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1.
Nat Chem Biol ; 12(12): 1065-1074, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27748751

RESUMO

Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 non-peptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.


Assuntos
Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacocinética , Células CACO-2 , Humanos , Estrutura Molecular , Permeabilidade , Estereoisomerismo , Relação Estrutura-Atividade
3.
J Org Chem ; 78(11): 5160-71, 2013 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-23692141

RESUMO

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.


Assuntos
Glicosídeos/síntese química , Glicosídeos/química , Conformação Molecular , Piranos/química , Estereoisomerismo
4.
J Org Chem ; 77(17): 7187-211, 2012 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-22853001

RESUMO

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.


Assuntos
Azetidinas/farmacocinética , Sistema Nervoso Central/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacocinética , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Animais , Azetidinas/sangue , Azetidinas/síntese química , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sistema Nervoso Central/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Camundongos , Estrutura Molecular , Solubilidade , Compostos de Espiro/sangue , Estereoisomerismo
5.
J Org Chem ; 76(6): 1898-901, 2011 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-21341742

RESUMO

All stereoisomers of a highly functionalized 2,3-unsaturated C-glycoside can be accessed in 10-100 g quantities from readily available starting materials and reagents in 3-7 steps. These chiral scaffolds contain three stereogenic centers along with orthogonally protected functional groups for downstream reactivity.


Assuntos
Glicosídeos/química , Glicosídeos/síntese química , Indicadores e Reagentes/química , Estereoisomerismo
6.
J Am Chem Soc ; 132(47): 16962-76, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21067169

RESUMO

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.


Assuntos
Aldeídos/química , Descoberta de Drogas/métodos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inibidores de Histona Desacetilases/química , Compostos Macrocíclicos/química , Camundongos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Especificidade por Substrato
7.
ACS Infect Dis ; 3(5): 349-359, 2017 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-28215073

RESUMO

In 2013, the Centers for Disease Control highlighted Clostridium difficile as an urgent threat for antibiotic-resistant infections, in part due to the emergence of highly virulent fluoroquinolone-resistant strains. Limited therapeutic options currently exist, many of which result in disease relapse. We sought to identify molecules specifically targeting C. difficile in high-throughput screens of our diversity-oriented synthesis compound collection. We identified two scaffolds with apparently novel mechanisms of action that selectively target C. difficile while having little to no activity against other intestinal anaerobes; preliminary evidence suggests that compounds from one of these scaffolds target the glutamate racemase. In vivo efficacy data suggest that both compound series may provide lead optimization candidates.


Assuntos
Isomerases de Aminoácido/antagonistas & inibidores , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Clostridioides difficile/efeitos dos fármacos , Enterocolite Pseudomembranosa/tratamento farmacológico , Compostos Heterocíclicos com 2 Anéis/farmacologia , Compostos de Fenilureia/farmacologia , Pirróis/farmacologia , Quinolinas/farmacologia , Isomerases de Aminoácido/genética , Isomerases de Aminoácido/metabolismo , Animais , Antibacterianos/síntese química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Clostridioides difficile/enzimologia , Clostridioides difficile/genética , Clostridioides difficile/crescimento & desenvolvimento , Desenho de Fármacos , Enterocolite Pseudomembranosa/microbiologia , Enterocolite Pseudomembranosa/mortalidade , Enterocolite Pseudomembranosa/patologia , Feminino , Expressão Gênica , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Compostos Heterocíclicos com 2 Anéis/síntese química , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Compostos de Fenilureia/síntese química , Pirróis/síntese química , Quinolinas/síntese química , Especificidade da Espécie , Relação Estrutura-Atividade , Análise de Sobrevida
8.
Antiviral Res ; 131: 19-25, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27059228

RESUMO

Respiratory syncytial virus (RSV) infections affect millions of children and adults every year. Despite the significant disease burden, there are currently no safe and effective vaccines or therapeutics. We employed a replicon-based high throughput screen combined with live-virus triaging assays to identify three novel diversity-oriented synthesis-derived scaffolds with activity against RSV. One of these small molecules is shown to target the RSV polymerase (L protein) to inhibit viral replication and transcription; the mechanisms of action of the other small molecules are currently unknown. The compounds described herein may provide attractive inhibitors for lead optimization campaigns.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Testes de Sensibilidade Microbiana , Replicon/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Antivirais/química , Antivirais/isolamento & purificação , Células Hep G2 , Humanos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Infecções por Vírus Respiratório Sincicial/terapia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/enzimologia , Vírus Sincicial Respiratório Humano/fisiologia , Proteínas Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos
9.
J Med Chem ; 57(6): 2746-54, 2014 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-24524242

RESUMO

Profiling of eight stereoisomeric T. cruzi growth inhibitors revealed vastly different in vitro properties such as solubility, lipophilicity, pKa, and cell permeability for two sets of four stereoisomers. Using computational chemistry and NMR spectroscopy, we identified the formation of an intramolecular NH→NR3 hydrogen bond in the set of stereoisomers displaying lower solubility, higher lipophilicity, and higher cell permeability. The intramolecular hydrogen bond resulted in a significant pKa difference that accounts for the other structure-property relationships. Application of this knowledge could be of particular value to maintain the delicate balance of size, solubility, and lipophilicity required for cell penetration and oral administration for chemical probes or therapeutics with properties at, or beyond, Lipinski's rule of 5.


Assuntos
Permeabilidade da Membrana Celular/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Algoritmos , Animais , Células CACO-2 , Biologia Computacional , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Cinética , Lipídeos/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Bibliotecas de Moléculas Pequenas , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade
10.
J Org Chem ; 73(3): 882-8, 2008 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-18171075

RESUMO

A unified strategy for the high-throughput synthesis of multigram quantities of the eta(3)-oxopyranyl- and eta(3)-oxopyridinylmolybdenum complexes TpMo(CO)(2)(eta(3)-oxopyranyl) and TpMo(CO)(2)(eta(3)-oxopyridinyl) is described (Tp = hydridotrispyrazolylborato). The strategy uses the oxa- and aza-Achmatowicz reaction for the preparation of these organometallic enantiomeric scaffolds, in both racemic and high enantiopurity versions.


Assuntos
Compostos Organometálicos/química , Piridinas/química , Compostos Aza/química , Cristalografia por Raios X , Isomerismo , Compostos Macrocíclicos/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Temperatura
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