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Small Molecule-Assisted PET: Approaches to Imaging of Conformational Diseases of the Brain

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World Journal of Neuroscience 2017年第1期7卷 106-139页

作者： Margit Pissarek Institute of Neuroscience and Medicine INM5-Nuclear Chemistry Forschungszentrum Jülich GmbH Jülich Germany

PET (positron emission tomography) in vivo imaging of cerebral conformational diseases is essentially based on non-peptide small molecule ligands used to detect early alterations in peptide secondary structures and subsequent accumulation of aberrant oligomers and protein deposits involved in progressive neurodegeneration, cognitive and movement disorders. In this article, an overview is given about tracers currently available and lead structures of potential PET probes for detection of?β-amyloid (Aβ), tau protein, α-synuclein, constitutive (PrPc) and infectious isoforms (PrPsc) of prions (proteinaceous infectious particles) as imaging targets. Whereas the styrylpyridine derivative florbetapir, approved for clinical applications, the stilbene derivative florbetaben and the benzoxazole derivative BF227 show high affinity binding to Aβ, preclinical investigations promise improved pharmacokinetics for benzoimidazothiazoles, aryloxazoles and benzofuran derivatives. Tau protein imaging based clinically, presently, on the pyridine-pyridoindole T807 has got new incentives following identification of a series of pyrrolopyridine quinolines and pharmacokinetic improvements of fluoropropoxy quinolines including for instance THK-5351. The pyridine isoquinoline MK6240 is involved now in clinical trials. Most forward-looking efforts apply to small molecule ligands of α-synuclein, which are expected to permit a breakthrough in differential diagnostics of Parkinson-related dementia and Lewy body diseases. However, at the moment the proposed lead structures are in affinity and blood brain barrier delivery properties below the possibilities of Aβ?and tau protein ligands. This is the case also for potential tracers of prion proteins.

关键词： Conformational Diseases PET Small Molecule ligands Brain Tau Protein α-Synuclein PrP

Soluble MICB in Plasma and Urine Explains Population Expansions of NKG2D<sup>+</sup>CD4 T Cells Inpatients with Juvenile-Onset Systemic Lupus Erythematosus

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Open Journal of Immunology 2017年第1期7卷 1-17页

作者： Satoru Hamada Andrea Caballero-Benitez Kate L. Duran Anne M. Stevens Thomas Spies Veronika Groh Clinical Research Division Fred Hutch Seattle WA USA Department of Pediatrics Ryukyus University Okinawa Prefecture Nishihara Japan Division of Rheumatology Department of Pediatrics University of Washington Medicine Seattle WA USA Center for Immunity and Immuno Therapies Seattle Children’s Research Institute Seattle WA USA

Abnormal NKG2D ligand expression has been implicated in the initiation and maintenance of various auto-inflammatory disorders including systemic lupus erythematosus (SLE). This study’s goal was to identify the cellular contexts providing NKG2D ligands for stimulation of the immunosuppressive NKG2D+CD4 T cell subset that has been implicated in modulating juvenile-onset SLE disease activity. Although previous observations with NKG2D+CD4 T cells in healthy individuals pointed towards peripheral B cell and myeloid cell compartments as possible sites of enhanced NKG2DL presence, we found no evidence for a disease-associated increase of NKG2DL-positivity among juvenile-onset SLE B cells and monocytes. However, juvenile-onset SLE patient plasma and matched urine samples were positive by ELISA for the soluble form of the NKG2D ligands MICA and MICB, suggesting that kidney and/or peripheral blood may constitute the NKG2DL positive microenvironments driving NKG2D+CD4 T cell population expansions in this disease.

关键词： NKG2D ligands NKG2D+ CD4 T Cells Juvenile-Onset Systemic Lupus Erythematosus B Cells Monocytes

Syntheses, Crystal Structure and Photoluminescence Properties of Piperidinium Tetrakis (1,3-Diphenyl-1,3-Propanedionato) Europate(III) Complex and Its Two Different Crystals

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Crystal Structure Theory and Applications 2017年第4期6卷 57-66页

作者： Tetsuji Moriguchi Naoya Kitou Daisuke Yakeya Akihiko Tsuge Kenji Yoza Venkataprasad Jalli Department of Applied Chemistry Faculty of Engineering Kyushu Institute of Technology Kitakyushu Japan Japan Bruker AXS K.K. Yokohama Japan Sankar Foundation Research and Development Division Visakhapatnam India

Treatment of 1,3-diphenyl-1,3-propanedione 1a with europium (III) chloride in the presence of piperidine results in the halide ligands exchange giving newly piperidinium tetrakis (1,3-diphenyl-1,3-propanedionato)europate(III) complex 2a. The complex was characterized by 1H-NMR, positive FAB-mass, and Elemental Analysis. The exact molecular structure of 2a was determined by single crystal X-ray diffraction with the monoclinic space group Cc (centrosymmetric, No.13). The large cavity sizes of the complex 2a facilitated the inclusion of water and benzene solvate molecules. The other two different crystals 2b, 2c having two water molecules and one benzene moleculewere obtained by the crystallization in different solvents and the exact molecular structures were determined by single crystal X-ray diffraction analysis with space groups P21/n (centrosymmetric, No.14), and P21/n (centrosymmetric, No.14), respectively. The eight coordinate structures of the complexes in the three crystals were slightly different due to the crystal packing and the existence of the solvent molecule(s). The photoluminescence studies indicated that four β-diketone ligands acted as strong antenna ligands and transferred the absorbed energy to europium (III) ion, consequently red luminescence was observed. These strong emissions wereattributed to the 5D0 → 7F2 transition of Europium (III) ions under UV excitation. The photoluminescence spectrum of the three crystals was almost same in solid as well as in solution.

关键词： Tetrakis Europium Complexes Luminescence β-Diketone ligands

Comparative effects of idazoxan, efaroxan, and BU 224 on insulin secretion in the rabbit: Not only interaction with pancreatic imidazoline I2 binding sites

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Health 2010年第2期2卷 112-123页

作者： María José García-Barrado María Francisca Pastor María Carmen Iglesias-Osma Christian Carpéné Julio Moratinos 不详

The nature of the binding site(s) involved in the insulin secretory activity of imidazoline compo- unds remains unclear. An imidazoline I2 binding site (I2BS) has been neglected since the classic I2 ligand, idazoxan, does not release insulin. Using the rabbit as an appropriate model for the study of this type of binding sites, we have tried to re-evaluate the effects of idazoxan, the selective I2 compound BU 224, and efaroxan on insulin secretion. Mimicking efaroxan, idazoxan and BU 224 potentiated insulin release from perifused islets in the presence of 8 mM glucose. In static incubation, insulin secretion induced by idazoxan and BU 224 exhibited both dose and glucose dependencies. ATP-sensitive K+ (KATP) channel blockade, though at a different site from the SUR1 receptor, with subsequent Ca2+ entry, mediates the insulin releasing effect of the three ligands. However, additional MAO independent intracellular steps in stimulus- secretion coupling linked to PKA and PKC activation are only involved in the effect of BU 224. Therefore, both an I2 related binding site at the channel level shared by the three ligands and a putative I3-intracellularly located binding site stimulated by BU 224 would be mediating insulin release by these compounds. In vivo experiments reassess the abilities of idazoxan and BU 224 to enhance glucose-induced insulin secretion and to elicit a modest blood glucose lowering response.

关键词： BU 224 Efaroxan Idazoxan Imidazoline ligands Insulin Secretion IVGTT (Intravenous Glucose Tolerance Test) KATP Channel PK Activity Rabbit Pancreatic Islets

Lack of MICA Expression Predicts a Worse Prognosis in Patients with Bladder Cancer

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Open Journal of Pathology 2013年第1期3卷 41-50页

作者： Mauricio Orozco-Levi Alba Ramírez-Sarmiento Michael Borchers Cristiane Murta-Nascimento Francesc Macià Beatriz Casado Maeba Polo Andrea Caballero-Benitez Fredy Diaz-Quijano Antoni Gelabert American Organization for the Promotion of Health Research (OLFIS) Bucaramanga Colombia Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CibeRes) Instituto de Salud Carlos III Ministerio de Ciencia y Tecnología Spain Consorcio de Investigación Biomédica de Epidemiología y Salud Pública (CIBERESP) Spain Department of Environmental Health University of Cincinnati College of Medicine Cincinnati USA Epidemiology and Health Services Evaluation Department Hospital del Mar-Parc de Salut Mar Barcelona Spain Group of Research in Injury Immune Response and Lung Function (LIF) Hospital del Mar Research Institute (IMIM) Urology Department Group of Research in Solid Tumors Universidad Autónoma de Barcelona Barcelona Spain

Background: Bladder and lung cancer are among the ten most common cancers in both genders. The NKG2D receptor and one of its ligands, MICA, are associated with smoking and susceptibility to both chronic obstructive pulmonary disease and lung cancer. Objective: We hypothesized that NKG2D-MICA system was associated with other smoking-related epithelial cancers such as bladder cancer. Design, Setting, and Participants: 70 cases of primary non-muscle invasive bladder cancer were screened for the MICA expression and CD8+, CD4+ and NK cell infiltration. Most patients (n = 55, 78.6%) were current or former smokers. Measurements: Tissue microarray (TMA) technology was chosen to evaluate MICA and tumor infiltrating lymphocytes in samples with confirmed bladder cancer. Kaplan-Meier curves and univariate Cox analysis was used to assess relapse, all-cancer mortality and specific bladder cancer mortality. Results and Limitations: MICA was expressed in most cancer specimens examined (i.e., 70%). Relapse of bladder cancer was not associated with the status of MICA expression (log rank p = 0.1123). Nevertheless, a significant association existed between high MICA expression and bladder cancer mortality (HR = 0.25;CI95% = 0.06 - 0.97). Tumor infiltrating CD4+ and CD8+ lymphocytes were found in the majority (64%) of samples. Cells expressing the NKG2D receptor were found in only 3% of the samples. There was no linear function between NKG2D+ cells and number or ratio of CD4+ and CD8+ TIL. Conclusions: MICA is expressed in a significant proportion of bladder carcinomas. MICA expression associates with significant survival advantages in the face of both all-cancer and bladder cancer. The NKG2D-MICA system could represent a common mechanism involved in the immunopathology and natural history of bladder neoplasms.

关键词： Bladder Cancer NKG2D ligands MICA Survival Prognosis

Novel Cytocidal Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl) Benzenesulfonates and Benzenesulfonamides with Affinity to the Colchicine-Binding Site: Is the Phenyl 2-Imidazolidinone Moiety a New Haptophore for the Design of New Antimitotics?

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Open Journal of Medicinal Chemistry 2015年第1期5卷 9-22页

作者： Sébastien Fortin Lianhu Wei Lakshmi P. Kotra René C.-Gaudreault Unité des Biotechnologies et de Bioingénierie Centre de Recherche du CHU de Québec H&ocircpital Saint-Fran&ccedilois d’Assise Université Laval Québec Canada Faculté de Pharmacie Université Laval Pavillon Vandry Québec Canada Department of Pharmaceutical Sciences University of Toronto Toronto Canada Center for Molecular Design and Preformulations Toronto General Research Institute University Health Network Toronto Canada Département de Médecine Moléculaire Faculté de Médecine Université Laval Pavillon Vandry Québec Canada

Phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and phenyl 4-(2-oxoimidazolidin- 1-yl)benzenesulfonamides (PIB-SAs) are new, potent combretastatin A-4 (CA-4) analogs designed on the basis of their common phenyl 2-imidazolidone moiety. This phenyl 2-imidazolidone group is a bioisosteric equivalent of the trimethoxyphenyl group also found in colchicine, podophyllotoxin and several other ligands of the colchicine-binding site (C-BS). In this study, we investigate the interactions involved in the binding of PIB-SO and PIB-SA into the C-BS. We describe three distinct pockets (I, II, and III) as key structural elements involved in the interactions between the C-BS and PIB-SOs as well as PIB-SAs. We show that PIB-SOs and PIB-SAs adopt 4 and 3 distinct binding conformations, respectively, within the C-BS. The binding conformations I and IV are common to most PIB-SOs and PIB-SAs exhibiting high affinity for the C-BS and high cytocidal potency. In addition, binding conformation I is the main conformation adopted by PIB-SOs, PIB-SAs, T138067, ABT-751, colchicine and CA-4. We also observe that the sulfonate and the sulfonamide moieties of PIB-SOs and PIB-SAs are bioisosteric equivalents. Interestingly, we further find that a large portion of the phenyl 2-imidazolidinone moiety in these analogs does not bind to pocket I unlike the trimethoxyphenyl moiety found in several antimicrotubule agents such as colchicine, CA-4 and podophyllotoxin, suggesting that the phenyl 2-imidazolidinone group may represent a new haptophoric moiety useful for the design of new C-BS inhibitors mimicking the tropolone and the methoxylated phenolic moieties of colchicine and CA-4, respectively.

关键词： Docking Colchicine-Binding Site ligands Antimicrotubule Agents PIB-SO PIB-SA

Ligand-Conjugated siRNA Delivery Systems Localizes in Hepatocytes and Elicits Robust RNAi-Mediated Gene Silencing

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Ligand-Conjugated siRNA Delivery Systems Localizes in Hepato...

Hexanuclear Complex of Platinum(II) with Cleavage Product of Cystamine Dihydrochloride by β-Mercaptoethylamine

第十届全国化学生物学学术会议

作者： Chao Yang Dongli Liu Zhen Xi State Key Laboratory of Elemento-Organic Chemistry and National Engineering Research Center of Pesticide College of ChemistryNankai University

Synthetic small interfering RNAs（siRNAs） can inhibit expression of disease-causing genes through post-transcriptional gene silencing mediated by the endogenous RNA interference（RNAi） pathway[1]. siRNAs have great therapeutic potential, but efficient delivery to target cells or organs remains a challenge[2]. Covalent conjugation of small molecules to siRNA is an approach that may avoid side effects resulting from the use of lipid nanoparticles（LNPs） or excipient-based delivery systems. Conjugation of siRNA to ligands of cell-surface receptors expressed only on certain cell types or ligands of receptors overexpressed on specific tissues as a result of certain disease conditions is a promising approach for targeted drug delivery[3]. The postsynthetic "click" conjugation strategy could be employed to introduce ligands to the different siRNAs[4]. Upon subcutaneous（SC） administration, these siRNA-ligands conjugates are conveyed into the targeted cells and robustly suppress gene expression of the targeted mRNA in liver.

关键词： RNA interference ligands Targeted delivery systems Gene silencing

来源： cnki会议评论

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Advances in Chemical Engineering and Science 2016年第1期6卷 29-33页

作者： Asmat N. Azizova Dilqam B. Tagiyev Shmid G. Gasimov Khudayar I. Gasanov The Institute of Catalysis and Inorganic Chemistry Named after Acad. M. F. Nagiyev of the National Academy of Sciences Azerbaijan Baku Azerbaijan

Six-nuclear complexes of Platinum(II) with cleavage of a cystamine dihydrochloride by β-mercaptoethylamine with composition [Pt6(H2NCH2CH2S)8]Cl4·5H2O had been syntesized for the first time. Structure of the complex had been installed together with IKS- and XRD analysis. It has been established that each atom of platinum is surrounded by two atoms of sulfur and nitrogen due to bidentate coordination of a ligand. Only two of the six platinum atoms are on the same plane;other four atoms are in the different crossing planes. Four platinum atoms form adurable metal chelate cycles, which collapse over temperature 260℃. The results of IR spectroscopy confirmed with the RS-analysis.

关键词： Mercaptoamine ligands Platinum Six-Nuclear Complexes Synthesis

Aqueous-Phase, Palladium-Catalyzed Suzuki Reactions under Mild Conditions

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Green and Sustainable Chemistry 2013年第4期3卷 1-5页

作者： Yueqin Cai Gonghua Song Zhongyuan Wu Jiawei Zhang School of Chemistry and Molecular Engineering East China University of Science and Technology Shanghai China Shanghai Key Laboratory of Chemical Biology Institute of Pesticides & Pharmaceuticals East China University of Science and Technology Shanghai China

Water-soluble ionic liquid-supported diols have been used as phosphine-free ligands in Suzuki couplings of aryl idides/bromides/chlorides under mild conditions in aqueous solvent. It was found that 2,2-bis((1-hexylimidazolium)-mehyl) propane-1,3-diol hexafluorophosphate (4) in combination with palladium (II) salts gave the most significant catalyst. Suzuki couplings of aryl iodides/bromides occurred efficiently at room temperature in water/acetonitrile. Notably, the reactions of hydrophilic aryl bromides gave high yields in neat water. The catalyst PdCl2-4 was recycled five times in Suzuki couplings in water before catalyst activity began to significantly drop. The average yield of five cycles was >95% per cycle.

关键词： Suzuki Reaction Ionic Liquid-Supported Diols Phosphine-Free ligands