- Bioisosteric Modification of To042: Synthesis and Evaluation of Promising Use-Dependent Inhibitors of Voltage-Gated Sodium Channels
-
Three analogues of To042, a tocainide-related lead compound recently reported for the treatment of myotonia, were synthesized and evaluated in vitro as skeletal muscle sodium channel blockers possibly endowed with enhanced use-dependent behavior. Patch-clamp experiments on hNav1.4 expressed in HEK293 cells showed that N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine, the aryloxyalkyl bioisostere of To042, exerted a higher use-dependent block than To042 thus being able to preferentially block the channels in over-excited membranes while preserving healthy tissue function. It also showed the lowest active transport across BBB according to the results of P-glycoprotein (P-gp) interacting activity evaluation and the highest cytoprotective effect on HeLa cells. Quantum mechanical calculations and dockings gave insights on the most probable conformation of the aryloxyalkyl bioisostere of To042 in solution and the target residues involved in the binding, respectively. Both approaches indicated the conformations that might be adopted in both the unbound and bound state of the ligand. Overall, N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine exhibits an interesting toxico-pharmacological profile and deserves further investigation.
- Milani, Gualtiero,Cavalluzzi, Maria Maddalena,Altamura, Concetta,Santoro, Antonella,Perrone, Mariagrazia,Muraglia, Marilena,Colabufo, Nicola Antonio,Corbo, Filomena,Casalino, Elisabetta,Franchini, Carlo,Pisano, Isabella,Desaphy, Jean-Fran?ois,Carrieri, Antonio,Carocci, Alessia,Lentini, Giovanni
-
p. 3588 - 3599
(2021/10/07)
-
- Convergent synthesis of (R)-silodosin via decarboxylative cross-coupling
-
A new approach to Silodosin capitalizing on a radical retrosynthetic strategy to dissect the molecule into two halves is reported. Using a reductive decarboxylative cross-coupling, a simple indoline can be coupled to a chiral pool-derived fragment to arrive at the target in only seven steps (LLS). This route avoids the use of resolution strategies or asymmetric hydrogenation that requires a subsequent Curtius rearrangement to install a key amino functionality.
- Baran, Phil S.,Chen, Tie-Gen,Delbrayelle, Dominique,Echeverria, Pierre-Georges,Jentzer, Olivier,Mele, Lucas,Vantourout, Julien C.
-
supporting information
(2021/08/06)
-
- NOVEL CRYPTOPHYCIN COMPOUNDS AND CONJUGATES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
-
The present invention relates to cryptophycin compounds of formula (I). The invention also relates to cryptophycin payloads, to cryptophycin conjugates, to compositions containing them and to their therapeutic use, especially as anticancer agents. The inv
- -
-
Page/Page column 161
(2017/06/30)
-
- Structural analysis of the dual-function thioesterase SAV606 unravels the mechanism of Michael addition of glycine to an α,β-unsaturated thioester
-
Thioesterases catalyze hydrolysis of acyl thioesters to release carboxylic acid or macrocyclization to produce the corresponding macrocycle in the biosynthesis of fatty acids, polyketides, or nonribosomal peptides. Recently, we reported that the thioesterase CmiS1 from Streptomyces sp. MJ635-86F5 catalyzes the Michael addition of glycine to an α,β-unsaturated fatty acyl thioester followed by thioester hydrolysis in the biosynthesis of the macrolactam antibiotic cremimycin. However, the molecular mechanisms of CmiS1-catalyzed reactions are unclear. Here, we report on the functional and structural characterization of the CmiS1 homolog SAV606 from Streptomyces avermitilis MA-4680. In vitro analysis indicated that SAV606 catalyzes the Michael addition of glycine to crotonic acid thioester and subsequent hydrolysis yielding (R)-N-carboxymethyl-3-aminobutyric acid. We also determined the crystal structures of SAV606 both in ligand-free form at 2.4 ? resolution and in complex with (R)-N-car-boxymethyl-3-aminobutyric acid at 2.0 ? resolution. We found that SAV606 adopts an α/β hotdog fold and has an active site at the dimeric interface. Examining the complexed structure, we noted that the substrate-binding loop comprising Tyr-53–Asn-61 recognizes the glycine moiety of (R)-N-carboxymethyl-3-aminobutyric acid. Moreover, we found that SAV606 does not contain an acidic residue at the active site, which is distinct from canonical hotdog thioesterases. Site-directed mutagenesis experiments revealed that His-59 plays a crucial role in both the Michael addition and hydrolysis via a water molecule. These results allow us to propose the reaction mechanism of the SAV606-catalyzed Michael addition and thioester hydrolysis and provide new insight into the multiple functions of a thioesterase family enzyme.
- Chisuga, Taichi,Miyanaga, Akimasa,Kudo, Fumitaka,Eguchi, Tadashi
-
p. 10926 - 10937
(2017/07/06)
-
- Design, synthesis, and biological activities of 1-aryl-1,4-diazepan-2-one derivatives as novel triple reuptake inhibitors
-
A novel series of triple reuptake inhibitors were explored by ligand-based drug design. A cyclic structure was designed from cyclopropane derivative 5 using the core structure of reported monoamine reuptake inhibitors, leading to the formation of the 1-aryl-1,4-diazepan-2-one derivative 23j-S. Compound 23j-S was shown to act as a potent TRI with an excellent ADME-Tox profile. Oral administration of 23j-S significantly enhanced norepinephrine, dopamine, and serotonin levels in the mouse prefrontal cortex and showed significant antidepressant-like activity in tail suspension tests in mouse.
- Honda, Eiji,Ishichi, Yuji,Kimura, Eiji,Yoshikawa, Masato,Kanzaki, Naoyuki,Nakagawa, Hideyuki,Terao, Yasuko,Suzuki, Atsuko,Kawai, Takayuki,Arakawa, Yuuichi,Ohta, Hiroyuki,Terauchi, Jun
-
p. 3898 - 3902
(2014/09/17)
-
- Heterocycle-to-heterocycle route to quinoline-4-amines: Reductive heterocyclization of 3-(2-nitrophenyl)isoxazoles
-
A variety of quinoline-4-amines were synthesized from substituted 3-(2-nitrophenyl)isoxazoles utilizing Zn0 or Fe0 dust and HOAc using a reductive heterocyclization process. The starting isoxazoles were synthesized from readily available starting materials. A brief survey of functional groups tolerated in this reductive heterocyclization was performed and several 10-amino-3,4-dihydrobenzo[b][1,6]naphthyridin-1(2H)-one and 9-amino-3,4-dihydroacridin-1(2H)-one examples were synthesized.
- Coffman, Keith C.,Duong, Vy,Bagdasarian, Alex L.,Fettinger, James C.,Haddadin, Makhluf J.,Kurth, Mark J.
-
p. 7651 - 7657
(2015/04/22)
-
- COMPOUNDS AND METHODS FOR THE TREATMENT OR PREVENTION OF FLAVIVIRUS INFECTIONS
-
A compound is represented by Structural Formula (I), or a pharmaceutically acceptable salt thereof, wherein the variables of Structural Formula (I) are as described in the specification and the claims. A pharmaceutical composition comprises a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier of excipient. A method of treating a HCV infection in a subject comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. A method of inhibiting or reducing the activity of HCV polymerase in a subject or in a biological in vitro sample comprises administering to the subject or to the sample a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.
- -
-
Page/Page column 185-186
(2012/02/01)
-
- Synthesis of tricyclic nitrogen heterocycles by a sequence of palladium-catalyzed N-H and C(sp3)-H arylations
-
A range of tricyclic nitrogen heterocycles were synthesized in a straightforward and efficient manner via a sequence involving palladium-catalyzed N-arylation and C(sp3)-H arylation as the key steps. Whereas the C(sp3)-H arylation furnished fused 6,5,6-membered ring systems efficiently, the formation of the more strained 6,5,5-membered systems proved to be more challenging and required a subtle adjustment of the reaction conditions.
- Guyonnet, Mathieu,Baudoin, Olivier
-
supporting information; experimental part
p. 398 - 401
(2012/02/15)
-
- Isoxazolodihydropyridinones: 1,3-dipolar cycloaddition of nitrile oxides onto 2,4-dioxopiperidines
-
Practical and efficient methods have been developed for the diversity-oriented synthesis of isoxazolodihydropyridinones via the 1,3-dipolar cycloaddition of nitrile oxides onto 2,4-dioxopiperidines. A select few of these isoxazolodihydropyridinones were further elaborated with triazoles by copper-catalyzed azide-alkyne cycloaddition reactions. A total of 70 compounds and intermediates were synthesized and analyzed for drug likeness. Sixty-four of these novel compounds were submitted to the NIH Molecular Libraries Small Molecule Repository for high-throughput biological screening.
- Coffman, Keith C.,Hartley, Timothy P.,Dallas, Jerry L.,Kurth, Mark J.
-
scheme or table
p. 280 - 284
(2012/05/19)
-
- New 7,8-dihydro-1,6-naphthyridin-5(6h)-one-derivatives as PDE4 inhibitors
-
New 7,8-dihydro-1,6-naphthyridin-5(6H)-one derivatives derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of the phosphodiesterase IV (PDE4).
- -
-
Page/Page column 20
(2011/11/07)
-
- Copper-catalyzed synthesis of medium-and large-sized nitrogen heterocycles via N-arylation of phosphoramidates and carbamates
-
(Chemical Equation Presented) We have developed an efficient method for the preparation of medium- and large-sized nitrogen heterocycles via copper-catalyzed intramolecular N-arylation of phosphoramidates and carbamates. Introduction of the phosphoryl gro
- Yang, Ting,Lin, Changxue,Fu, Hua,Jiang, Yuyang,Zhao, Yufen
-
p. 4781 - 4784
(2007/10/03)
-
- Synthesis of 4-aza analogs of epothilone D
-
An efficient synthesis of epothilone D analogs of type 1 has been developed, which is based on a highly diastereoselective Evans aldol reaction as one of the key steps. A profound difference in the relative stabilities of TBS-protecting groups on C7-O and C15-O was observed between secondary and primary amide groups at C5-N4. Although modeling studies had suggested analogs of type 1 to assume a conformation similar to the NMR-derived conformation of tubulin-bound epothilone A, compounds 1a-d were found to be significantly less active than the parent compound epothilone D.
- Cachoux, Frédéric,Schaal, Franck,Teichert, Antje,Wagner, Trixie,Altmann, Karl-Heinz
-
p. 2709 - 2712
(2007/10/03)
-
- A Lewis acid-mediated protocol for the protection of aryl amines as their Boc-derivatives
-
A new protocol of protection of poorly reactive aryl amines and functionalized amines with Boc2O in the presence of Zn(ClO 4)2·6H2O as the catalyst is reported. The catalytic action of Zn(ClO4)2·6H2O is specific for the activation of the pyrocarbonates, thus acid sensitive functionalities and stereochemical configurations of the starting materials remain unaltered in the protection process.
- Bartoli, Giuseppe,Bosco, Marcella,Locatelli, Manuela,Marcantoni, Enrico,Massaccesi, Massimo,Melchiorre, Paolo,Sambri, Letizia
-
p. 1794 - 1798
(2007/10/03)
-
- Piperidine amides as modulators of chemo kine receptor activity
-
The present application describes modulators of CCR3 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma and other allergic diseases.
- -
-
-
- Substituted pyridine compounds useful for controlling chemical synaptic transmission
-
The present invention is directed to a series of substituted pyridine compounds, a method for selectively controlling neurotransmitter release in mammals using these compounds, and pharmaceutical compositions containing these compounds. Preferred compounds are 3′-(5′- and/or 6′-substituted) pyridyl ethers.
- -
-
-
- Urethane N-carboxyanhydrides from β-amino acids
-
A general method has been developed for the synthesis of N-tert-butyloxycarbonyl N-carboxyanhydrides from β-amino acids using Vilsmeier complex. These β-UNCA are stable, and the reactivity with different nucleophiles (alcohol, amine, lithium enolate) was studied.
- McKiernan,Huck,Fehrentz,Roumestant,Viallefont,Martinez
-
p. 6541 - 6544
(2007/10/03)
-
- Substituted pyridine compounds useful for controlling chemical synaptic transmission
-
The present invention is directed to a series of substituted pyridine compounds, a method for selectively controlling neurotransmitter release in mammals using these compounds, and pharmaceutical compositions containing these compounds. Preferred compounds are 3′-(5′- and/or 6′-substituted) pyridyl ethers.
- -
-
-
- 2,2'-dithiobisbenzamides derived from α-, β- and γ-amino acids possessing anti-HIV activities: Synthesis and structure-activity relationship
-
Nucleocapsid protein (NCp7), which contains highly conserved retroviral zinc fingers, is essential in the early as well as the late phase of human immunodeficiency virus (HIV) life cycle and constitutes a novel target for AIDS therapy. HIV-1 NCp7 is a basic 55 amino acid protein containing two C(X)2C(X)4H(X)4C motif zinc fingers flanked by basic amino acids on each side. 2,2'-dithiobisbenzamides have previously been reported to release zinc from these NCp7 zinc fingers and also to inhibit HIV replication. Specifically, 2,2'-dithiobisbenzamides derived from simple amino acids showed good antiviral activities. The benzisothiazolone 3, the cyclic derivative of 2, was selected for clinical trials as an agent for AIDS therapy. Herein we report the syntheses and antiviral activities, including therapeutic indices, of 2,2'-dithiobisbenzamides derived from α-, β- and γ-amino acids. Electrospray ionization mass spectrometry was used to study the zinc-ejection activity of these compounds. Among the α-amino acid derived 2,2'-dithiobisbenzamides, analogues containing alkyl side chains were found to be antivirally active with good therapeutic indices. 2,2'-Dithiobisbenzamides, derived from β- and γ-amino acids, were found to possess better antiviral and therapeutic efficacies than the α-amino acid analogues. Thus compound 59 was found to possess an EC50 of 1.9μM with a therapeutic index of >50. Interestingly, 2,2'-dithiobisbenzamides derived from α-amino acids containing a protected acid function and polar side chains also exhibited very good antiviral activity. Copyright (C) 1998 Elsevier Science Ltd.
- Vara Prasad,Loo, Joseph A.,Boyer, Frederick E.,Stier, Michael A.,Gogliotti, Rocco D.,Turner, William J.,Harvey, Patricia J.,Kramer, Melissa R.,Mack, David P.,Scholten, Jefferey D.,Gracheck, Stephen J.,Domagala, John M.
-
p. 1707 - 1730
(2007/10/03)
-
- Substituted anilide compounds which are useful in the treatment of arrhythmia
-
A substituted anilide derivative of the formula STR1 wherein R1 represents a mononuclear or binuclear heterocyclic group which contains 1 to 3 nitrogen atoms as ring members and may have a substituent. A represents a single bond, a carbonyl gro
- -
-
-