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1.
J Org Chem ; 78(11): 5160-71, 2013 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-23692141

RESUMEN

A diversity-oriented synthesis (DOS) strategy was developed for the synthesis of stereochemically diverse fused-ring systems containing a pyran moiety. Each scaffold contains an amine and methyl ester for further diversification via amine capping and amide coupling. Scaffold diversity was evaluated in comparison to previously prepared scaffolds by a shape-based principal moments of inertia (PMI) analysis.


Asunto(s)
Glicósidos/síntesis química , Glicósidos/química , Conformación Molecular , Piranos/química , Estereoisomerismo
2.
J Org Chem ; 77(17): 7187-211, 2012 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-22853001

RESUMEN

The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged, and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of a 1976-membered library of spirocyclic azetidines is also described.


Asunto(s)
Azetidinas/farmacocinética , Sistema Nervioso Central/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacocinética , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Animales , Azetidinas/sangre , Azetidinas/síntesis química , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Sistema Nervioso Central/citología , Células Endoteliales/efectos de los fármacos , Humanos , Ratones , Estructura Molecular , Solubilidad , Compuestos de Espiro/sangre , Estereoisomerismo
3.
J Med Chem ; 64(24): 17777-17794, 2021 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-34871500

RESUMEN

In our efforts to identify novel small molecule inhibitors for the treatment of adrenoleukodystrophy (ALD), we conducted a high-throughput radiometric screen for inhibitors of elongation of very long chain fatty acid 1 (ELOVL1) enzyme. We developed a series of highly potent, central nervous system (CNS)-penetrant pyrimidine ether-based compounds with favorable pharmacokinetics culminating in compound 22. Compound 22 is a selective inhibitor of ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts and lymphocytes in vitro. Compound 22 reduced C26:0 lysophosphatidyl choline (LPC), a subtype of VLCFA, in the blood of ATP binding cassette transporter D1 (ABCD1) KO mice, a murine model of ALD to near wild-type levels. Compound 22 is a low-molecular-weight, potent ELOVL1 inhibitor that may serve as a useful tool for exploring therapeutic approaches to the treatment of ALD.


Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Elongasas de Ácidos Grasos/antagonistas & inhibidores , Pirimidinas/farmacología , Administración Oral , Adrenoleucodistrofia/tratamiento farmacológico , Animales , Disponibilidad Biológica , Perros , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Éteres/química , Células HEK293 , Humanos , Macaca fascicularis , Ratones , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Ratas
4.
J Am Chem Soc ; 132(47): 16962-76, 2010 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-21067169

RESUMEN

An aldol-based build/couple/pair (B/C/P) strategy was applied to generate a collection of stereochemically and skeletally diverse small molecules. In the build phase, a series of asymmetric syn- and anti-aldol reactions were performed to produce four stereoisomers of a Boc-protected γ-amino acid. In addition, both stereoisomers of O-PMB-protected alaninol were generated to provide a chiral amine coupling partner. In the couple step, eight stereoisomeric amides were synthesized by coupling the chiral acid and amine building blocks. The amides were subsequently reduced to generate the corresponding secondary amines. In the pair phase, three different reactions were employed to enable intramolecular ring-forming processes: nucleophilic aromatic substitution (S(N)Ar), Huisgen [3+2] cycloaddition, and ring-closing metathesis (RCM). Despite some stereochemical dependencies, the ring-forming reactions were optimized to proceed with good to excellent yields, providing a variety of skeletons ranging in size from 8- to 14-membered rings. Scaffolds resulting from the RCM pairing reaction were diversified on the solid phase to yield a 14 400-membered library of macrolactams. Screening of this library led to the discovery of a novel class of histone deacetylase inhibitors, which display mixed enzyme inhibition, and led to increased levels of acetylation in a primary mouse neuron culture. The development of stereo-structure/activity relationships was made possible by screening all 16 stereoisomers of the macrolactams produced through the aldol-based B/C/P strategy.


Asunto(s)
Aldehídos/química , Descubrimiento de Drogas/métodos , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Animales , Productos Biológicos/síntesis química , Productos Biológicos/química , Productos Biológicos/farmacología , Evaluación Preclínica de Medicamentos , Inhibidores de Histona Desacetilasas/química , Compuestos Macrocíclicos/química , Ratones , Modelos Moleculares , Conformación Molecular , Estereoisomerismo , Especificidad por Sustrato
6.
Org Lett ; 9(25): 5203-6, 2007 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-17997565

RESUMEN

Alkylidene indane and ring-expanded scaffolds have been prepared using an enantioselective crotylation/Heck cyclization sequence. Further diversification using consecutive cyclopropanation-Cope rearrangement affords novel chemotypes including spiroindane frameworks.


Asunto(s)
Indanos/química , Indanos/clasificación , Alquilación , Compuestos Azo/síntesis química , Compuestos Azo/química , Ciclización , Indanos/síntesis química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Estereoisomerismo , Compuestos de Vinilo/síntesis química , Compuestos de Vinilo/química
7.
Org Lett ; 7(20): 4435-8, 2005 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-16178552

RESUMEN

[reaction: see text] Preparation and use of anthracene-tagged organosilanes in an iterative, resin-capture-release protocol for the stereocontrolled synthesis of polypropionate arrays are described.


Asunto(s)
Antracenos/química , Propionatos/síntesis química , Silanos/química , Productos Biológicos/química , Cromatografía Líquida de Alta Presión , Espectroscopía de Resonancia Magnética , Estructura Molecular , Propionatos/química , Estereoisomerismo
8.
Photochem Photobiol ; 76(2): 153-7, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12194210

RESUMEN

The synthesis of a molecule containing hypericin and luciferin moieties joined by a tether is reported. The light-induced (in vitro) antiviral activity as well as the photophysical properties of this new compound are measured and compared with those of the parent compounds, hypericin and pseudohypericin. This tethered molecule exhibits excited-state behavior that is very similar to that of its parent compounds and antiviral activity that is identical, within experimental error, to that of its more closely related parent compound, pseudohypericin. The implications for a photodynamic therapy that is independent of external light sources are discussed.


Asunto(s)
Luciferina de Luciérnaga/efectos de la radiación , Perileno/análogos & derivados , Perileno/efectos de la radiación , Fármacos Fotosensibilizantes/efectos de la radiación , Antracenos , Luciferina de Luciérnaga/síntesis química , Luciferina de Luciérnaga/química , Perileno/síntesis química , Perileno/química , Fotoquímica , Fotoquimioterapia , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química
10.
ACS Comb Sci ; 14(11): 621-30, 2012 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-23088641

RESUMEN

A 2328-membered library of 2,3,4-trisubstituted tetrahydroquinolines was produced using a combination of solution- and solid-phase synthesis techniques. A tetrahydroquinoline (THQ) scaffold was prepared via an asymmetric Povarov reaction using cooperative catalysis to generate three contiguous stereogenic centers. A matrix of 4 stereoisomers of the THQ scaffold was prepared to enable the development of stereo/structure-activity relationships (SSAR) upon biological testing. A sparse matrix design strategy was employed to select library members to be synthesized with the goal of generating a diverse collection of tetrahydroquinolines with physicochemical properties suitable for downstream discovery.


Asunto(s)
Quinolonas/química , Urea/química , Catálisis , Estudios de Factibilidad , Estereoisomerismo , Relación Estructura-Actividad
11.
Org Lett ; 11(11): 2257-60, 2009 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-19473044

RESUMEN

A regioselective intramolecular Huisgen cycloaddition was performed on various azido alkyne substrates giving rise to macrocyclic triazole rings. Using catalyst control, a common intermediate has been converted to two structurally unique macrocycles with either a 1,5- or a 1,4-triazole resulting in an n or n + 1 ring size. This is the first example of an intramolecular ruthenium-catalyzed Huisgen cycloaddition.


Asunto(s)
Alquinos/química , Rutenio/química , Triazoles/síntesis química , Catálisis , Técnicas Químicas Combinatorias , Ciclización , Estructura Molecular , Triazoles/química
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