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1.
Antimicrob Agents Chemother ; 59(6): 3450-9, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25824229

RESUMEN

To identify novel antivirals to the hepatitis C virus (HCV) NS4B protein, we utilized encoded library technology (ELT), which enables purified proteins not amenable to standard biochemical screening methods to be tested against large combinatorial libraries in a short period of time. We tested NS4B against several DNA-encoded combinatorial libraries (DEL) and identified a single DEL feature that was subsequently progressed to off-DNA synthesis. The most active of the initial synthesized compounds had 50% inhibitory concentrations (IC50s) of 50 to 130 nM in a NS4B radioligand binding assay and 300 to 500 nM in an HCV replicon assay. Chemical optimization yielded compounds with potencies as low as 20 nM in an HCV genotype 1b replicon assay, 500 nM against genotype 1a, and 5 µM against genotype 2a. Through testing against other genotypes and genotype 2a-1b chimeric replicons and from resistance passage using the genotype 1b replicon, we confirmed that these compounds were acting on the proposed first transmembrane region of NS4B. A single sequence change (F98L) was identified as responsible for resistance, and it was thought to largely explain the relative lack of potency of this series against genotype 2a. Unlike other published series that appear to interact with this region, we did not observe sensitivity to amino acid substitutions at positions 94 and 105. The discovery of this novel compound series highlights ELT as a valuable approach for identifying direct-acting antivirals to nonenzymatic targets.


Asunto(s)
Hepacivirus/genética , Replicón/genética , Línea Celular , Genotipo , Humanos , Replicación Viral/genética , Replicación Viral/fisiología
3.
Org Lett ; 9(9): 1707-10, 2007 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-17385874

RESUMEN

[reaction: see text] Dehydrochlorination of methyl 2-chloroaziridine 2-carboxylates generates the first examples of enantiopure 2-substituted 2H-azirine 3-carboxylates which undergo the aza Diels-Alder reaction with dienes to give bicyclic and tricyclic aziridines in good yields.


Asunto(s)
Azirinas/química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntesis química , Estructura Molecular , Estereoisomerismo
4.
Nat Commun ; 8: 16081, 2017 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-28714473

RESUMEN

The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.


Asunto(s)
Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/farmacología , Descubrimiento de Drogas/métodos , Biblioteca de Genes , Mycobacterium tuberculosis/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas , Staphylococcus aureus/efectos de los fármacos , Acinetobacter baumannii/metabolismo , Evaluación Preclínica de Medicamentos , Terapia Molecular Dirigida , Mycobacterium tuberculosis/metabolismo , Staphylococcus aureus/metabolismo
5.
Org Lett ; 7(4): 621-3, 2005 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-15704909

RESUMEN

The asymmetric synthesis of the cytotoxic marine metabolite (-)-agelastatin A (1) has been achieved from the C-ring intermediate 4,5-diamino cyclopenten-2-enone (-)-2. This key intermediate was efficiently prepared from the sulfinimine-derived alpha,beta-diamino ester 4 using ring-closing metathesis. [reaction: see text]


Asunto(s)
Alcaloides/síntesis química , Oxazolidinonas/síntesis química , Iminas , Indicadores y Reactivos , Modelos Moleculares
6.
ACS Comb Sci ; 17(12): 722-31, 2015 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-26562224

RESUMEN

DNA-encoded small-molecule library technology has recently emerged as a new paradigm for identifying ligands against drug targets. To date, this technology has been used with soluble protein targets that are produced and used in a purified state. Here, we describe a cell-based method for identifying small-molecule ligands from DNA-encoded libraries against integral membrane protein targets. We use this method to identify novel, potent, and specific inhibitors of NK3, a member of the tachykinin family of G-protein coupled receptors (GPCRs). The method is simple and broadly applicable to other GPCRs and integral membrane proteins. We have extended the application of DNA-encoded library technology to membrane-associated targets and demonstrate the feasibility of selecting DNA-tagged, small-molecule ligands from complex combinatorial libraries against targets in a heterogeneous milieu, such as the surface of a cell.


Asunto(s)
Acetatos/farmacología , ADN/química , Quinolinas/farmacología , Receptores de Neuroquinina-3/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Acetatos/química , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Ligandos , Estructura Molecular , Quinolinas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad
7.
Org Lett ; 6(16): 2789-92, 2004 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-15281770

RESUMEN

Addition of differentially N-protected glycine enolates to enantiopure sulfinimines affords syn- and anti-alpha,beta-diamino esters with high diastereoselectivities and good yields.


Asunto(s)
Amidas/química , Compuestos de Bencilideno/química , Glicina/química , Fenilpropionatos/química , Aminoácidos Diaminos/síntesis química , Estereoisomerismo
8.
J Med Chem ; 56(9): 3666-79, 2013 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-23570514

RESUMEN

The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research.


Asunto(s)
Descubrimiento de Drogas , Pirimidinas/química , Pirimidinas/farmacología , Sirtuinas/antagonistas & inhibidores , Humanos , Modelos Moleculares , Conformación Proteica , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/química , Sirtuina 2/antagonistas & inhibidores , Sirtuina 2/química , Sirtuina 3/antagonistas & inhibidores , Sirtuina 3/química , Sirtuinas/química
9.
ACS Med Chem Lett ; 2(2): 142-7, 2011 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-24900293

RESUMEN

The discovery of potent and selective cyanamide-based inhibitors of the cysteine protease cathepsin C is detailed. Optimization of the template with regard to plasma stability led to the identification of compound 17, a potent cathepsin C inhibitor with excellent selectivity over other cathepsins and potent in vivo activity in a cigarette smoke mouse model.

10.
J Org Chem ; 68(13): 5147-52, 2003 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-12816469

RESUMEN

The highly stereoselective intramolecular metal carbenoid insertion reaction of sulfinimine-derived delta-amino alpha-diazoesters is used to prepare cis-5-tert-butylproline. A concerted or nearly concerted metal carbenoid N-H insertion reaction mechanism is proposed.


Asunto(s)
Compuestos Organometálicos/química , Prolina/análogos & derivados , Prolina/química , Rodio/química , Aminas/química , Catálisis , Química Orgánica/métodos , Ésteres/química , Cetonas/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Estereoisomerismo
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