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1.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-34548400

RESUMEN

The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) ß5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf20S than to human constitutive 20S (Hs20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf20S and Hs20Sc in complex with MPI-5 and Pf20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in P. falciparum, underpinning the design of potent and selective antimalarial proteasome inhibitors.


Asunto(s)
Compuestos de Boro/farmacología , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/química , Inhibidores de Proteasoma/farmacología , Administración Oral , Animales , Compuestos de Boro/administración & dosificación , Compuestos de Boro/química , Dominio Catalítico , Humanos , Malaria Falciparum/enzimología , Malaria Falciparum/parasitología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Modelos Moleculares , Plasmodium falciparum/enzimología , Inhibidores de Proteasoma/administración & dosificación , Inhibidores de Proteasoma/química
2.
Bioorg Med Chem Lett ; 23(10): 2863-7, 2013 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-23587425
3.
J Med Chem ; 64(10): 6902-6923, 2021 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-34000802

RESUMEN

Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.


Asunto(s)
Proteínas de la Membrana/agonistas , Nucleótidos Cíclicos/química , Pirimidinas/química , Administración Intravenosa , Animales , Sitios de Unión , Línea Celular Tumoral , Semivida , Humanos , Inmunoterapia , Proteínas de la Membrana/metabolismo , Ratones , Simulación del Acoplamiento Molecular , Neoplasias/patología , Neoplasias/terapia , Nucleótidos Cíclicos/metabolismo , Nucleótidos Cíclicos/uso terapéutico , Fosfatos/química , Ratas , Relación Estructura-Actividad , Trasplante Heterólogo
4.
Org Lett ; 7(20): 4399-402, 2005 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-16178543

RESUMEN

[structure: see text] A second generation total synthesis of the potent antitumor agent (+)-phorboxazole A (1) has been achieved. The cornerstone of this approach comprises a more convergent strategy, involving late-stage Stille union of a fully elaborated C(1-28) macrocycle with a C(29-46) side chain. The second generation synthesis entails the longest linear sequence of 24 steps, with an overall yield of 4.2%.


Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Oxazoles/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Estructura Molecular , Oxazoles/química
5.
Org Lett ; 4(17): 2953-5, 2002 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-12182597

RESUMEN

[reaction: see text] A linear but concise synthetic approach toward the structurally related natural products myriaporone and tedanolide is reported. The route is highlighted by a stereoselective homoallenylboration and a regio- and chemoselective nitrile oxide cycloaddition. Installation of the (Z)-olefin completed the carbon skeleton of myriaporone 1.


Asunto(s)
Alquenos/síntesis química , Compuestos Epoxi/síntesis química , Lactonas/síntesis química , Alquenos/química , Animales , Antineoplásicos/síntesis química , Compuestos de Boro/química , Macrólidos/síntesis química , Nitrilos/química , Poríferos/química , Estereoisomerismo
6.
J Org Chem ; 73(4): 1192-200, 2008 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-18215058

RESUMEN

A highly convergent second-generation synthesis of (+)-phorboxazole A has been achieved. Highlights of the synthetic approach include improved Petasis-Ferrier union/rearrangement conditions on a scale to assemble multigram quantities of the C(11-15) and C(22-26) cis-tetrahydropyrans inscribed with the phorboxazole architecture, a convenient method to prepare E- and Z-vinyl bromides from TMS-protected alkynes utilizing radical isomerization of Z-vinylsilanes, and a convergent late-stage Stille union to couple a fully elaborated C(1-28) macrocyclic iodide with a C(29-46) oxazole stannane side chain to establish the complete phorboxazole skeleton. The synthesis, achieved with a longest linear sequence of 24 steps, proceeded in 4.6% overall yield.


Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Oxazoles/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Espectroscopía de Resonancia Magnética , Oxazoles/química , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Infrarroja
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