RESUMEN
This article describes the evolution of a Nazarov cyclization-based synthetic strategy targeting the anticancer, antiinflammatory, and insecticidal natural product (±)-rocaglamide. Initial pursuit of a polarized heteroaromatic Nazarov cyclization to construct the congested cyclopentane core revealed an unanticipated electronic bias in the pentadienyl cation. This reactivity was harnessed in a successful second-generation approach using an oxidation-initiated Nazarov cyclization of a heteroaryl alkoxyallene. Full details of these two approaches are given, as well as the characterization of undesired reaction pathways available to the Nazarov cyclization product. A sequence of experiments that led to an understanding of the unexpected reactivity of this key intermediate is described, which culminated in the successful total synthesis of (+)-rocaglamide.
Asunto(s)
Alcadienos/química , Benzofuranos/síntesis química , Ciclopentanos/química , Antiinflamatorios/síntesis química , Antineoplásicos Fitogénicos/síntesis química , Benzofuranos/química , Ciclización , Insecticidas/síntesis química , Cetonas/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Oxidación-Reducción , EstereoisomerismoRESUMEN
As an anti-inflammatory strategy, MAPK-activated protein kinase-2 (MK2) inhibition can potentially avoid the clinical failures seen for direct p38 inhibitors, especially tachyphylaxis. CC-99677, a selective targeted covalent MK2 inhibitor, employs a rare chloropyrimidine that bonds to the sulfur of cysteine 140 in the ATP binding site via a nucleophilic aromatic substitutions (SNAr) mechanism. This irreversible mechanism translates biochemical potency to cells shown by potent inhibition of heat shock protein 27 (HSP27) phosphorylation in LPS-activated monocytic THP-1 cells. The cytokine inhibitory profile of CC-99677 differentiates it from known p38 inhibitors, potentially suppressing a p38 pathway inflammatory response while avoiding tachyphylaxis. Dosed orally, CC-99677 is efficacious in a rat model of ankylosing spondylitis. Single doses, 3 to 400 mg, in healthy human volunteers show linear pharmacokinetics and apparent sustained tumor necrosis factor-α inhibition, with a favorable safety profile. These results support further development of CC-99677 for autoimmune diseases like ankylosing spondylitis.
Asunto(s)
Enfermedades Autoinmunes , Espondilitis Anquilosante , Adenosina Trifosfato , Animales , Antiinflamatorios , Enfermedades Autoinmunes/tratamiento farmacológico , Cisteína , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Lipopolisacáridos , Proteínas Serina-Treonina Quinasas , Ratas , Azufre , Factor de Necrosis Tumoral alfa , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Retinoic acid receptor-related orphan nuclear receptor (ROR) γt is a member of the RORC nuclear hormone receptor family of transcription factors. RORγt functions as a critical regulator of thymopoiesis and immune responses. RORγt is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production. However, excessive IL-17A production has been linked to numerous autoimmune diseases. Moreover, Th17 cells have been shown to elicit both pro- and anti-tumor effects. Thus, modulation of the RORγt/IL-17A axis may represent an attractive therapeutic target for the treatment of autoimmune disorders and some cancers. Herein we report the design, synthesis and characterization of three selective allosteric RORγt inhibitors in preclinical models of inflammation and tumor growth. We demonstrate that these compounds can inhibit Th17 differentiation and maintenance in vitro and Th17-dependent inflammation and associated gene expression in vivo, in a dose-dependent manner. Finally, RORγt inhibitors were assessed for efficacy against tumor formation. While, RORγt inhibitors were shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids in vitro and modulate RORγt target genes in vivo, this activity was not sufficient to delay tumor volume in a KP/C human tumor mouse model of pancreatic cancer.
Asunto(s)
Expresión Génica/efectos de los fármacos , Inflamación/genética , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Células Th17/efectos de los fármacos , Animales , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Inflamación/metabolismo , Interleucina-17/metabolismo , Ratones , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Células Th17/metabolismoRESUMEN
The total syntheses of aglafolin, rocagloic acid, and rocaglamide using Nazarov cyclization are described. Generation of the necessary oxyallyl cation intermediate was accomplished via peracid oxidation of an allenol ether to generate an unusual oxycarbenium ion species that undergoes cyclization. The synthesis is efficient, highly diastereoselective, and strategically distinct from previous syntheses of rocaglamide.
Asunto(s)
Benzofuranos/síntesis química , Ciclización , Compuestos Epoxi/química , Oxidación-Reducción , EstereoisomerismoRESUMEN
A general, catalytic method for efficient Nazarov cyclization of systems containing heteroaromatic components has been developed. Scandium triflate was identified as the most reactive promoter, and it was found that addition of lithium perchlorate was necessary for synthetically useful catalytic cyclizations. The method was used to synthesize a range of cyclopentanone-fused heteroaromatic systems in 36-97% yield, and the reactivity trends observed demonstrate the impact of polarization on cyclization efficiency. [reaction: see text].
RESUMEN
Silver and large gold nanoparticles are more efficient scatterers than smaller particles, which can be advantageous for a variety of single-particle-based sensing and spectroscopic applications. The increased susceptibility to surface oxidation and the larger surface area of these particles, however, present challenges to colloid stability and controllable bio-conjugation strategies. In this chapter, ligand syntheses and particle passivation procedures for yielding stable and bio-conjugatable colloids of silver and large gold nanoparticles are described.
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ADN de Cadena Simple/química , Oro/química , Nanopartículas del Metal/química , Nanopartículas/química , Plata/química , Espectroscopía de Absorción de Rayos X/métodos , Materiales Biocompatibles , Cromatografía/métodos , Electroforesis en Gel de Agar , Ligandos , Tamaño de la PartículaRESUMEN
The molecular structure of chloronitromethane was studied in the gas phase at a nozzle-tip temperature of 373 K. The experimental data were interpreted using a dynamic model where the molecules are undergoing torsional motion governed by a potential function: V = V2/2x(1 - cos 2tau) + V4/2x(1 - cos 4tau) with V2 = 0.81(30) and V4 = 0.12(40) kcal/mol (tau is the dihedral angle between the C-Cl and N-O bond). The conformer with a zero degree dihedral angle is the most stable conformer. Comparison with results from HF/MP2/B3LYP 6-311G(d,p) calculations were made. The important geometrical parameter values (for the eclipsed form) obtained from least-squares refinements are the following: r(C-H) = 1.061(18)A, r(C-N) = 1.509 (5)A, r(N-O) = 1.223(1)A, r(C-Cl) = 1.742(2)A, angleClCN = 115.2(7) degrees, angleO4NC = 118.9(10) degrees, angleO5NC = 114.9(16) degrees, and angleClCH 115(4) degrees.