Evaluation of Two Novel Hydantoin Derivatives Using Reconstructed Human Skin Model EpiskinTM: Perspectives for Application as Potential Sunscreen Agents

This study aimed to assess two novel 5-arylideneimidazolidine-2,4-dione (hydantoin) derivatives (JH3 and JH10) demonstrating photoprotective activity using the reconstructed human skin model Episkin^TM. The skin permeability, irritation, and phototoxicity of the compounds was evaluated in vitro. Moreover, the in vitro genotoxicity and human metabolism of both compounds was studied. For skin permeation and irritation experiments, the test compounds were incorporated into a formulation. It was shown that JH3 and JH10 display no skin irritation and no phototoxicity. Both compounds did not markedly enhance the frequency of micronuclei in CHO-K1 cells in the micronucleus assay. Preliminary in vitro studies with liver microsomes demonstrated that hydrolysis appears to constitute their important metabolic pathway. Episkin^TM permeability experiments showed that JH3 permeability was lower than or close to currently used UV filters, whereas JH10 had the potential to permeate the skin. Therefore, a restriction of this compound permeability should be obtained by choosing the right vehicle or by optimizing it, which should be addressed in future studies.     

Exploring the N-terminus region: Synthesis,bioactivity and 3D-QSAR of allatostatin analogs as novel insect growth regulators

Two series of peptidomimetic analogs with different substituents on the N-terminus region were designed and synthesized to explore the relationship between the structure and the inhibition activity in vitro. In addition, 3D-QSAR study was performed to highlight the structural requirements of AST analogs.     

靛红类双功能抑制剂: 调控SARS-3CL蛋白酶聚集状态与活性

1-(2-萘甲基)靛红-5-甲酰胺类化合物通过与底物口袋结合来抑制SARS-3CL 蛋白酶的活性, 而SARS-3CL蛋白酶自身的N端8 肽是作用于蛋白二聚界面的抑制剂. 本文设计同时占据SARS-3CL蛋白酶底物口袋和二聚界面的双功能抑制剂, 通过固相多肽合成方法制备由1-(2-萘甲基)靛红-5-甲酸和N端8肽组成的化合物, 得到不同长度连接链的6 个目标产物. 用显色底物方法测定化合物对SARS-3CL蛋白酶的抑制活性,其中化合物3的活性最高, IC₅₀值(半抑制率)为3.8 μmol·L^-1, 连接偶数甘氨酸的活性明显要好于连接奇数甘氨酸的化合物. 用超速离心沉降速率方法研究了化合物3对SARS-3CL蛋白酶聚集状态与活性的调控作用, 其同时具有诱导与抑制二聚的双重能力, 综合调控结果是抑制SARS-3CL蛋白酶的二聚. 这项研究给应用合成的化合物研究酶活性调节机制提供了一个示例.     

Studies of inhibitor binding to the [4Fe-4S] cluster of quinolinate synthase

Stop for NadA! A [4Fe-4S] enzyme, NadA, catalyzes the formation of quinolinic acid in de?novo nicotinamide adenine dinucleotide (NAD) biosynthesis. A structural analogue of an intermediate, 4,5-dithiohydroxyphthalic acid (DTHPA), has an in?vivo NAD biosynthesis inhibiting activity in E. coli. The inhibitory effect can be explained by the coordination of DTHPA thiolate groups to a unique Fe site of the NadA [4Fe-4S] cluster.     

THE STRUCTURE OF PHYCOBILISOMES IN MUTANTS OF Synechococcus sp. STRAIN PCC 7942 DEVOID OF SPECIFIC LINKER POLYPEPTIDES

Abstract— The effect of elimination of the 30, 33 and 9 kDa phycobilisome rod-linker polypeptides on rod length was examined by electron microscopy of phycobilisomes isolated from wild-type Synechococcus sp. strain PCC 7942 and from genetically engineered mutants with lesions in the genes encoding the rod-linker polypeptides. The maximum rod length in the absence of the 33 kDa linker polypeptide was two phycocyanin hexamers, whereas rods with up to five hexamers were found in the mutant strain lacking the 30 kDa linker polypeptide. Elimination of the 9 kDa linker polypeptide did not have a significant effect on rod length. Finally, mutants lacking either the 30 or 33 kDa rod-associated linker polypeptides had an increased number of rods that terminated with a phycocyanin trimer. These observations are discussed with respect to the role of the linker polypeptides in the biosynthesis of the rod substructure.     

Multivalent drug design. Synthesis and in vitro analysis of an array of vancomycin dimers

The design, synthesis, and in vitro microbiological analysis of an array of forty covalently linked vancomycin dimers are reported. This work was undertaken to systematically probe the impact of linkage orientation and linker length on biological activity against susceptible and drug-resistant Gram-positive pathogens. To prepare the array, monomeric vancomycin synthons were linked through four distinct positions of the glycopeptide (C-terminus (C), N-terminus (N), vancosamine residue (V), and resorcinol ring (R)) in 10 unique pairwise combinations. Amphiphilic, peptide-based linkers of four different lengths (11, 19, 27, and 43 total atoms) were employed. Both linkage orientation and linker length were found to affect in vitro antibacterial potency. The V-V series displayed the greatest potency against vancomycin-susceptible organisms and vancomycin-resistant Enterococcus faecalis (VRE) of VanB phenotype, while the C-C, C-V, and V-R series displayed the most promising broad-spectrum activity that included VRE of VanA phenotype. Dimers bearing the shortest linkers were in all cases preferred for activity against VRE. The effects of linkage orientation and linker length on in vitro potency were not uniform; for example, (1) no single compound displayed activity that was superior against all test organisms to that of vancomycin or the other dimers, (2) linker length effects varied with test organism, and (3) whereas one-half of the dimers were more potent than vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA), only one dimer was more potent against methicillin-resistant S. aureus (MRSA) and glycopeptide-intermediate susceptible S. aureus (GISA). In interpreting the results, we have considered the potential roles of multivalency and of other phenomena.     

Design,Synthesis, and Biological Evaluation of HDAC Degraders with CRBN E3 Ligase Ligands

Histone deacetylases (HDACs) play important roles in cell growth, cell differentiation, cell apoptosis, and many other cellular processes. The inhibition of different classes of HDACs has been shown to be closely related to the therapy of cancers and other diseases. In this study, a series of novel CRBN-recruiting HDAC PROTACs were designed and synthesized by linking hydroxamic acid and benzamide with lenalidomide, pomalidomide, and CC-220 through linkers of different lengths and types. One of these PROTACs, denoted 21a, with a new benzyl alcohol linker, exhibited comparably excellent HDAC inhibition activity on different HDAC classes, acceptable degradative activity, and even better in vitro anti-proliferative activities on the MM.1S cell line compared with SAHA. Moreover, we report for the first time the benzyl alcohol linker, which could also offer the potential to be used to develop more types of potent PROTACs for targeting more proteins of interest (POI).     

RO-heparin Inhibits L-Selectin-mediated Neutrophils Adhesion to Vascular Endothelium Under Flow Conditions

Introduction Migrationandrecruitmentofleukocytesfromblood toinflammatorylesionsitesaresequentiallyregulated byadhesionmoleculesandtheirreceptors[1].These lectinfamilyplaysamajorroleininitiatingattachement ofneutrophilstotheactivatedendothelium.P selectin,…     

Further studies on the pharmacological effect of the anti-inflammatory compound, bis[2-(E-2-octenoylamino)ethyl] disulfide

Further studies on the pharmacological effect of orally administered bis[2-(E-2-octenoyl-amino)ethyl] disulfide (compd. I-3) was examined by using several experimental models in vivo. Compound I-3 showed analgesic activity, inhibiting both acetic acid- and acetylcholine-induced writhings in mice. This compound also showed antipyretic activity against yeast-induced fever in rats, and significantly inhibited arachidonic acid-induced mortality in mice. However, it had no effect on serotonin-induced paw edema formation or platelet activating factor-acether-induced mortality in mice. The effects of compd. I-3 are suggested to be due to inhibition of prostaglandin biosynthesis.     

BP-M345, a New Diarylpentanoid with Promising Antimitotic Activity

Previously, we reported the in vitro growth inhibitory effect of diarylpentanoid BP-M345 on human cancer cells. Nevertheless, at that time, the cellular mechanism through which BP-M345 exerts its growth inhibitory effect remained to be explored. In the present work, we report its mechanism of action on cancer cells. The compound exhibits a potent tumor growth inhibitory activity with high selectivity index. Mechanistically, it induces perturbation of the spindles through microtubule instability. As a consequence, treated cells exhibit irreversible defects in chromosome congression during mitosis, which induce a prolonged spindle assembly checkpoint-dependent mitotic arrest, followed by massive apoptosis, as revealed by live cell imaging. Collectively, the results indicate that the diarylpentanoid BP-M345 exerts its antiproliferative activity by inhibiting mitosis through microtubule perturbation and causing cancer cell death, thereby highlighting its potential as antitumor agent.     

Structure of homoplatensimide A: a potential key biosynthetic intermediate of platensimycin isolated from Streptomyces platensis

Platensimycin and platencin are novel natural product antibiotics that inhibit bacterial growth by inhibiting fatty acid biosynthesis enzymes FabF and FabF/FabH, respectively. Continued search for the natural congeners for structure activity relationship studies led to the isolation of a congener which possesses all of the twenty carbons of diterpenoid unit, a potential biosynthetic intermediate of platensic acid unit of platensimycin. Isolation, structure, and activity of homoplatensimide A and biosynthetic relationship to platensimycin have been described.     

Structure-activity studies on a library of potent calix[4]arene-based PDGF antagonists that inhibit PDGF-stimulated PDGFR tyrosine phosphorylation

Platelet-derived growth factor (PDGF) and its receptor PDGFR are required for tumor growth and angiogenesis, so disruption of the PDGF-PDGFR interaction should lead to starvation of tumors and reduction of tumor growth. Potent PDGF antagonists have been discovered through the synthesis of a series of calix[4]arene-based compounds that are designed to bind to the three-loop region of PDGF. The effect of lower-rim alkylation, linker and number of interacting head groups on the calix[4]arene scaffold on PDGF affinity and cellular activity has been investigated.     

Effect of Joule heating on electrokinetic transport

The Joule heating (JH) is a ubiquitous phenomenon in electrokinetic flow due to the presence of electrical potential gradient and electrical current. JH may become pronounced for applications with high electrical potential gradients or with high ionic concentration buffer solutions. In this review, an in-depth look at the effect of JH on electrokinetic processes is provided. Theoretical modeling of EOF and electrophoresis (EP) with the presence of JH is presented and the important findings from the previous studies are examined. A numerical study of a fused-silica capillary PCR reactor powered by JH is also presented to extend the discussion of favorable usage of JH.     

Structure and semisynthesis of platensimide A, produced by Streptomyces platensis

Platensimycin and platencin are novel natural product antibiotics that inhibit bacterial growth by inhibiting condensing enzymes FabF and FabF/FabH of fatty acid biosynthesis pathways, respectively. Continued search for the natural congeners of these compounds led to the isolation of platensic acid, the free C-17 tetracyclic enoic acid, and platensimide A, a 2,4-diaminobutyric acid amide derivative. Isolation, structure, semisynthesis, and activity of these compounds are described.     

Aromatic Nitrogen Mustard‐Based Prodrugs: Activity,Selectivity, and the Mechanism of DNA Cross‐Linking

Three novel H₂O₂‐activated aromatic nitrogen mustard prodrugs ( 6 – 8 ) are reported. These compounds contain a DNA alkylating agent connected to a H₂O₂‐responsive trigger by different electron‐withdrawing linkers so that they are inactive towards DNA but can be triggered by H₂O₂ to release active species. The activity and selectivity of these compounds towards DNA were investigated by measuring DNA interstrand cross‐link (ICL) formation in the presence or absence of H₂O₂. An electron‐withdrawing linker unit, such as a quaternary ammonia salt ( 6 ), a carboxyamide ( 7 ), and a carbonate group ( 8 ), is sufficient to deactivate the aromatic nitrogen mustard resulting in less than 1.5 % cross‐linking formation. However, H₂O₂ can restore the activity of the effectors by converting a withdrawing group to a donating group, therefore increasing the cross‐linking efficiency (>20 %). The stability and reaction sites of the ICL products were determined, which revealed that alkylation induced by 7 and 8 not only occurred at the purine sites but also at the pyrimidine site. For the first time, we isolated and characterized the monomer adducts formed between the canonical nucleosides and the aromatic nitrogen mustard ( 15 ) which supported that nitrogen mustards reacted with dG, dA, and dC. The activation mechanism was studied by NMR spectroscopic analysis. An in vitro cytotoxicity assay demonstrated that compound 7 with a carboxyamide linker dramatically inhibited the growth of various cancer cells with a GI₅₀ of less than 1 μM , whereas compound 6 with a charged linker did not show any obvious toxicity in all cell lines tested. These data indicated that a neutral carboxyamide linker is preferable for developing nitrogen mustard prodrugs. Our results showed that 7 is a potent anticancer prodrug that can serve as a model compound for further development. We believe these novel aromatic nitrogen mustards will inspire further and effective applications.     

苯对Pt/Ga2O3/WO3/ZrO2 和Pd/Al2O3/ WO3/ZrO2催化剂上正己烷异构化反应的影响

研究了苯对Pt/Ga2O3/WO3/ZrO2 (PtGWZ)和Pd/Al2O3/ WO3/ZrO2(PdAWZ)催化剂上正己烷异构化反应的影响。结果表明,苯可影响PtGWZ和PdAWZ上正己烷异构化反应性能,苯含量越高影响越显著。与PdAWZ相比较,苯对PtGWZ上正己烷异构化反应的影响相对较小;苯对PtGWZ上正己烷异构化反应活性的影响是可逆的,撤除苯后PtGWZ对正己烷异构化的催化性能可完全恢复;苯对PtGWZ上正己烷异构化反应的稳定性没有影响。苯对PdAWZ上正己烷异构化反应活性的影响是不可逆的,PdAWZ用于含苯正己烷异构化反应催化剂会逐渐失活。热失重法积炭分析结果表明,相同条件下,含苯正己烷异构化反应后,PtGWZ上的积炭量较PdAWZ上的积炭量少。分析讨论了苯对PtGWZ和PdAWZ上正己烷异构化反应影响差异性的原因。     

硒化壳聚糖抑制人早幼粒白血病细胞增殖的研究

为探讨硒化壳聚糖对体外培养人早幼粒白血病细胞增殖的抑制作用,用SRB法和集落形成法检测了药物对细胞增殖的抑制作用,流式法检测了细胞周期阻断作用。结果表明,25、50、100mg／L硒化壳聚糖作用HL60细胞48h对细胞有增殖抑制作用（P〈0．01）;50、100mg／L硒化壳聚糖作用细胞48h后,G0／G1期细胞数较对照组增加了14．9％-22．0％（P〈0．05）,S期细胞减少了14．3％～20．1％（P〈0．05）。可见硒化壳聚糖对人早幼粒白血病细胞增殖具有抑制作用。     

新型金属卟啉的合成及其对大肠杆菌生长代谢的抑制作用

以5,10,15,20-四（对羟基苯基）卟啉（2）为原料,合成并表征了一系列 水溶性和非水溶性的金属卟啉。使用LKB 2277热活性监测器测定了大肠杆菌在金属 卟啉4a ～ 4f和7a ～ 7f作用下的生热曲线,得到了不同金属卟啉在不同浓度下大 肠杆菌生长代谢的生热速率常数k,最大发热功率p_(max)和最大发热功率的出现时 间t。结果发现,含有吡啶溴化盐的水溶性金属卟啉7a ～ 7f对大肠杆菌生长代谢 的抑制活性要明显大于含有酯基的金属卟啉4a ～ 4f。     

Synthesis and anti-tumour activities of sulphated polysaccharide obtained from Momordica charantia

A native polysaccharide (MCP2) was extracted and isolated from Momordica charantia. Four sulphated derivatives of MCP2 were prepared by chlorosulphonic acid method. The structures of the sulphated derivatives were characterised by FT-IR spectra. Depending on the reaction conditions, the sulphated derivatives showed different degree of substitution (DS) ranging from 0.56 to 1.10, and different weight-average molecular mass (Mw) ranging from 7.2 to 9.3?KDa. It implied the efficient substitution of hydroxyl groups in the polysaccharides by sulphated groups with degradation. The effects of the sulphated derivatives on inhibiting the growth of HepG2 cells and Hela cells in?vitro were compared with taking non-modified MCP2 as control. The sulphated derivatives inhibited the growth of HepG2 cells and Hela cells in?vitro significantly, which indicated that sulphated modification could enhance the anti-tumour activity of MCP2.