- Structure-Based Design and Development of Chemical Probes Targeting Putative MOR-CCR5 Heterodimers to Inhibit Opioid Exacerbated HIV-1 Infectivity
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Crystal structures of ligand-bound G-protein-coupled receptors provide tangible templates for rationally designing molecular probes. Herein, we report the structure-based design, chemical synthesis, and biological investigations of bivalent ligands targeting putative mu opioid receptor C-C motif chemokine ligand 5 (MOR-CCR5) heterodimers. The bivalent ligand VZMC013 possessed nanomolar level binding affinities for both the MOR and CCR5, inhibited CCL5-stimulated calcium mobilization, and remarkably improved anti-HIV-1BaL activity over previously reported bivalent ligands. VZMC013 inhibited viral infection in TZM-bl cells coexpressing CCR5 and MOR to a greater degree than cells expressing CCR5 alone. Furthermore, VZMC013 blocked human immunodeficiency virus (HIV)-1 entry in peripheral blood mononuclear cells (PBMC) cells in a concentration-dependent manner and inhibited opioid-accelerated HIV-1 entry more effectively in phytohemagglutinin-stimulated PBMC cells than in the absence of opioids. A three-dimensional molecular model of VZMC013 binding to the MOR-CCR5 heterodimer complex is constructed to elucidate its mechanism of action. VZMC013 is a potent chemical probe targeting MOR-CCR5 heterodimers and may serve as a pharmacological agent to inhibit opioid-exacerbated HIV-1 entry.
- Huang, Boshi,Wang, Huiqun,Zheng, Yi,Li, Mengchu,Kang, Guifeng,Barreto-De-Souza, Victor,Nassehi, Nima,Knapp, Pamela E.,Selley, Dana E.,Hauser, Kurt F.,Zhang, Yan
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p. 7702 - 7723
(2021/06/28)
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- Syntheses of a flobufen metabolite and dapoxetine based on enantioselective allylation of aromatic aldehydes
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The enantioselective allylation of an aromatic aldehyde to give a chiral homoallylic alcohol was employed as the key step in the syntheses of a flobufen metabolite and dapoxetine. In the former case, the homoallylic alcohol moiety (99 % ee) was converted into a five-membered lactone ring with good preservation of the optical purity, and the target compound, a flobufen metabolite, was obtained in 95 % ee. In the latter case, the homoallylic alcohol moiety (97 % ee) was transformed over several steps into a 3-aminopropanol moiety. During the course of the synthesis, the gradual loss of optical purity was observed, and the target compound, dapoxetine, was obtained in 85 % ee. The enantioselective allylation of an aromatic aldehyde to give the corresponding homoallylic alcohol was the key step in the syntheses of a flobufen metabolite and dapoxetine. In the first case, the homoallylic moiety was converted into a chiral five-membered lactone ring. In the second case, it was transformed into a chiral 1,3-amino alcohol moiety. Copyright
- Hessler, Filip,Korotvicka, Ales,Necas, David,Valterova, Irena,Kotora, Martin
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p. 2543 - 2548
(2014/05/06)
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- Asymmetric synthesis of maraviroc (UK-427,857)
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The asymmetric synthesis of Maraviroc (UK-427,857), a chemochine receptor 5 (CCR-5) receptor antagonist, based on an expeditious organocatalytic enantioselective assembly of the chiral βamino aldehyde key fragment is presented. The reactions were performed on a gram-scale and allow for the rapid construction of new Maraviroc analogues.
- Zhao, Gui-Ling,Lin, Shuangzheng,Korotvicka, Ales,Deiana, Luca,Kullberg, Martin,Cordova, Armando
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supporting information; experimental part
p. 2291 - 2298
(2010/12/20)
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- Highly efficient, enantioselective syntheses of (S)-(+)- and (R)-(-)-dapoxetine starting with 3-phenyl-1-propanol
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(Chemical Equation Presented) A highly efficient, enantioselective sequence has been developed for the synthesis of (S)- and (R)-dapoxetine. The pathways involve the intermediacy of the 6-membered-ring sulfamate esters 4, which were generated by Du Bois asymmetric C-Hamination reactions of the prochiral sulfamate 3, catalyzed by the chiral dirhodium(II) complexes. During the course of our research, the absolute configuration of the enantiomer of 4-pheny[1,2,3]oxathiazinane 2,2-dioxide (4r), prepared by the Du Bois asymmetric C-H amination reaction of 3 and the Rh2(S-nap)4 catalyst, is determined to be R and not S as was originally reported.
- Kang, Soyeong,Lee, Hyeon-Kyu
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supporting information; experimental part
p. 237 - 240
(2010/04/06)
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- Development of a bulk enabling route to maraviroc (UK-427,857), a CCR-5 receptor antagonist
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A bulk enabling synthesis of the CCR-5 receptor antagonist, Maraviroc (UK-427,857) (1), is presented. Synthesis of the three key fragments, β-amino ester 3,4,4-difluorohexanecarboxylic acid (2), and 1,3,4-triazole-substituted tropane fragment 4 are described. Coupling strategies for these fragments are discussed and described, including synthetic challenges, protection strategies, impurity generation, and final scale-up of the developed route to 1.
- Haycock-Lewandowski, Sarah J.,Wilder, Alexander,Ahman, Jens
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p. 1094 - 1103
(2013/01/03)
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- A general and enantiodivergent method for the asymmetric synthesis of piperidine alkaloids: concise synthesis of (R)-pipecoline, (S)-coniine and other 2-alkylpiperidines
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A simple and very efficient protocol for the preparation of highly enantioenriched 2-alkylpiperidines has been set up, which allows the preparation of the final heterocycles with any wanted configuration at the stereogenic center starting from the same starting material. The key step of the synthesis relies on a diastereodivergent aza-Michael reaction protocol using the readily available and cheap reagent (+)-(S,S)-pseudoephedrine as chiral auxiliary.
- Etxebarria, Juan,Vicario, Jose L.,Badía, Dolores,Carrillo, Luisa
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p. 11421 - 11428
(2008/03/13)
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- (S,S)-(+)-pseudoephedrine as chiral auxiliary in asymmetric aza-Michael reactions. Unexpected selectivity change when manipulating the structure of the auxiliary
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The asymmetric aza-Michael reaction of metal benzylamides to α,β-unsaturated amides derived from the chiral amino alcohol (S,S)-(+)-pseudoephedrine has been studied in detail. A deep study of the most important experimental parameters (solvent, temperatur
- Etxebarria, Juan,Vicario, Jose L.,Badia, Dolores,Carrillo, Luisa,Ruiz, Nerea
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p. 8790 - 8800
(2007/10/03)
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