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1.
Nat Prod Rep ; 39(5): 946-968, 2022 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-34931646

RESUMEN

Covering: up to 2021Rearranged indole diterpenes of the paxilline type comprise a large group of fungal metabolites that possess diverse structural features and potentially useful biological effects. The unique indoloterpenoid motif, which is common to all congeners, was first confirmed by crystallographic studies of paxilline. This family of natural products has fascinated organic chemists for the past four decades and has inspired numerous syntheses and synthetic approaches. The present review highlights efforts that have laid the foundation and introduced new directions to this field of natural product synthesis. The introduction includes a summary of biosynthetic considerations and biological activities, the main body of the manuscript provides a detailed discussion of selected syntheses, and the review concludes with a brief outlook on the future of the field.


Asunto(s)
Productos Biológicos , Diterpenos , Productos Biológicos/química , Diterpenos/química , Indoles/química
2.
Bioorg Med Chem ; 28(24): 115826, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33160146

RESUMEN

UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase (LpxC), the zinc metalloenzyme catalyzing the first committed step of lipid A biosynthesis in Gram-negative bacteria, has been a target for antibacterial drug discovery for many years. All inhibitor chemotypes reaching an advanced preclinical stage and clinical phase 1 have contained terminal hydroxamic acid, and none have been successfully advanced due, in part, to safety concerns, including hemodynamic effects. We hypothesized that the safety of LpxC inhibitors could be improved by replacing the terminal hydroxamic acid with a different zinc-binding group. After choosing an N-hydroxyformamide zinc-binding group, we investigated the structure-activity relationship of each part of the inhibitor scaffold with respect to Pseudomonas aeruginosa and Escherichia coli LpxC binding affinity, in vitro antibacterial potency and pharmacological properties. We identified a novel, potency-enhancing hydrophobic binding interaction for an LpxC inhibitor. We demonstrated in vivo efficacy of one compound in a neutropenic mouse E. coli infection model. Another compound was tested in a rat hemodynamic assay and was found to have a hypotensive effect. This result demonstrated that replacing the terminal hydroxamic acid with a different zinc-binding group was insufficient to avoid this previously recognized safety issue with LpxC inhibitors.


Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/farmacología , Inhibidores Enzimáticos/química , Formamidas/química , Hemodinámica/efectos de los fármacos , Amidohidrolasas/metabolismo , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/uso terapéutico , Sitios de Unión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Escherichia coli/efectos de los fármacos , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/patología , Femenino , Formamidas/metabolismo , Formamidas/farmacología , Formamidas/uso terapéutico , Semivida , Masculino , Ratones , Simulación de Dinámica Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
3.
J Am Chem Soc ; 137(49): 15410-3, 2015 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-26593869

RESUMEN

A synthetic approach to paxilline indole diterpenes is described. The route to the pentacyclic core relies on a new regioselective alkenylation of ketones and a tandem radical addition-aldol reaction sequence to access vicinal quaternary stereocenters. Emindole SB, the simplest member of the family, is synthesized in 11 steps from commercially available material to demonstrate the application of this approach.


Asunto(s)
Diterpenos/química , Indoles/química , Terpenos/química , Estructura Molecular
4.
Environ Microbiol ; 17(2): 395-411, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25040129

RESUMEN

Ascospores of Neosartorya, Byssochlamys and Talaromyces can be regarded as the most stress-resistant eukaryotic cells. They can survive exposure at temperatures as high as 85°C for 100 min or more. Neosartorya fischeri ascospores are more viscous and more resistant to the combined stress of heat and desiccation than the ascospores of Talaromyces macrosporus which contain predominantly trehalose. These ascospores contain trehalose-based oligosaccharides (TOS) that are novel compatible solutes, which are accumulated to high levels. These compounds are also found in other members of the genus Neosartorya and in some other genera within the order Eurotiales that also include Byssochlamys and Talaromyces. The presence of oligosaccharides was observed in species that had a relatively high growth temperature. TOS glasses have a higher glass transition temperature (Tg ) than trehalose, and they form a stable glass with crystallizing molecules, such as mannitol. Our data indicate that TOS are important for prolonged stabilization of cells against stress. The possible unique role of these solutes in protection against dry heat conditions is discussed.


Asunto(s)
Neosartorya/metabolismo , Esporas Fúngicas/metabolismo , Estrés Fisiológico/fisiología , Talaromyces/metabolismo , Trehalosa/metabolismo , Deshidratación , Microbiología de Alimentos , Calor , Prevalencia , Esporas Fúngicas/crecimiento & desarrollo , Temperatura , Viscosidad
5.
J Med Chem ; 60(22): 9184-9204, 2017 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-29120638

RESUMEN

We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compounds was demonstrated using the cellular thermal shift assay (CETSA), and drug-target residence time was determined via SPR. Analysis of these data suggests that drug-target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target.


Asunto(s)
Inhibidores Enzimáticos/farmacología , L-Lactato Deshidrogenasa/antagonistas & inhibidores , Pirazoles/farmacología , Tiazoles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Ensayos Analíticos de Alto Rendimiento , Humanos , Masculino , Membranas Artificiales , Ratones , Microsomas Hepáticos/efectos de los fármacos , Permeabilidad , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacocinética , Ratas , Solubilidad , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/farmacocinética
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