RESUMO
A number of methods to improve the passive permeability of a set of cyclic peptides have been investigated using 6- and 7-mer macrocyclic templates. In many cases the peptides were designed by molecular dynamics calculations to evaluate the methods. The aim of this study was not only to improve passive permeability, but also to balance permeability with other physicochemical properties with the goal of understanding and applying the knowledge to develop active cyclic peptides into drug candidates. Evaluation of the methods herein suggest that increasing passive permeability often occurs at the expense of solubility and lipophilicity. Computational methods can be useful when attempting to predict and design features to balance these properties, though limitations were observed.
Assuntos
Peptídeos Cíclicos/metabolismo , Ligação de Hidrogênio , Peptídeos Cíclicos/química , Permeabilidade , Estrutura Terciária de Proteína , Solubilidade , EstereoisomerismoRESUMO
Over the past decade, the integration of synthetic chemistry with flow processing has resulted in a powerful platform for molecular assembly that is making an impact throughout the chemical community. Herein, we demonstrate the extension of these tools to encompass complex natural product synthesis. We have developed a number of novel flow-through processes for reactions commonly encountered in natural product synthesis programs to achieve the first total synthesis of spirodienal A and the preparation of spirangienâ A methyl ester. Highlights of the synthetic route include an iridium-catalyzed hydrogenation, iterative Roush crotylations, gold-catalyzed spiroketalization and a late-stage cis-selective reduction.
Assuntos
Policetídeo Sintases/química , CiclizaçãoRESUMO
Mechanistic studies of a palladium-catalyzed regioselective aryl C-H functionalization of 2-pyrrole phenyl iodide with norbornene are presented. Kinetic and spectroscopic analyses together with crystallographic data provide evidence for intermediates in a proposed stepwise mechanism. On the basis of the mechanistic studies, the origin of the regioselectivity is due to a ligand exchange between I(-) and HO(-) on the norbornyl palladium complex. These mechanistic studies also implicate that either alkoxide or water is responsible for the formation of the palladacycle, but a reversible ring-opening-ring-closing process of the palladacycle with HX can retard the rate of reaction of a key intermediate. The significant aspects of the proposed mechanism are discussed in detail.
Assuntos
Alcenos/química , Norbornanos/química , Paládio/química , Catálise , Cristalografia por Raios X , Iodetos/química , Modelos Moleculares , Pirróis/química , Estereoisomerismo , Água/químicaRESUMO
A rapid, four-step approach to alkyl- and aryl-substituted benzomorpholines is accomplished by a Pd-catalyzed domino C-C/C-N bond coupling using a norbornene template. Extension to phenoxazines and dihydrodibenzoxazepines is presented.
Assuntos
Benzoxazinas/síntese química , Morfolinas/síntese química , Norbornanos/química , Oxazinas/síntese química , Paládio/química , Benzoxazinas/química , Catálise , Estrutura Molecular , Morfolinas/química , Oxazinas/química , EstereoisomerismoRESUMO
Nitrogen heterocycles are abundant in natural products and pharmaceuticals. An emerging interest among synthetic chemists is to use C-H functionalization to construct the nitrogen-containing core of these heterocycles. The following article will provide a brief overview of this concept with respect to the type of C-H bond functionalized.
Assuntos
Compostos Heterocíclicos/síntese química , Ligação de Hidrogênio , Nitrogênio/química , Compostos Heterocíclicos/química , Estrutura MolecularRESUMO
A palladium-catalyzed domino ortho-alkylation/alkenylation forming up to three new C-C bonds furnishes functionalized tetrahydroisoquinolines in up to 87% yield. Extension to the formation of tetrahydrobenzoazepines and tetrahydroisoquinolinones is presented.
Assuntos
Tetra-Hidroisoquinolinas/síntese química , Azepinas/síntese química , Azepinas/química , Catálise , Cinética , Paládio/química , Tetra-Hidroisoquinolinas/químicaRESUMO
A general procedure for the palladium-catalyzed annulation of substituted haloanilines with norbornadiene gives functionalized indolines in 51-98% yield. These indolines can be rapidly converted to benzenoid-substituted indoles and tricyclic indolines. Extension to the use of substituted halobenzamides gives functionalized isoquinolinones in up to 86% yield.
Assuntos
Acetileno/química , Compostos de Anilina/química , Benzamidas/química , Indóis/síntese química , Isoquinolinas/síntese química , Norbornanos/química , Paládio/química , Indóis/química , Isoquinolinas/químicaRESUMO
DNA-encoded library technology (ELT) is a cutting-edge enabling technology platform for drug discovery. Here we describe how to design and synthesize a macrocyclic DNA-encoded library; how to perform selection, sequencing, and data analysis to identify potential active peptides; and how to synthesize off-DNA peptides to confirm activity. This approach provides an effective tool for pharmaceutical research based on peptides.
Assuntos
DNA/química , Compostos Macrocíclicos/síntese química , Biblioteca de Peptídeos , Peptídeos Cíclicos/química , Descoberta de Drogas , Sequenciamento de Nucleotídeos em Larga Escala , Compostos Macrocíclicos/química , Peptídeos Cíclicos/síntese química , Domínios e Motivos de Interação entre Proteínas , Bibliotecas de Moléculas Pequenas/metabolismoRESUMO
A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 1012 members composed of 4-20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. On the basis of selection data, some peptides were selected for resynthesis without a DNA tag, and their activity was confirmed.
Assuntos
Biblioteca de Peptídeos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Proteínas Virais/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Aminoácidos/química , DNA/química , Avaliação Pré-Clínica de Medicamentos/métodos , Terapia de Alvo Molecular , Peptídeos Cíclicos/genética , Reação em Cadeia da Polimerase , Vírus Sinciciais Respiratórios , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/química , Proteína Supressora de Tumor Von Hippel-Lindau/químicaRESUMO
A palladium-catalyzed domino intermolecular alkylation/intramolecular amination of functionalized aryl iodides represents a new strategy for the synthesis of benzannulated N-heterocycles, affording functionalized indolines and tetrahydroquinolines from simple precursors.
Assuntos
Aminas/química , Benzeno/química , Compostos de Bromo/química , Carbono/química , Compostos Heterocíclicos/síntese química , Nitrogênio/química , Paládio/química , Alquilação , Catálise , Compostos Heterocíclicos/química , Hidroquinonas/química , Indóis/química , Estrutura MolecularRESUMO
A variety of di- and trisubstituted thiophenes were synthesized by a one-pot palladium-catalyzed ortho-alkylation sequence terminated by either Heck or C-H coupling. Initial results toward the functionalization of indoles are also presented.
RESUMO
[reaction: see text] An N-heterocyclic carbene palladium catalyst system is used to promote direct arylation of a broad range of aryl chlorides to form six- and five-membered ring biaryls. An influence of the halide on the palladium precatalyst on catalyst activation has been revealed, as has a beneficial effect of NHC salts that allows the turnover numbers to be increased by simple addition of imidazolium salts to the reaction mixture.