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1.
ACS Chem Biol ; 16(11): 2116-2123, 2021 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-34648268

RESUMO

Natural products and their analogues are often challenging to synthesize due to their complex scaffolds and embedded functional groups. Solely relying on engineering the biosynthesis of natural products may lead to limited compound diversity. Integrating synthetic biology with synthetic chemistry allows rapid access to much more diverse portfolios of xenobiotic compounds, which may accelerate the discovery of new therapeutics. As a proof-of-concept, by supplementing an Escherichia coli strain expressing the violacein biosynthesis pathway with 5-bromo-tryptophan in vitro or tryptophan 7-halogenase RebH in vivo, six halogenated analogues of violacein or deoxyviolacein were generated, demonstrating the promiscuity of the violacein biosynthesis pathway. Furthermore, 20 new derivatives were generated from 5-brominated violacein analogues via the Suzuki-Miyaura cross-coupling reaction directly using the crude extract without prior purification. Herein we demonstrate a flexible and rapid approach to access a diverse chemical space that can be applied to a wide range of natural product scaffolds.


Assuntos
Produtos Biológicos/química , Indóis/química , Vias Biossintéticas , Estrutura Molecular , Biologia Sintética
2.
Chembiochem ; 22(4): 712-716, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33058439

RESUMO

A nonenzymatic Pictet-Spengler reaction has been postulated to give rise to a subset of naturally occurring uridyl peptide antibiotics (UPAs). Here, using a combination of strain engineering and synthetic chemistry, we demonstrate that Pictet-Spengler chemistry may be employed to generate even greater diversity in the UPAs. We use an engineered strain to afford access to meta-tyrosine containing pacidamycin 4. Pictet-Spengler diversification of this compound using a small series of aryl-aldehydes was achieved with some derivatives affording remarkable diastereomeric control.


Assuntos
Antibacterianos/síntese química , Oligopeptídeos/síntese química , Peptídeos/síntese química , Streptomyces/metabolismo , Uridina/análogos & derivados , Uridina/síntese química
3.
Curr Opin Struct Biol ; 65: 51-60, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32619660

RESUMO

Over 5000 halogenated natural products have been reported so far, many of these arising from the marine environment. The introduction of a halogen into a molecule can significantly impact its bioavailability and bioactivity. More recently enzymatic halogenation has been used to enable late stage functionalisation through site-selective halogenation and cross-coupling. Halogenases are becoming increasingly valued tools. This review outlines the various classes of halogenases that have been discovered, and examines these from both a structural and a mechanistic perspective, reflecting upon the many recent advances in halogenase discovery.


Assuntos
Cloreto Peroxidase , Halogenação , Cloreto Peroxidase/química , Cloreto Peroxidase/metabolismo , Especificidade por Substrato
4.
Chem Commun (Camb) ; 55(91): 13653-13656, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31593201

RESUMO

Blending synthetic biology and synthetic chemistry represents a powerful approach to diversity complex molecules. To further enable this, compatible synthetic tools are needed. We report the first Buchwald Hartwig amination reactions with unprotected halotryptophans under aqueous conditions and demonstrate this methodology is applicable also to the modification of unprotected tripeptides and the natural product barettin.


Assuntos
Oligopeptídeos/química , Peptídeos Cíclicos/química , Triptofano/análogos & derivados , Água/química , Aminação , Compostos de Anilina/química , Catálise , Halogênios/química , Oligopeptídeos/síntese química , Paládio/química , Triptofano/síntese química
5.
ACS Med Chem Lett ; 7(8): 768-73, 2016 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-27563401

RESUMO

CZ415, a potent ATP-competitive mTOR inhibitor with unprecedented selectivity over any other kinase is described. In addition to a comprehensive characterization of its activities in vitro, in vitro ADME, and in vivo pharmacokinetic data are reported. The suitability of this inhibitor for studying in vivo mTOR biology is demonstrated in a mechanistic mouse model monitoring mTOR proximal downstream phosphorylation signaling. Furthermore, the compound reported here is the first ATP-competitive mTOR inhibitor described to show efficacy in a semitherapeutic collagen induced arthritis (CIA) mouse model.

6.
J Med Chem ; 53(5): 2215-26, 2010 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-20151671

RESUMO

We report the molecular design and synthesis of EG00229, 2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRP1) and the structural characterization of NRP1-ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRP1 b1 domain and a peptide fragment of VEGF-A was shown to bind at the same site by NMR, providing the basis for small molecule design. Compound 2 demonstrated inhibition of VEGF-A binding to NRP1 and attenuated VEGFR2 phosphorylation in endothelial cells. Inhibition of migration of endothelial cells was also observed. The viability of A549 lung carcinoma cells was reduced by 2, and it increased the potency of the cytotoxic agents paclitaxel and 5-fluorouracil when given in combination. These studies provide the basis for design of specific small molecule inhibitors of ligand binding to NRP1.


Assuntos
Antineoplásicos/síntese química , Neuropilina-1/fisiologia , Fragmentos de Peptídeos/síntese química , Fator A de Crescimento do Endotélio Vascular/fisiologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Mutagênese Sítio-Dirigida , Neuropilina-1/antagonistas & inibidores , Neuropilina-1/ultraestrutura , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/ultraestrutura , Fosforilação , Relação Estrutura-Atividade , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/ultraestrutura
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