124397-96-2Relevant articles and documents
Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition
Cornelison, Jeffery L.,Cato, Michael L.,Johnson, Alyssa M.,D'Agostino, Emma H.,Melchers, Diana,Patel, Anamika B.,Mays, Suzanne G.,Houtman, René,Ortlund, Eric A.,Jui, Nathan T.
, (2020)
LRH-1 is a nuclear receptor that regulates lipid metabolism and homeostasis, making it an attractive target for the treatment of diabetes and non-alcoholic fatty liver disease. Building on recent structural information about ligand binding from our labs, we have designed a series of new LRH-1 agonists that further engage LRH-1 through added polar interactions. While the current synthetic approach to this scaffold has, in large part, allowed for decoration of the agonist core, significant variation of the bridgehead substituent is mechanistically precluded. We have developed a new synthetic approach to overcome this limitation, identified that bridgehead substitution is necessary for LRH-1 activation, and described an alternative class of bridgehead substituents for effective LRH-1 agonist development. We determined the crystal structure of LRH-1 bound to a bridgehead-modified compound, revealing a promising opportunity to target novel regions of the ligand binding pocket to alter LRH-1 target gene expression.
Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease
Kato, Atsushi,Nakagome, Izumi,Sato, Kasumi,Yamamoto, Arisa,Adachi, Isao,Nash, Robert J.,Fleet, George W. J.,Natori, Yoshihiro,Watanabe, Yasuka,Imahori, Tatsushi,Yoshimura, Yuichi,Takahata, Hiroki,Hirono, Shuichi
, p. 1039 - 1048 (2016)
We report on the synthesis and biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives as pharmacological chaperones for Gaucher disease. The parent compound, DAB, did not show inhibition of human β-glucocerebrosidase but showed moderate intestinal α-glucosidase inhibition; in contrast, extension of α-1-C-alkyl chain length gave a series of highly potent and selective inhibitors of the β-glucocerebrosidase. Our design of α-1-C-tridecyl-DAB (5j) produced a potent inhibitor of the β-glucocerebrosidase, with IC50 value of 0.77 μM. A molecular docking study revealed that the α-1-C-tridecyl group has a favorable interaction with the hydrophobic pocket and the sugar analogue part (DAB) interacted with essential hydrogen bonds formed to Asp127, Glu235 and Glu340. Furthermore, α-1-C-tridecyl-DAB (5j) displayed enhancement of activity at an effective concentration 10-times lower than isofagomine. α-1-C-Tridecyl-DAB therefore provides the first example of a pyrrolidine iminosugar as a new class of promising pharmacological chaperones with the potential for treatment of Gaucher disease. 2016 The Royal Society of Chemistry.
Synthese et reactivite de quelques organozinciques dans des solvants peu courants en chimie organometallique
Grodin, Joseph,Sebban, Mohammed,Vottero, Philippe,Blancou, Hubert,Commeyras, Auguste
, p. 237 - 242 (1989)
The use of solvents strange to organometallic chemistry viz. carbonic or phosphoric esters, or sulfolane allows zinc to react with organic halides, which are usually unreactive towards this metal.The ractions of the organozinc compounds thus synthesised (
Enantio- and Regioconvergent Nickel-Catalyzed C(sp3)?C(sp3) Cross-Coupling of Allylic Electrophiles Steered by a Silyl Group
Kranidiotis-Hisatomi, Nektarios,Oestreich, Martin,Yi, Hong
, p. 13652 - 13655 (2021)
A two-step sequence for the enantio- and diastereoselective synthesis of exclusively alkyl-substituted acyclic allylic systems with a stereocenter in the allylic position is reported. The asymmetric induction and the site selectivity are controlled in an
Direct transformation of aryl 2-pyridyl esters to secondary benzylic alcohols by nickel relay catalysis
Wu, Xianqing,Li, Xiaobin,Huang, Wenyi,Wang, Yun,Xu, Hui,Cai, Liangzhen,Qu, Jingping,Chen, Yifeng
supporting information, p. 2453 - 2458 (2019/03/29)
A direct transformation of aryl esters to secondary benzylic alcohols via tandem Ni-catalyzed cross-coupling reactions of aromatic 2-pyridyl esters with alkyl zinc reagents and carbonyl group reduction by Ni-H species is achieved. Preliminary mechanistic studies reveal that the Ni-H species is generated in situ via β-hydride elimination of the Negishi reagents. The reaction is catalyzed by bench-stable nickel salts under mild conditions with wide functional group tolerance.
Access to Functionalized Quaternary Stereocenters via the Copper-Catalyzed Conjugate Addition of Monoorganozinc Bromide Reagents Enabled by N, N-Dimethylacetamide
Fulton, Tyler J.,Alley, Phebe L.,Rensch, Heather R.,Ackerman, Adriana M.,Berlin, Cameron B.,Krout, Michael R.
, p. 14723 - 14732 (2018/11/23)
Monoorganozinc reagents, readily obtained from alkyl bromides, display excellent reactivity with β,β-disubstituted enones and TMSCl in the presence of Cu(I) and Cu(II) salts to synthesize a variety of cyclic functionalized β-quaternary ketones in 38-99% yields and 9:1-20:1 diastereoselectivities. The conjugate addition features a pronounced improvement in DMA using monoorganozinc bromide reagents. A simple one-pot protocol that harnesses in situ generated monoorganozinc reagents delivers comparable product yields.
Palladium(I) Dimer Enabled Extremely Rapid and Chemoselective Alkylation of Aryl Bromides over Triflates and Chlorides in Air
Kalvet, Indrek,Sperger, Theresa,Scattolin, Thomas,Magnin, Guillaume,Schoenebeck, Franziska
supporting information, p. 7078 - 7082 (2017/06/13)
Disclosed herein is the first general chemo- and site-selective alkylation of C?Br bonds in the presence of COTf, C?Cl and other potentially reactive functional groups, using the air-, moisture-, and thermally stable dinuclear PdI catalyst, [Pd(μ-I)PtBu3]2. The bromo-selectivity is independent of the substrate and the relative positioning of the competing reaction sites, and as such fully predictable. Primary and secondary alkyl chains were introduced with extremely high speed (5 min reaction time) at room temperature and under open-flask reaction conditions.
An efficient and reliable procedure for the preparation of highly reactive Rieke zinc
Kudret, Suleyman,D'Haen, Jan,Lutsen, Laurence,Vanderzande, Dirk,Maes, Wouter
, p. 569 - 575 (2013/05/09)
Rieke zinc has a wide potential for applications in organic chemistry, notably for the synthesis of highly chemoselective organozinc reagents. However, due to the rather unreliable preparation method, leading to large batch to batch variations, its use has been rather limited. Rieke zinc is commonly prepared by the reduction of zinc chloride with lithium using a stoichiometric amount of naphthalene. In our hands, it was observed that the reaction outcome was highly dependent on the naphthalene source and purity grade. The presence of benzothiophene seems crucial to avoid coagulation of the zinc particles and the amount of benzothiophene has a large effect on the physical properties and the reactivity of the resulting zinc powder. Accordingly, highly reactive Rieke zinc was easily prepared from zinc chloride by adding an optimum amount (3 mol% with regard to ZnCl2) of benzothiophene into the lithium naphthalenide solution (prepared in situ). The Rieke zinc obtained in this way was successfully employed in the so-called "Rieke method" to prepare regioregular poly(3-hexylthiophene) (P3HT). The novel approach enables preparation of Rieke zinc in a reproducible manner, which considerably facilitates its use in both small molecule and polymer synthesis.
α-1-C-Butyl-1,4-Dideoxy-1,4-Imino-L-Arabinitol as a second-Generation iminosugar-based oral α-Glucosidase inhibitor for improving postprandial hyperglycemia
Kato, Atsushi,Hayashi, Erina,Miyauchi, Saori,Adachi, Isao,Imahori, Tatsushi,Natori, Yoshihiro,Yoshimura, Yuichi,Nash, Robert J.,Shimaoka, Hideyuki,Nakagome, Izumi,Koseki, Jun,Hirono, Shuichi,Takahata, Hiroki
, p. 10347 - 10362 (2013/02/23)
We report on the synthesis and the biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-l-arabinitol (LAB) derivatives. The asymmetric synthesis of the derivatives was achieved by asymmetric allylic alkylation, ring-closing metathesis, and Negishi cross-coupling as key reactions. α-1-C-Butyl-LAB is a potent inhibitor of intestinal maltase, isomaltase, and sucrase, with IC50 values of 0.13, 4.7, and 0.032 μM, respectively. Matrix-assisted laser desorption ionization time-of-flight mass spectrometric analysis revealed that this compound differs from miglitol in that it does not influence oligosaccharide processing and the maturation of glycoproteins. A molecular docking study of maltase-glucoamylase suggested that the interaction modes and the orientations of α-1-C-butyl-LAB and miglitol are clearly different. Furthermore, α-1-C-butyl-LAB strongly suppressed postprandial hyperglycemia at an early phase, similar to miglitol in vivo. It is noteworthy that the effective dose was about 10-fold lower than that for miglitol. α-1-C-Butyl-LAB therefore represents a new class of promising compounds that can improve postprandial hyperglycemia.
Formation of coordinated RZn(macrocycle)+ cations and organozincate anions from reactions of organozinc compounds and macrocycles
Fabicon, Ronaldo M.,Richey Jr., Herman G.
, p. 4018 - 4023 (2008/10/08)
An RZnZ compound (R = alkyl) and a macrocycle react in benzene to form RZn(macrocycle)+ ions when the macrocycle is an effective coordinator for RZn+ and Z- can exist as the anion or become attached to an organometallic acceptor to form an organometalate anion. R2Zn and R3Al form RZn(macrocycle)+R4Al- with 14N4 (1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane) 15N5 (1,4,7,10,13-pentamethyl-1,4,7,10,13-pentaazacyclopentadecane), 2,1,1-cryptand, or 2,2,1-cryptand but not with 1,4,7,10,13,16-hexamethyl-1,4,7,10,13,16-hexaazacyclo-octadecane, 2,2,2-cryptand, 15-crown-5, or 18-crown-6. RZnZ, R2Zn, and 14N4 form RZn(14N4)+R2ZnZ- when Z is Cl, Br, I, or 3,5-di-tert-butylphenoxy but not when Z is tert-butoxy. Various combinations of RZnZ with Z = Cl, Br, I, 2,6-di-tert-butylphenoxy, or 3,5-di-tert-butylphenoxy and 14N4, 15N5, 2,1,1-cryptand, or 2,2,1-cryptand form RZn(macrocycle)+Z- solids; solids do not form when Z is methoxy or tert-butoxy nor when the macrocycle is 12-crown-4, 15-crown-5, or 18-crown-6.
