this study, we summarize the latest advances in knowledge regarding the development of effective highly stable anticancer drugs formulated as stable prodrugs or entrapped in nanosystems.     

Crystal Structure of Human CD47 in Complex with Engineered SIRPα.D1(N80A)

Background: Targeting the CD47/SIRPα signaling pathway represents a novel approach to enhance anti-tumor immunity. However, the crystal structure of the CD47/SIRPα has not been fully studied. This study aims to analyze the structure interface of the complex of CD47 and IMM01, a novel recombinant SIRPα-Fc fusion protein. Methods: IMM01-Fab/CD47 complex was crystalized, and diffraction images were collected. The complex structure was determined by molecular replacement using the program PHASER with the CD47-SIRPαv2 structure (PDB code 2JJT) as a search model. The model was manually built using the COOT program and refined using TLS parameters in REFMAC from the CCP4 program suite. Results: Crystallization and structure determination analysis of the interface of IMM01/CD47 structure demonstrated CD47 surface buried by IMM01. Comparison with the literature structure (PDB ID 2JJT) showed that the interactions of IMM01/CD47 structure are the same. All the hydrogen bonds that appear in the literature structure are also present in the IMM01/CD47 structure. These common hydrogen bonds are stable under different crystal packing styles, suggesting that these hydrogen bonds are important for protein binding. In the structure of human CD47 in complex with human SIRPα, except SER66, the amino acids that form hydrogen bonds are all conserved. Furthermore, comparing with the structure of PDB ID 2JJT, the salt bridge interaction from IMM01/CD47 structure are very similar, except the salt bridge bond between LYS53 in IMM01 and GLU106 in CD47, which only occurs between the B and D chains. However, as the side chain conformation of LYS53 in chain A is slightly different, the salt bridge bond is absent between the A and C chains. At this site between chain A and chain C, there are a salt bridge bond between LYS53 (A) and GLU104 (C) and a salt bridge bond between HIS56 (A) and GLU106 (C) instead. According to the sequence alignment results of SIRPα, SIRPβ and SIRPγ in the literature of PDB ID 2JJT, except ASP100, the amino acids that form common salt bridge bonds are all conserved. Conclusion: Our data demonstrated crystal structure of the IMM01/CD47 complex and provides a structural basis for the structural binding interface and future clinical applications.     

Virtual Screening of Alkaloid and Terpenoid Inhibitors of SMT Expressed in Naegleria sp.

The pathogenic form of thermophilic Naegleria sp. i.e., Naegleria fowleri, also known as brain eating amoeba, causes primary amoebic encephalitis (PAM) with a >97% fatality rate. To date, there are no specific drugs identified to treat this disease specifically. The present antimicrobial combinatorial chemotherapy is hard on many patients, especially children. Interestingly, Naegleria fowleri has complex lipid biosynthesis pathways like other protists and also has a strong preference to utilize absorbed host lipids for generating energy. The ergosterol biosynthesis pathway provides a unique drug target opportunity, as some of the key enzymes involved in this pathway are absent in humans. Sterol 24-C Methyltransferase (SMT) is one such enzyme that is not found in humans. To select novel inhibitors for this enzyme, alkaloids and terpenoids inhibitors were screened and tested against two isozymes of SMT identified in N. gruberi (non-pathogenic) as well as its homolog found in yeast, i.e., ERG6. Five natural product derived inhibitors i.e., Cyclopamine, Chelerythrine, Berberine, Tanshinone 2A, and Catharanthine have been identified as potential drug candidates based on multiple criteria including binding affinity, ADME scores, absorption, and, most importantly, its ability to cross the blood brain barrier. This study provides multiple leads for future drug exploration against Naegleria fowleri.