100751-63-1Relevant articles and documents
Exploring the Effect of Aliphatic Substituents on Aryl Cyano Amides on Enhancement of Fluorescence upon Binding to Amyloid-β Aggregates
Ehrlich, Rachel S.,Shiao, Alexander L.,Li, Meihan,Teppang, Kristine L.,Jeoung, Kun Yong,Theodorakis, Emmanuel A.,Yang, Jerry
, p. 2946 - 2952 (2021)
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.
A dicyanoisophorone-based, near-infrared, lysosome-targeting pH sensor with an extremely large Stokes shift
Cai, Chunhui,Shen, Wei,Wang, Lei,Yi, Wenjun,Yu, Shian,Zhu, Qing,Zhu, Shen
, (2020)
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.
Aminonaphthalene 2-cyanoacrylate (ANCA) probes fluorescently discriminate between amyloid-β and prion plaques in brain
Cao, Kevin,Dakanali, Marianna,Chang, Willy M.,Theodorakis, Emmanuel A.,Yang, Jerry,Farahi, Mona,Sigurdson, Christina J.
, p. 17338 - 17341,4 (2012)
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.
Comprehensive structure-activity-relationship of azaindoles as highly potent FLT3 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
, p. 692 - 699 (2019)
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.
Photoactuators based on the dynamic molecular crystals of naphthalene acrylic acids driven by stereospecific [2+2] cycloaddition reactions
Liu, Jiaxi,Ye, Kaiqi,Shen, Yanbing,Peng, Jiang,Sun, Jingbo,Lu, Ran
, p. 3165 - 3175 (2020)
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.
METHODS OF DETECTING NEUROLOGICAL DISORDERS VIA BINDING TO PHOSPHORYLATED TAU PROTEIN
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Page/Page column 88, (2021/04/01)
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.
Ruthenium-catalyzed ester reductions applied to pharmaceutical intermediates
Shaalan, Youssef,Boulton, Lee,Jamieson, Craig
supporting information, p. 2745 - 2751 (2020/11/30)
Ruthenium pincer complexes were synthesized and used for catalytic ester reductions under mild conditions (～5 bar of hydrogen). An experimental design approach was used to optimize the conditions for yield, purity, and robustness. Evidence for the catalytically active ruthenium dihydride species is presented. Observed intermediates and side products, as well as time-course data, were used to build mechanistic insight. The optimized procedure was further demonstrated through scaled-up reductions of two pharmaceutically relevant esters, both in batch and continuous flow.
