- METHODS OF DETECTING NEUROLOGICAL DISORDERS VIA BINDING TO PHOSPHORYLATED TAU PROTEIN
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Provided herein are methods and compositions for determining whether a patient suffers from a neurological disease or disorder is provided, comprising detecting the presence of a phosphorylated tau protein in a tissue of the patient, wherein the detecting comprises contacting the phosphorylated tau protein with a compound described herein.
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Page/Page column 88; 89
(2021/04/01)
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- Exploring the Effect of Aliphatic Substituents on Aryl Cyano Amides on Enhancement of Fluorescence upon Binding to Amyloid-β Aggregates
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The self-assembly of amyloid-β (Aβ) peptides into amyloid aggregates is a pathological hallmark of Alzheimer's Disease. We previously reported a fluorescent Aryl Cyano Amide (ARCAM) probe that exhibits an increase in fluorescence emission upon binding to Aβ aggregates in solution and in neuronal tissue. Here, we investigate the effect of introducing small aliphatic substituents on the spectroscopic properties of ARCAM both free in solution and when bound to aggregated Aβ. We found that introducing substituents designed to hinder the rotation of bonds between the electron donor and acceptor on these fluorophores can affect the overall brightness of fluorescence emission of the probes in amyloid-free solutions, but the relative fluorescence enhancement of these probes in amyloid-containing solutions is dependent on the location of the substituents on the ARCAM scaffold. We also observed the capability to tune the excitation or emission wavelength of these probes by introducing electron-donating or -withdrawing substituents that putatively affect either the energy required for photoexcitation or the stability of the photoexcited state. These studies reveal new design principles for developing ARCAM-based fluorescent Aβ-binding probes with an enhanced fluorescence signal compared to background and tunable spectroscopic properties, which may lead to improved chemical tools for aiding in the diagnosis of amyloid-associated neurodegenerative diseases.
- Ehrlich, Rachel S.,Shiao, Alexander L.,Li, Meihan,Teppang, Kristine L.,Jeoung, Kun Yong,Theodorakis, Emmanuel A.,Yang, Jerry
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p. 2946 - 2952
(2021/08/06)
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- COMPOSITIONS AND METHODS FOR DETECTION OF TRAUMATIC BRAIN INJURY
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The present disclosure relates generally to compositions and methods for determining whether a patient suffers from a traumatic brain injury (TBI) by detecting the presence of an amyloid beta protein in an eye of the patient. Also provided are compositions and methods for preparing a patient for diagnosis and treatment of traumatic brain injury (TB).
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- Photoactuators based on the dynamic molecular crystals of naphthalene acrylic acids driven by stereospecific [2+2] cycloaddition reactions
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The photomechanical effects of the dynamic molecular crystals of halogen-substituted naphthalene acrylic acids (1FNaAA, 1ClNaAA, 1BrNaAA, 1INaAA and 6BrNaAA) have been investigated. Upon UV irradiation, the needle-like crystal of 1FNaAA curls away from the light source, while the slice-like crystal of 6BrNaAA bends towards the light source. Moreover, the light-induced bending, flipping and bursting are observed for the elongated needle-like crystals of 1FNaAA, and the slice-like crystals of 1ClNaAA and 1BrNaAA show bending, cracking, coiling, rotating and twisting triggered by 365 nm light. It is found that stereospecific [2+2] cycloaddition reactions take place in the crystals to afford one stereoisomer of β-type cyclobutanes, since 1FNaAA, 1ClNaAA, 1BrNaAA and 6BrNaAA pack in a head-to-head mode, which satisfies the Schmidt's topo-photochemical criteria. The strain can be generated and accumulated during the photodimerization, and the release of the strain leads to the photomechanical effects. This provides new clues for the development of photomechanical molecular crystals based on acrylic acids bearing halogen-substituted aromatic units.
- Liu, Jiaxi,Ye, Kaiqi,Shen, Yanbing,Peng, Jiang,Sun, Jingbo,Lu, Ran
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p. 3165 - 3175
(2020/03/19)
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- A dicyanoisophorone-based, near-infrared, lysosome-targeting pH sensor with an extremely large Stokes shift
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Intracellular pH plays an important role in various biological processes; abnormal pH changes in the intracellular compartment leads to the production of free radicals, the disruption of membrane contractility, inappropriate apoptosis, and necrosis, resulting in serious illness. Although fluorescent probes have widely been used to detect pH levels owing to their high sensitivity and specificity, there is still a demand for near-infrared (NIR) fluorescent probes with high Stokes shift. Here, a NIR fluorescent probe, PipDC, comprising N-ethyl piperazine (response unit) and naphthyl dicyanoisophorone (fluorophore), was designed for pH sensing. The probe has an extremely large Stokes shift (290 nm), and its fluorescence intensity at 730 nm sharply increases when the environment changes from basic to acidic owing to the protonation of piperazine, which results in the quenching of the photoinduced electron transfer effect. It exhibited a specific response to acidic microenvironments regardless of other interfering substances. In addition, PipDC operates well in the lysosome environment in living cells and displays an off-on fluorescence response with pH alterations. Together, these results suggest that PipDC is a promising fluorescent probe for intracellular pH sensing.
- Cai, Chunhui,Shen, Wei,Wang, Lei,Yi, Wenjun,Yu, Shian,Zhu, Qing,Zhu, Shen
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- Design, synthesis, and characterization of 6-[(trimethyl)silylethynyl]naphthalene-2-ethene: A new precursor for the preparation of high-refractive-index organic materials
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A new polymerizable naphthalene derivative has been designed, prepared, and characterized by 1H, 13C NMR, and MS. The new monomer synthesis has successfully been accomplished from a cheap commercially available raw material, in only four steps with good yields. The four steps can be easily scaled up for manufacturing purposes. It is anticipated that the new precursor can be very useful in the preparation of valuable materials with high refractive index for numerous opto-electronic applications.
- Hannu-Kuure, Milja,K?rkk?inen, Ari,Legrand, Sacha
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- Method to discriminate amyloids using fluorescent probes
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The aggregation of misfolded proteins into amyloids is a common characteristic of many neurodegenerative and non-neurologic diseases. Fluorescent amyloid-targeting probes that discriminate amyloids based on differences in protein composition can provide rapid information to aid in disease diagnosis. In this chapter, we present protocols for the synthesis and use of ANCA-11 as an environmentally-sensitive amyloid-targeting probe that can fluorescently discriminate between amyloids with different disease origin. We also present a protocol for preparing amyloid samples of synthetic Amyloid-β(1-42), as problems with amyloid preparations can be a large driver of time and cost for research. The methods presented here can be generalized for evaluation of other amyloid-targeting fluorescent probes with different aggregates of amyloidogenic proteins in solution or in tissue.
- Teppang, Kristine L.,Ehrlich, Rachel S.,Yang, Jerry
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- Comprehensive structure-activity-relationship of azaindoles as highly potent FLT3 inhibitors
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Acute myeloid leukemia (AML) is characterized by fast progression and low survival rates, in which Fms-like tyrosine kinase 3 (FLT3) receptor mutations have been identified as a driver mutation in cancer progression in a subgroup of AML patients. Clinical trials have shown emergence of drug resistant mutants, emphasizing the ongoing need for new chemical matter to enable the treatment of this disease. Here, we present the discovery and topological structure-activity relationship (SAR) study of analogs of isoquinolinesulfonamide H-89, a well-known PKA inhibitor, as FLT3 inhibitors. Surprisingly, we found that the SAR was not consistent with the observed binding mode of H-89 in PKA. Matched molecular pair analysis resulted in the identification of highly active sub-nanomolar azaindoles as novel FLT3-inhibitors. Structure based modelling using the FLT3 crystal structure suggested an alternative, flipped binding orientation of the new inhibitors.
- Grimm, Sebastian H.,Gagestein, Berend,Keijzer, Jordi F.,Liu, Nora,Wijdeven, Ruud H.,Lenselink, Eelke B.,Tuin, Adriaan W.,van den Nieuwendijk, Adrianus M.C.H.,van Westen, Gerard J.P.,van Boeckel, Constant A.A.,Overkleeft, Herman S.,Neefjes, Jacques,van der Stelt, Mario
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p. 692 - 699
(2019/01/22)
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- Enantioselective α-Benzylation of Acyclic Esters Using π-Extended Electrophiles
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The first asymmetric cooperative Lewis base/palladium catalyzed benzylic alkylation of acyclic esters is reported. This reaction proceeds via stereodefined C1-ammonium enolate nucleophiles. Critical to its success was the identification of benzylic phosphate electrophiles, which were uniquely reactive. Alkylated products were obtained with very high levels of enantioselectivity, and this method has been applied toward the synthesis of the thrombin inhibitor DX-9065a.
- Schwarz, Kevin J.,Yang, Chao,Fyfe, James W. B.,Snaddon, Thomas N.
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supporting information
p. 12102 - 12105
(2018/09/11)
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- CERAMIDE GALACTOSYLTRANSFERASE INHIBITORS FOR THE TREATMENT OF DISEASE
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Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with the enzyme ceramide galactosyltransferase (CGT), such as, for example, lysosomal storage diseases. Examples of lysosomal storage diseases include, for example, Krabbe disease and Metachromatic Leukodystrophy.
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Paragraph 00249; 00250; 001167; 001169
(2018/07/29)
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- Linear aggregation-induced fluorescent probe, preparation method therefor and application of linear aggregation-induced fluorescent probe
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The invention discloses a linear aggregation-induced fluorescent probe, a preparation method therefor and an application of the linear aggregation-induced fluorescent probe. The fluorescent probe hasa structural general formula as follows: a formula shown in the description, wherein R1 is a formula shown in the description, a formula shown in the description, a formula shown in the description, aformula shown in the description or a formula shown in the description, R2 is H, alkyl, amido-terminated alkyl or hydroxyl-terminated alkyl, Ar1 is a benzene ring or naphthalene ring, Ar2 is a formula shown in the description, a formula shown in the description, a formula shown in the description, a formula shown in the description, a formula shown in the description, a formula shown in the description or a formula shown in the description, and R3 is fluoro-, chloro-, bromo-, iodo-, alkyl, alkoxy, hydroxyl, cyano, nitro, amino, N,N-dialkyl or aromatic ring. By using the fluorescent probe disclosed by the invention, fluorescence imaging and super-resolution imaging are combined, A[beta] deposited clots are more intuitively observed and have higher resolution, thus, specific morphologies ofthe A[beta] clots can be clearly observed, and quantitative detection on fibrin, particularly chicken egg-white lysozyme fibers can be achieved according to fluorescence strength.
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- AMYLOID TARGETING AGENTS AND METHODS OF USING THE SAME
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Provided herein is the design and synthesis of novel molecular rotor fluorophores useful for detection of amyloid or amyloid like proteins. The fluorophores are designed to exhibit enhanced fluorescence emission upon associating with amyloid or amyloid like proteins as compared to unbound compound. Also disclosed herein are methods for treating diseases associated with amyloid or amyloid like proteins.
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Paragraph 0825-0827
(2018/12/04)
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- Design, synthesis and biological evaluation of GPR55 agonists
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GPR55, a G protein-coupled receptor, is an attractive target to alleviate inflammatory and neuropathic pain and treat osteoporosis and cancer. Identifying a potent and selective ligand will aid to further establish the specific physiological roles and pharmacology of the receptor. Towards this goal, a targeted library of 22 compounds was synthesized in a modular fashion to obtain structure-activity relationship information. The general route consisted of coupling a variety of p-aminophenyl sulfonamides to isothiocyanates to form acylthioureas. For the synthesis of a known naphthyl ethyl alcohol motif, route modification led to a shorter and more efficient process. The 22 analogues were analyzed for their ability to serve as agonists at GPR55 and valuable information for both ends of the molecule was ascertained.
- Fakhouri, Lara,Cook, Christopher D.,Al-Huniti, Mohammed H.,Console-Bram, Linda M.,Hurst, Dow P.,Spano, Michael B.S.,Nasrallah, Daniel J.,Caron, Marc G.,Barak, Larry S.,Reggio, Patricia H.,Abood, Mary E.,Croatt, Mitchell P.
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p. 4355 - 4367
(2017/07/22)
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- IN VITRO COMPOSITIONS COMPRISING HUMAN SAMPLE AND AMYLOID TARGETING AGENT
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Provided herein are compositions and methods useful for detection of amyloid related disorders in samples, such as human tissue, cell or body fluid. Use of the compositions and methods herein allows for the rapid, in vitro detection of amyloid accumulation, often before amyloid disorder symptoms are manifest or without introduction of foreign fluorophore molecules into a subject.
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- Liquid crystal compound, a liquid crystal display element and a liquid crystal composition (by machine translation)
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PROBLEM TO BE SOLVED: high stability to light, high point, a lower limit temperature of the crystal phase, low viscosity, appropriate optical anisotropy, large dielectric constant anisotropy, large dielectric constant of the short axis direction, a suitable elastic constant, physical properties such as compatibility with at least one of a liquid crystalline compound satisfiability 1, a liquid crystal composition, the composition of the liquid crystal display element. SOLUTION: compound represented by eq. (1). (R 1 the C1-15 alkyl; ring A 1-ring A 4 is 1,4 - 1,4-phenylene; Z 1-Z 5 cyclometallized ethylxylene or to at least one of the 1-CF 2 O-; X 1 or fluorine-OCF 3; W 1 and W 2 are independent of the specific position, H, F, or chlorine substituted 1,4-phenylene group or naphthalene -2,6-diyl group; each a-d, 0 or 1) selected drawing: no (by machine translation)
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- Diarylethene based fluorescent switchable probes for the detection of amyloid-β pathology in Alzheimer's disease
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Two fluorescent switchable diarylethene derivatives which exhibit high affinity for amyloid-β aggregates with the increase of fluorescence intensity were reported. Moreover, the probes show excellent photochromic and anti-photobleaching properties both in vitro and in vivo. This journal is
- Lv, Guanglei,Cui, Baiping,Lan, Haichuang,Wen, Ying,Sun, Anyang,Yi, Tao
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supporting information
p. 125 - 128
(2015/02/05)
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- Xanthene Salts and Dye Comprising the Same
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The present invention relates to a xanthene salt having excellent solubility and thermal stability and a dye for a color filter having less color change including the same.COPYRIGHT KIPO 2015
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Paragraph 0073-0075; 0077; 0088-0091; 0096-0099
(2021/05/20)
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- Xanthene Derivatives and Dye Comprising the Same
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The present invention relates to xanthene derivatives having a wide light absorbing wavelength range and a dye for a color filter including the same.COPYRIGHT KIPO 2015
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Paragraph 0065-0067; 0069; 0080-0083; 0088-0091
(2021/06/13)
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- AMYLOID TARGETING AGENTS AND METHODS OF USING THE SAME
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Provided herein is the design and synthesis of novel molecular rotor fluorophores useful for detection of amyloid or amyloid like proteins. The fluorophores are designed to exhibit enhanced fluorescence emission upon associating with amyloid or amyloid like proteins as compared to unbound compound. Also disclosed herein are the methods for treating of diseases associated with an amyloid or amyloid like proteins.
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Paragraph 00812; 00813
(2015/11/10)
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- Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase
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Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that incorporate a 7-indolizinylamino or 2-naphthylamino substituent on a pyrimidine or 1,3,5-triazine core. The most potent compounds show below 10 nanomolar activity towards wild-type HIV-1 and variants bearing Tyr181Cys and Lys103Asn/Tyr181Cys resistance mutations. The compounds also feature good aqueous solubility. Crystal structures for two complexes enhance the analysis of the structure-activity data.
- Lee, Won-Gil,Frey, Kathleen M.,Gallardo-Macias, Ricardo,Spasov, Krasimir A.,Chan, Albert H.,Anderson, Karen S.,Jorgensen, William L.
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p. 4824 - 4827
(2015/10/28)
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- Aminonaphthalene 2-cyanoacrylate (ANCA) probes fluorescently discriminate between amyloid-β and prion plaques in brain
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A major challenge for diagnosing and monitoring the progression of amyloid-based diseases is the capability to distinguish between amyloid deposits that are associated with related, but distinctly different, diseases. Here, we demonstrate that aminonaphthalenyl 2-cyanoacrylate-based probes can fluorescently discriminate between different types of amyloid deposits in brain. The discriminating capability of these molecular rotors is due to the stabilization of the ground versus excited states of these probes as a function of the polarity of their microenvironment (i.e., within the binding pocket on the amyloid). This property makes it possible, for the first time, to estimate the inherent static relative permittivity (ε0) of the binding pocket of each amyloid within tissue. The capability to selectively follow the deposition of specific amyloids in tissue may provide important information for therapeutic development that is not readily accessible from currently available technology.
- Cao, Kevin,Dakanali, Marianna,Chang, Willy M.,Theodorakis, Emmanuel A.,Yang, Jerry,Farahi, Mona,Sigurdson, Christina J.
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supporting information
p. 17338 - 17341,4
(2012/12/12)
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- Aminonaphthalene 2-cyanoacrylate (ANCA) probes fluorescently discriminate between amyloid-β and prion plaques in brain
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A major challenge for diagnosing and monitoring the progression of amyloid-based diseases is the capability to distinguish between amyloid deposits that are associated with related, but distinctly different, diseases. Here, we demonstrate that aminonaphthalenyl 2-cyanoacrylate-based probes can fluorescently discriminate between different types of amyloid deposits in brain. The discriminating capability of these molecular rotors is due to the stabilization of the ground versus excited states of these probes as a function of the polarity of their microenvironment (i.e., within the binding pocket on the amyloid). This property makes it possible, for the first time, to estimate the inherent static relative permittivity (ε0) of the binding pocket of each amyloid within tissue. The capability to selectively follow the deposition of specific amyloids in tissue may provide important information for therapeutic development that is not readily accessible from currently available technology.
- Cao, Kevin,Farahi, Mona,Dakanali, Marianna,Chang, Willy M.,Sigurdson, Christina J.,Theodorakis, Emmanuel A.,Yang, Jerry
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supporting information
p. 17338 - 17341
(2013/01/15)
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- AMYLOID BINDING AGENTS
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There are provided compounds and methods for the detection of amyloids and treatment of diseases related to amyloids including Alzheimer?s disease and other related amyloid-based neurodegenerative diseases
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Page/Page column 44-46
(2011/06/26)
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- Lipopeptide Compounds and Their Use
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The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain lipopeptide compounds comprising a cyclic peptide bearing a lipid side chain (for convenience, collectively referred to herein as “LP compounds”), which, inter alia, are antimicrobial, particularly antibacterial. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to provide an antimicrobial function, particularly an antibacterial function, and in the treatment of diseases and conditions that are mediated by microbes, particularly bacteria, that are ameliorated by the antimicrobial function, particularly an antibacterial function, including bacterial diseases, optionally in combination with another agent, for example, another antibacterial agent.
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- SUBSTITUTED THIOPHENECARBOXAMIDES AS IKK-BETA SERINE-, THREONINE-PROTEIN KINASE INHIBITORS
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Compounds of formula (IA) or (IB) are IKK inhibitors useful in the treatment of autoimmune and inflammatory diseases: wherein R7 is hydrogen or optionally substituted (C1-C6)alkyl; A is an optionally substituted aryl or heteroaryl of 5-13 ring atoms; Z is a radical of formula R1C( R2)(R3)NH-Y-L1-X1-(CH2)z- wherein R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular esterase enzymes to a carboxylic acid group; and R2 and R3 independently represent the side chain of a natural or non-natural alpha amino acid but neither of R2 and R3 is hydrogen, or R2 and R3 taken together with the carbon atom to which they are attached form a C3-C7 cycloalkyl ring, and z, Y, L1 and X1 are as defined in the claims.
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- Synthesis of mono- and bibrachial naphthalene-based macrocycles with pyrene or ferrocene units for anion detection
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Three bibrachial cyclobisintercaland-type macrocycles with a 2,6-naphthylene scaffold and pyrene, ferrocene, or primary amino groups in side chains were synthesized by a [2+2]-cyclocondensation of functionalized diethylenetriamine derivatives with naphthalene-2,6-dialdehyde, whereas their monobrachial counterparts were prepared by a [1+1]-cyclocondensation of polyamines with a corresponding dialdehyde building block. The pyrene-functionalized macrocycles are able to bind orthophthalate and terephthalate anions in aqueous medium, as monitored by the changes in their fluorescence (excimer or monomer) properties.
- Granzhan, Anton,Teulade-Fichou, Marie-Paule
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experimental part
p. 1349 - 1360
(2009/04/18)
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- ASYMMETRIC STYRYL DERIVATIVES AND ORGANIC LIGHT EMITTING DIODE PREPARED USING THE SAME
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Disclosed are asymmetric styryl derivatives and an organic light emitting diode prepared using the same. More particularly, there are provided asymmetric styryl derivatives that can provide a blue organic light emitting diode with superior thermal stability, as well as improved luminous efficiency, improved brightness, and extended lifetime, by synthesizing a novel thermally stable compound with a styryl structure represented by Formula 1, and using the compound as a dopant in an organic light emitting layer (EML) of a multilayered organic light emitting diode, and an organic light emitting diode prepared by the same.
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Page/Page column 12
(2008/12/07)
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- Heterocyclic derivatives for the treatment of cancer and other proliferative diseases
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The invention relates to certain heterocyclic compounds useful for the treatment of cancer and other diseases, having the Formula (I): wherein: (a) m is an integer 0 or 1; (b) R12 is an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a heterocyclic, a substituted heterocyclic, a heteroaryl, a substituted heteroaryl, an aryl or a substituted aryl residue; (c) Ar3 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (d) Ar4 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (e) R5 is hydrogen, hydroxy, alkyl or substituted alkyl; (f) - - - - - represents a bond present or absent; and (g) W, X, Y and Z are independently or together C(O)—, C(S), S, O, or NH; or a pharmaceutically acceptable salt thereof.
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- Synthesis and antifungal activities of R-102557 and related dioxane- triazole derivatives
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Novel triazole compounds with a dioxane ring were synthesized. Condensation of the diol precursor 10 with various aromatic aldehydes 11 - 13 under acidic conditions afforded a series of dioxane-triazole compounds 14 - 16. The antifungal activities of the compounds 14 - 16 were evaluated in vivo in mice infection models against Candida and Aspergillus species. High activities were seen for the derivatives with one or two double bond(s) and an aromatic ring substituted with an electron-withdrawing group in the side chain. Among the derivatives, R-102557 (16R: Ar=4-(2,2,3,3- tetrafluoropropoxy)phenyl) showed excellent in vivo activities against Candida, Aspergillus and Cryptococcus species. It also showed high tolerance in a preliminary toxicity study in rats.
- Oida, Sadao,Tajima, Yawara,Konosu, Toshiyuki,Nakamura, Yoshie,Somada, Atsushi,Tanaka, Teruo,Habuki, Shinobu,Harasaki, Tamako,Kamai, Yasuki,Fukuoka, Takashi,Ohya, Satoshi,Yasuda, Hiroshi
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p. 694 - 707
(2007/10/03)
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- ALPHA-MERCAPTOACRYLIC ACID DERIVATIVES HAVING CALPAIN INHIBITORY ACTIVITY
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The invention covers a novel series of α-mercaptoacrylic acid derivatives that inhibit both calpain I and calpain II with a high affinity and selectivity. The compounds are useful in the treatment of neurodegenerative disorders including cerebrovascular disorders, brain injury, spinal cord, and peripheral nerve injury, cardiac infarction, cataracts, inflammation, restenosis, muscular dystrophy, and platelet aggregation. Pharmaceutical compositions, methods of using processes for preparing and novel intermediates useful in the processes are also disclosed.
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