RESUMEN
A novel and stereo-controlled method for the preparation of functionalized macrolactams was developed. The process involves stereoselective enol ether formation, followed by an azacyclic ring expansion via an aza-Claisen rearrangement. Herewith, we describe a systematic investigation of an aza-Claisen rearrangement-induced ring expansion of azacycles prepared by appending E/Z-enol ethers to the medium-sized lactams as well as the stereochemical outcome. In addition, the strategy was successfully applied to the total synthesis of fluvirucinine A(1) and 3-epi-fluvirucinine A(1). This method offers an attractive alternative to the intramolecular amide-aldol reaction for the elaboration of ß-alkoxy-α-substituted motifs.
Asunto(s)
Compuestos Aza/química , Lactamas Macrocíclicas/química , Estereoisomerismo , Especificidad por SustratoRESUMEN
The first asymmetric total synthesis of fluvirucinine A(2) has been accomplished. A key feature of the synthesis is an iterative lactam ring expansion to provide rapid access to the 14-membered lactam skeleton and three stereogenic centers. The excellent remote control of the three stereogenic centers relied on stereoselective amidoalkylation followed by an amide-enolate-induced aza-Claisen rearrangement. In addition, the structure of fluvirucinine A(2) has been completely elucidated by our total synthesis.
Asunto(s)
Lactonas/síntesis química , Ciclización , Lactonas/química , Estructura MolecularRESUMEN
Recently, 1,3-diarylalkyl thioureas have merged as one of the promising nonvanilloid TRPV1 antagonists possessing excellent therapeutic potential in pain regulation. In this paper, the full structure-activity relationship for TRPV1 antagonism of a novel series of 1,3-diarylalky thioureas is reported. Exploration of the structure-activity relationship, by systemically modulating three essential pharmacophoric regions, led to six examples of 1,3-dibenzyl thioureas, which exhibit Ca(2+) uptake inhibition in rat DRG neuron with IC(50) between 10 and 100 nM.
Asunto(s)
Canales Iónicos/antagonistas & inhibidores , Tiourea/análogos & derivados , Tiourea/síntesis química , Animales , Animales Recién Nacidos , Calcio/metabolismo , Ganglios Espinales/citología , Técnicas In Vitro , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Canales Catiónicos TRPV , Tiourea/farmacologíaRESUMEN
The structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. The 2-halogen analogues showed enhanced antagonism compared to the prototype antagonist.
Asunto(s)
Sulfonamidas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Tiourea/análogos & derivados , Tiourea/farmacología , Animales , Células CHO , Calcio/metabolismo , Cricetinae , Ligandos , Estructura Molecular , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Canales Catiónicos TRPV/metabolismo , Tiourea/químicaRESUMEN
The structure-activity relationships for the 'B-region' of N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. A docking model of potent antagonist 2 with the sensor region of TRPV1 is proposed.
Asunto(s)
Sulfonamidas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Tiourea/análogos & derivados , Tiourea/farmacología , Animales , Células CHO , Cricetinae , Ligandos , Modelos Moleculares , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Sulfonamidas/química , Canales Catiónicos TRPV/química , Canales Catiónicos TRPV/metabolismo , Tiocarbamatos/síntesis química , Tiocarbamatos/química , Tiourea/químicaRESUMEN
[reaction: see text]. Unified and highly convergent total syntheses of (+)-macrosphelides A and B are described. Key features of the syntheses include (1) concise synthesis of the optically active delta-hydroxy-gamma-keto alpha,beta-unsaturated acid fragment via the direct addition of a trans-vinylogous ester anion equivalent to the readily available Weinreb amide and (2) facile construction of the 16-membered macrolide core of the macrosphelide series via an intramolecular nitrile-oxide cycloaddition (INOC).
Asunto(s)
Macrólidos/síntesis química , Ciclización , Compuestos Heterocíclicos/síntesis química , Hongos Mitospóricos/química , Estructura Molecular , EstereoisomerismoRESUMEN
Syntheses and excellent anti-MRSA activities of the mansonone F analogs are reported. In addition, the minimal structural requirements for its anti-MRSA activities as well as its structure-activity relationship including the C3 substituents effects on anti-MRSA activity are also described. In particular, this study revealed that both ortho-quinone and tricyclic systems of mansonone F are essential for anti-MRSA activities.
Asunto(s)
Antibacterianos/síntesis química , Resistencia a la Meticilina/efectos de los fármacos , Naftoquinonas/síntesis química , Naftoquinonas/farmacología , Sesquiterpenos/síntesis química , Sesquiterpenos/farmacología , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/farmacología , Humanos , Resistencia a la Meticilina/fisiología , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/crecimiento & desarrollo , Relación Estructura-ActividadRESUMEN
Comparative molecular field analysis and comparative molecular similarity indices analysis were performed on twenty five analogues of pimarane COX-2 inhibitor to optimize their cyclooxygenase-2 (COX-2) selective anti-inflammatory activities.
Asunto(s)
Abietanos/química , Inhibidores de la Ciclooxigenasa/química , Isoenzimas/antagonistas & inhibidores , Relación Estructura-Actividad Cuantitativa , Abietanos/farmacología , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/farmacología , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismoRESUMEN
Syntheses and excellent anti-inflammatory effects of a series of novel acanthoic acid analogs are reported. In particular, the mechanistic basis for their anti-inflammatory effects is also described.
Asunto(s)
Abietanos/síntesis química , Antiinflamatorios no Esteroideos/síntesis química , Diterpenos/síntesis química , Abietanos/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Células Cultivadas , Inhibidores de la Ciclooxigenasa/metabolismo , Diterpenos/farmacología , Edema/metabolismo , Modelos Químicos , Óxido Nítrico/antagonistas & inhibidoresRESUMEN
[reaction: see text] The asymmetric total synthesis of bacillariolide III has been achieved via 15 linear steps in 14.6% overall yield. The key feature of this synthetic route involves the highly stereoselective construction of the vinyl-substituted bicyclic lactone by an intramolecular Pd(0)-catalyzed allylic alkylation and its facile conversion to the hydroxy bicyclic lactone skeleton of bacillariolide III, induced by stereoselective vinylcerium addition to the aldehyde. In addition, the (Z)-pentenoic acid was efficiently introduced by the internal hydroxy group tethered ring-closing metathesis (RCM).
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Diatomeas/química , Lactonas/síntesis química , Aldehídos/química , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Ciclización , Lactonas/química , Estructura Molecular , EstereoisomerismoRESUMEN
A novel non-vanilloid VR1 antagonist consisting of a new vanilloid equivalent exhibits excellent analgesic effects as well as highly potent antagonistic activities in both capsaicin single channel and calcium uptake assays. In addition, the structural requirement for the vanilloid equivalent of the potent VR1 antagonist has also been elucidated.
Asunto(s)
Analgésicos/síntesis química , Capsaicina/análogos & derivados , Receptores de Droga/antagonistas & inhibidores , Analgésicos/química , Analgésicos/farmacología , Animales , Capsaicina/síntesis química , Capsaicina/química , Capsaicina/farmacología , Ratones , Modelos Moleculares , Conformación Molecular , Dolor/prevención & control , Relación Estructura-ActividadRESUMEN
[reaction: see text] The highly stereoselective synthesis of beta-amino acids via the chiral 4-phenyloxazolidinone-controlled linear N-acyliminium ion reaction has been achieved by employing chiral N,O-acetal TMS ethers. In addition, the mechanism of the excellent stereochemical outcome has been elucidated. The oxazolidinone auxiliary plays a dual role in stereocontrol: the E/Z geometry control of the N-acyliminium ion induced by an initial stereoselective amide reduction, leading to the chiral N,O-acetal TMS ether, and face control of the nucleophile attack in the N-acyliminium ion reaction.
Asunto(s)
Acetales/química , Aminoácidos/síntesis química , Éteres/química , Iminas/química , Oxazolidinonas/química , Compuestos de Trimetilsililo/química , Acilación , Cationes/química , Cristalografía por Rayos X , Estructura Molecular , EstereoisomerismoRESUMEN
The total synthesis of (+)-brefeldin A has been accomplished via 15 linear steps in a 7.9% overall yield from the known Weinreb amide 6. The key parts of this approach include the stereoselective construction of the cis-disubstituted hydroxycyclopentane skeleton and the direct introduction of the C1-C3 acrylate moiety using a new variant of a trans-vinylogous acyl anion equivalent.