112766-18-4Relevant articles and documents
Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors
Ksander, Gary M.,Ghai, Raj D.,deJesus, Reynalda,Diefenbacher, Clive G.,Yuan, Andrew,et al.
, p. 1689 - 1700 (1995)
The synthesis of three series of dicarboxylic acid dipeptide neutral endopeptidase 24.11 (NEP) inhibitors is described.In particular, the amino butyramide 21a exhibited potent NEP inhibitory activity (IC50 = 5.0 nM) in vitro and in vivo.Blood levels of 21a were determined using an ex vivo method by measuring plasma inhibitory activity in conscious rats, mongrel dogs, and cynomolgus monkeys.Free drug concentrations were 10-1500 times greater than the inhibitory constant for NEP over the course of a 6 h experiment.A good correlation of free drug concentrations was obtained when comparing values determined by the ex vivo analysis to those calculated from direct HPLC measurements.Plasma atrial natriuretic factor (exogenous) levels were elevated in rats and dogs after oral administration of 19a.Urinary volume and urinary sodium excretion were also potentiated in anesthetized dogs treated with 21a.
Palladium-catalyzed borylation of l-tyrosine triflate derivative with pinacolborane: practical route to 4-borono-l-phenylalanine (l-BPA) derivatives
Iimura, Shinya,Wu, Wenxue
, p. 1353 - 1355 (2010)
Efficient palladium-catalyzed borylation of protected l-tyrosine triflate with pinacolborane was achieved despite previous reports to the contrary. In addition to the use of an inexpensive boron source, the reaction was carried out in the presence of only 0.5 mol % palladium catalyst. Furthermore, the borylation can be performed using pinacolborane prepared in situ from pinacol and borane-diethylaniline complex. This represents a practical entry to 4-borono-l-phenylalanine (l-BPA) derivatives.
Synthesis of Isotopically Labeled, Spin-Isolated Tyrosine and Phenylalanine for Protein NMR Applications
Cui, Yixin,Das, Jitendra,Kalodimos, Charalampos G.,Rankovic, Zoran,Rossi, Paolo,Slavish, P. Jake,Sowaileh, Munia,Young, Brandon M.
, p. 6288 - 6292 (2021)
Isotopically labeled amino acids are widely used to study the structure and dynamics of proteins by NMR. Herein we describe a facile, gram-scale synthesis of compounds 1b and 2b under standard laboratory conditions from the common intermediate 7. 2b is ob
Efficient synthesis and in vivo incorporation of acridon-2-ylalanine, a fluorescent amino acid for lifetime and Foerster resonance energy transfer/luminescence resonance energy transfer studies
Speight, Lee C.,Muthusamy, Anand K.,Goldberg, Jacob M.,Warner, John B.,Wissner, Rebecca F.,Willi, Taylor S.,Woodman, Bradley F.,Mehl, Ryan A.,Petersson, E. James
, p. 18806 - 18814 (2013)
The amino acid acridon-2-ylalanine (Acd) can be a valuable probe of protein conformational change because it is a long lifetime, visible wavelength fluorophore that is small enough to be incorporated during ribosomal biosynthesis. Incorporation of Acd into proteins expressed in Escherichia coli requires efficient chemical synthesis to produce large quantities of the amino acid and the generation of a mutant aminoacyl tRNA synthetase that can selectively charge the amino acid onto a tRNA. Here, we report the synthesis of Acd in 87% yield over five steps from Tyr and the identification of an Acd synthetase by screening candidate enzymes previously evolved from Methanococcus janaschii Tyr synthetase for unnatural amino acid incorporation. Furthermore, we characterize the photophysical properties of Acd, including quenching interactions with select natural amino acids and Foerster resonance energy transfer (FRET) interactions with common fluorophores such as methoxycoumarin (Mcm). Finally, we demonstrate the value of incorporation of Acd into proteins, using changes in Acd fluorescence lifetimes, Mcm/Acd FRET, or energy transfer to Eu3+ to monitor protein folding and binding interactions.
Discovery of acyl guanidine tryptophan hydroxylase-1 inhibitors
Goldberg, Daniel R.,De Lombaert, Stéphane,Aiello, Robert,Bourassa, Patricia,Barucci, Nicole,Zhang, Qing,Paralkar, Vishwas,Stein, Adam J.,Valentine, Jim,Zavadoski, William
, p. 2855 - 2860 (2016)
An increasing number of diseases have been linked to a dysfunctional peripheral serotonin system. Given that tryptophan hydroxylase 1 (TPH1) is the rate limiting enzyme in the biosynthesis off serotonin, it represents an attractive target to regulate peripheral serotonin. Following up to our first disclosure, we report a new chemotype of TPH1 inhibitors where-by the more common central planar heterocycle has been replaced with an open-chain, acyl guanidine surrogate. Through our work, we found that compounds of this nature provide highly potent TPH1 inhibitors with favorable physicochemical properties that were effective in reducing murine intestinal 5-HT in vivo. Furthermore, we obtained a high resolution (1.90 ?) X-ray structure crystal structure of one of these inhibitors (compound 51) that elucidated the active conformation along with revealing a dimeric form of TPH1 for the first time.
Site-Specific Incorporation of a Photoactivatable Fluorescent Amino Acid
Tang, Juan,Yu, Chenfei,Loredo, Axel,Chen, Yuda,Xiao, Han
, p. 501 - 504 (2020/11/03)
Photoactivatable fluorophores are emerging optical probes for biological applications. Most photoactivatable fluorophores are relatively large in size and need to be activated by ultraviolet light; this dramatically limits their applications. To introduce photoactivatable fluorophores into proteins, recent investigations have explored several protein-labeling technologies, including fluorescein arsenical hairpin (FlAsH) Tag, HaloTag labeling, SNAPTag labeling, and other bioorthogonal chemistry-based methods. However, these technologies require a multistep labeling process. Here, by using genetic code expansion and a single sulfur-for-oxygen atom replacement within an existing fluorescent amino acid, we have site-specifically incorporated the photoactivatable fluorescent amino acid thioacridonylalanine (SAcd) into proteins in a single step. Moreover, upon exposure to visible light, SAcd can be efficiently desulfurized to its oxo derivatives, thus restoring the strong fluorescence of labeled proteins.
Rhodium-Catalyzed Dealkenylative Arylation of Alkenes with Arylboronic Compounds
Das, Mowpriya,Glorius, Frank,Maisuls, Iván,Strassert, Cristian A.,Tan, Guangying
supporting information, p. 15650 - 15655 (2021/06/08)
The C?C bond formation reaction represents a fundamental and important transformation in synthetic chemistry, and exploring new types of C?C bond formation reactions is recognized as appealing, yet challenging. Herein, we disclose the first example of rhodium-catalyzed dealkenylative arylation of alkenes with arylboronic compounds, thereby providing an unconventional access to bi(hetero)aryls with excellent chemoselectivity. In this method, C(aryl)?C(alkenyl) and C(alkenyl)?C(alkenyl) bonds in various alkenes and 1,3-dienes can be cleaved via a hydrometalation and followed by β-carbon elimination pathway for Suzuki–Miyaura reactions. Furthermore, a series of novel organic fluorescent molecules with excellent photophysical properties has been efficiently constructed with this protocol.
Process Development of Tryptophan Hydroxylase Inhibitor LX1031, a Drug Candidate for the Treatment of Irritable Bowel Syndrome
Bednarz, Mark S.,Iimura, Shinya,Kanamarlapudi, Ramanaiah C.,Lim, Ngiap-Kie,Wu, Wenxue,Yan, Jie,Zhang, Haiming,Zhao, Matthew M.
, p. 261 - 273 (2020/03/10)
Two process routes for LX1031, a tryptophan hydroxylase inhibitor for the treatment of irritable bowel syndrome, were developed. They shared the same left-hand and right-hand starting materials as well as the penultimate intermediate. The chiral center in
P(III)/P(V)-Catalyzed Methylamination of Arylboronic Acids and Esters: Reductive C-N Coupling with Nitromethane as a Methylamine Surrogate
Li, Gen,Qin, Ziyang,Radosevich, Alexander T.
supporting information, p. 16205 - 16210 (2020/10/26)
The direct reductive N-arylation of nitromethane by organophosphorus-catalyzed reductive C-N coupling with arylboronic acid derivatives is reported. This method operates by the action of a small ring organophosphorus-based catalyst (1,2,2,3,4,4-hexamethylphosphetane P-oxide) together with a mild terminal reductant hydrosilane to drive the selective installation of the methylamino group to (hetero)aromatic boronic acids and esters. This method also provides for a unified synthetic approach to isotopically labeled N-methylanilines from various stable isotopologues of nitromethane (i.e., CD3NO2, CH315NO2, and 13CH3NO2), revealing this easy-to-handle compound as a versatile precursor for the direct installation of the methylamino group.
Combining photoredox and silver catalysis for azidotrifluoromethoxylation of styrenes
Cong, Fei,Wei, Yongliang,Tang, Pingping
supporting information, p. 4473 - 4476 (2018/05/03)
The first example of an azidotrifluoromethoxylation of styrenes has been achieved by synergistic visible-light-mediated photoredox and silver catalysis. Trifluoromethyl arylsulfonate (TFMS) and the Zhdankin reagent were used as the trifluoromethoxylation reagent and the azide source, respectively. A good functional group tolerance and mild reaction conditions of this method are applicable to late-stage azidotrifluoromethoxylation of complex small molecules. Furthermore, the mechanistic investigations indicate the single-electron transfer involved in the reaction.
