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1.
J Am Chem Soc ; 141(49): 19436-19447, 2019 12 11.
Artículo en Inglés | MEDLINE | ID: mdl-31765162

RESUMEN

Sequence-defined peptoids, or N-substituted glycines, are an attractive class of bioispired polymer due to their biostability and efficient synthesis. However, the de novo design of folded peptoids with precise three-dimensional structures has been hindered by limited means to deterministically control backbone conformation. Peptoid folds are generally destabilized by the cis/trans backbone-amide isomerization, and few side-chains are capable of enforcing a specific amide conformation. Here, we show that a novel class of cationic alkyl ammonium ethyl side-chains demonstrates significant enforcement of the cis-amide backbone (Kcis/trans up to 70) using an unexpected ensemble of weak intramolecular CH-O and/or NH-O hydrogen bonds between the side-chain and the backbone carbonyl moieties. These interactions are evidenced by X-ray crystallography, variable-temperature NMR spectroscopy, and DFT calculations. Moreover, these side-chains are inexpensive, structurally diverse, hydrophilic, and can be integrated into longer peptoid sequences via solid-phase synthesis. Notably, we extended these concepts to synthesize a water-soluble peptoid 10-mer that adopts one predominant fold in solution, as determined by multidimensional NMR spectroscopy. This decamer, to the best of our knowledge, is the longest linear peptoid sequence atomically characterized to retain a well-folded structure. These findings fill a critical gap in peptoid folding and should propel the development of peptoid applications in a broad range of contexts, from pharmaceutical to material sciences.


Asunto(s)
Amidas/química , Modelos Moleculares , Peptoides/síntesis química , Pliegue de Proteína , Cristalografía por Rayos X , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética , Estructura Molecular , Glicinas N-Sustituídas/síntesis química , Glicinas N-Sustituídas/química , Peptoides/química , Compuestos de Amonio Cuaternario/química , Técnicas de Síntesis en Fase Sólida , Estereoisomerismo , Termodinámica
2.
J Org Chem ; 80(22): 11275-80, 2015 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-26523334

RESUMEN

The previously illusive (2S,3S)-configured α-(1-oxoisoindolin-3-yl)glycines can be prepared under mild DBU-catalyzed, low-basicity conditions. The overall process includes a cascade of aldol addition, cyclization, rearrangement, and conjugate addition reactions, leading to the target products with moderate to good chemical yields and diastereoselectivity.


Asunto(s)
Indoles/síntesis química , Glicinas N-Sustituídas/síntesis química , Catálisis , Ciclización , Indoles/química , Cinética , Estructura Molecular , Glicinas N-Sustituídas/química , Estereoisomerismo
4.
J Med Chem ; 54(4): 980-8, 2011 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-21235243

RESUMEN

The synthesis and the effect of a combination of 6-glycine and 14-phenylpropoxy substitutions in N-methyl- and N-cycloproplymethylmorphinans on biological activities are described. Binding studies revealed that all new 14-phenylpropoxymorphinans (11-18) displayed high affinity to opioid receptors. Replacement of the 14-methoxy group with a phenylpropoxy group led to an enhancement in affinity to all three opioid receptor types, with most pronounced increases in δ and κ activities, hence resulting in a loss of µ receptor selectivity. All compounds (11-18) showed potent and long-lasting antinociceptive effects in the tail-flick test in rats after subcutaneous administration. For the N-methyl derivatives 13 and 14, analgesic potencies were in the range of their 14-methoxy analogues 9 and 10, respectively. Even derivatives 15-18 with an N-cyclopropylmethyl substituent acted as potent antinociceptive agents, being several fold more potent than morphine. Subcutaneous administration of compounds 13 and 14 produced significant and prolonged antinociceptive effects mediated through peripheral opioid mechanisms in carrageenan-induced inflammatory hyperalgesia in rats.


Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Morfinanos/síntesis química , Morfinanos/farmacología , Glicinas N-Sustituídas/síntesis química , Glicinas N-Sustituídas/farmacología , Receptores Opioides/metabolismo , Analgésicos/química , Animales , Unión Competitiva , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Espectroscopía de Resonancia Magnética , Morfinanos/química , Glicinas N-Sustituídas/química , Dolor/tratamiento farmacológico , Ratas , Espectrometría de Masa por Ionización de Electrospray , Espectroscopía Infrarroja por Transformada de Fourier , Relación Estructura-Actividad
5.
Molecules ; 15(8): 5282-335, 2010 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-20714299

RESUMEN

Peptoids (N-substituted polyglycines and extended peptoids with variant backbone amino-acid monomer units) are oligomeric synthetic polymers that are becoming a valuable molecular tool in the biosciences. Of particular interest are their applications to the exploration of peptoid secondary structures and drug design. Major advantages of peptoids as research and pharmaceutical tools include the ease and economy of synthesis, highly variable backbone and side-chain chemistry possibilities. At the same time, peptoids have been demonstrated as highly active in biological systems while resistant to proteolytic decay. This review with 227 references considers the solid-phase synthetic aspects of peptoid preparation and utilization up to 2010 from the instigation, by R. N. Zuckermann et al., of peptoid chemistry in 1992.


Asunto(s)
Glicinas N-Sustituídas/análogos & derivados , Glicinas N-Sustituídas/síntesis química , Estructura Cuaternaria de Proteína , Acilación , Aminación , Glicinas N-Sustituídas/química , Solventes
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