RESUMEN
(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl (2E)-3-(3,4-dihydroxyphenyl)acrylate (1 a), which possesses significant neuritogenic activity, was isolated from the traditional Chinese medicine (TCM) plant, Desmodium sambuense. To confirm the structure and to assess biological activity, we semi-synthesized 1 a from commercially available oleanolic acid. A series of novel 1 a derivatives was then designed and synthesized for a structure-activity relationship (SAR) study. All synthetic derivatives were characterized by analysis of spectral data, and their neuritogenic activities were evaluated in assays with PC12 cells. The SAR results indicate that the number and position of the hydroxy groups on the phenyl ring and the triterpene moiety, as well as the length of the (saturated or unsaturated) alkyl chain that links the phenyl ring with the triterpene critically influence neuritogenic activity. Among all the tested compounds, 1 e [(3S,4R)-23,28-dihydroxyolean-12-en-3-yl (2E)-3-(3,4,5-trihydroxyphenyl)acrylate] was found to be the most potent, inducing significant neurite outgrowth at 1â µm.
Asunto(s)
Neuritas/efectos de los fármacos , Ácido Oleanólico/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Medicina Tradicional China , Estructura Molecular , Ácido Oleanólico/síntesis química , Ácido Oleanólico/química , Células PC12 , Ratas , Relación Estructura-ActividadRESUMEN
Here, we report an efficient one-cycle affinity selection using a natural-protein or random-peptide T7 phage pool for identification of binding proteins or peptides specific for small-molecules. The screening procedure involved a cuvette type 27-MHz quartz-crystal microbalance (QCM) apparatus with introduction of self-assembled monolayer (SAM) for a specific small-molecule immobilization on the gold electrode surface of a sensor chip. Using this apparatus, we attempted an affinity selection of proteins or peptides against synthetic ligand for FK506-binding protein (SLF) or irinotecan (Iri, CPT-11). An affinity selection using SLF-SAM and a natural-protein T7 phage pool successfully detected FK506-binding protein 12 (FKBP12)-displaying T7 phage after an interaction time of only 10 min. Extensive exploration of time-consuming wash and/or elution conditions together with several rounds of selection was not required. Furthermore, in the selection using a 15-mer random-peptide T7 phage pool and subsequent analysis utilizing receptor ligand contact (RELIC) software, a subset of SLF-selected peptides clearly pinpointed several amino-acid residues within the binding site of FKBP12. Likewise, a subset of Iri-selected peptides pinpointed part of the positive amino-acid region of residues from the Iri-binding site of the well-known direct targets, acetylcholinesterase (AChE) and carboxylesterase (CE). Our findings demonstrate the effectiveness of this method and general applicability for a wide range of small-molecules.
Asunto(s)
Bacteriófago T7/genética , Técnicas Biosensibles , Proteínas Portadoras/metabolismo , Biblioteca de Péptidos , Péptidos/metabolismo , Secuencia de Aminoácidos , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/metabolismo , Bacteriófago T7/metabolismo , Técnicas Biosensibles/instrumentación , Camptotecina/análogos & derivados , Camptotecina/química , Camptotecina/metabolismo , Proteínas Portadoras/biosíntesis , Proteínas Portadoras/química , Evaluación Preclínica de Medicamentos , Electrodos , Oro/química , Irinotecán , Ligandos , Datos de Secuencia Molecular , Péptidos/química , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Proteínas de Unión a Tacrolimus/química , Proteínas de Unión a Tacrolimus/metabolismoRESUMEN
A phenylselenenyl chloride (PhSeCl)-mediated allylic oxidation to give allylically rearranged alcohol has been developed. A possible mechanism for the present reaction is generation of allylic selenide from prenyl moiety via [1,3]-sigmatropic rearrangement, followed by oxidation and [2,3]-sigmatropic rearrangement to afford 3-isopenten-2-ol.