RESUMO
As a part of our ongoing synthetic quest to expand the frontiers of contemporary medicinal chemistry, we now report an expedient synthesis of a potentially useful bicyclo[1.1.1]pentane building block, 3-(pyrazin-2-yl)bicyclo[1.1.1]pentane-1-carboxylic acid. This report also showcases the application of this motif as a probe in a biological study.
RESUMO
Exploration of novel chemical space, a modern trend in medicinal chemistry, is heavily reliant on synthetic access to new and interesting building blocks. In this direction, the following work describes an expedient synthesis of one such moiety, 3-fluorobicyclo[1.1.1]pentan-1-amine, by employing radical fluorination.
Assuntos
Aminas/química , Compostos Bicíclicos com Pontes/síntese química , Química Farmacêutica , Compostos Bicíclicos com Pontes/química , Halogenação , Estrutura MolecularRESUMO
The gut absorbs dietary nutrients and provides a barrier to xenobiotics and microbiome metabolites. To cope with toxin exposures, the intestinal epithelium is one of the most rapidly proliferating tissues in the body. The stem cell niche supplies essential signaling factors including Wnt proteins secreted by subepithelial myofibroblasts. Unexpectedly, therapeutically effective doses of orally administered PORCN inhibitors that block all Wnt secretion do not affect intestinal homeostasis. We find that intestinal myofibroblasts are intrinsically resistant to multiple xenobiotics, including PORCN inhibitors and the anthracycline antibiotic doxorubicin. These myofibroblasts have high expression of a subset of drug transporters; knockout of Mrp1/Abcc1 enhances drug sensitivity. Tamoxifen administration to Rosa26CreERT2;mT/mG mice visually highlights the drug-resistant intestinal stromal compartment and identifies small populations of drug-resistant cells in lung, kidney, and pancreatic islets. Xenobiotic resistance of the Wnt-producing myofibroblasts can protect the intestinal stem cell niche in the face of an unpredictable environment.
Assuntos
Aciltransferases/fisiologia , Proliferação de Células/efeitos dos fármacos , Resistência a Múltiplos Medicamentos , Mucosa Intestinal/efeitos dos fármacos , Proteínas de Membrana/fisiologia , Miofibroblastos/efeitos dos fármacos , Nicho de Células-Tronco/efeitos dos fármacos , Aciltransferases/antagonistas & inibidores , Animais , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos Hormonais/farmacologia , Broncodilatadores/farmacologia , Células Cultivadas , Doxorrubicina/farmacologia , Feminino , Homeostase , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Masculino , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Miofibroblastos/citologia , Miofibroblastos/metabolismo , Propionatos/farmacologia , Quinolinas/farmacologia , Transdução de Sinais , Tamoxifeno/farmacologia , Proteínas Wnt/metabolismoRESUMO
Over the last few decades, resveratrol has gained significance due to its impressive array of biological activities; however, its true potential as a drug has been severely constrained by its poor bioavailability. Indeed, several studies have implicated this bioavailability trait as a major road-block to resveratrol's potential clinical applications. To mitigate this pharmacokinetic issue, we envisioned a tactical bioisosteric modification of resveratrol to bicyclo[1.1.1]pentane (BCP) resveratrol. Relying on the beneficial bioisosteric potential demonstrated by the BCP-scaffold, we hypothesized that BCP-resveratrol would have an inherently better in vivo PK profile as compared to its natural counterpart. To validate such a hypothesis, it was necessary to secure a synthetic access to this novel structure. Herein we describe the first synthesis of BCP-resveratrol and disclose its PK properties.
RESUMO
Enantioselective routes to functionalized, seven-, eight-, and nine-membered oxacycles that are amenable to further elaboration have been developed. Salient features of the methodology include highly diastereoselective and regioselective transformations of an ephedrine-derived epoxy morpholinone to functionalized precursors of the oxacycles. The ephedrine scaffold exerts remote stereocontrol in the functionalization of the appended oxacycle. [reaction: see text]
Assuntos
Compostos Heterocíclicos com 1 Anel/síntese química , Ciclização , Elétrons , Indicadores e Reagentes , Lactamas/química , Lítio/química , Metilação , Niacina/química , Niacinamida/química , Piperidinas/química , Piridinas/químicaRESUMO
[reaction: see text] An expedient, enantioselective synthesis of a key precursor to (-)-quinic acid has been achieved from an ephedrine-derived morpholine-dione. The salient features of this approach are a highly diastereoselective conversion of the dione to a dialkenyl morpholinone and a subsequent ring-closing metathesis reaction. Removal of the ephedrine portion generates an enantiomerically enriched hydroxycyclohexene carboxamide that is readily converted to the quinic acid precursor.
Assuntos
Ácido Quínico/síntese química , Alquilação , Estrutura Molecular , Ácido Quínico/química , Ácido Chiquímico/síntese química , Ácido Chiquímico/química , EstereoisomerismoAssuntos
Antimaláricos/síntese química , Diterpenos/síntese química , Alcanos/química , Animais , Antozoários/química , Antimaláricos/química , Antimaláricos/toxicidade , Cristalografia por Raios X , Diterpenos/química , Diterpenos/toxicidade , Compostos Macrocíclicos/química , Conformação Molecular , Plasmodium falciparum/efeitos dos fármacosRESUMO
Recently, the potential utility of the BCP motif, as a contemporary lead optimization tactic, has generated substantial interest in medicinal chemistry. To facilitate this inquisitiveness, the concomitant development of efficient synthetic protocols is crucial. The following work discloses a new, expedient and versatile approach to one such potentially useful BCP derivative.
Assuntos
Aminas/química , Compostos Bicíclicos com Pontes/química , Alquilação , Benzeno/químicaRESUMO
From a medicinal chemistry perspective, bicyclo[1.1.1]pentan-1-amine (1) has served as a unique and important moiety. Synthetically, however, this compound has received little attention, and only one scalable route to this amine has been demonstrated. Reduction of an easily available and potentially versatile intermediate, 1-azido-3-iodobicyclo[1.1.1]pentane (2), can offer both a flexible and scalable alternative to this target. Herein, we describe our scrutiny of this reportedly elusive transformation and report our ensuing success with this endeavor.
Assuntos
Aminas/química , Azidas/química , Compostos Bicíclicos com Pontes/síntese química , Hidrocarbonetos Iodados/química , Pentanos/química , Pentanos/síntese química , Compostos Bicíclicos com Pontes/química , Estrutura MolecularRESUMO
PhI(OAc)(2) in the presence of OsO(4) (cat.) and 2,6-lutidine cleaves olefinic bonds to yield the corresponding carbonyl compounds, albeit, in some cases, with alpha-hydroxy ketones as byproduct. A more practical and clean protocol to effect oxidative cleavage of olefinic bonds involves NMO, OsO(4) (cat.), 2,6-lutidine, and PhI(OAc)(2).
Assuntos
Acetatos/química , Alcenos/química , Óxidos N-Cíclicos/química , Iodobenzenos/química , Morfolinas/química , Tetróxido de Ósmio/química , Aldeídos/síntese química , Aldeídos/química , Catálise , Cetonas/síntese química , Cetonas/química , Estrutura Molecular , Oxirredução , EstereoisomerismoRESUMO
A convergent enantioselective route to an advanced intermediate for the synthesis of the marine natural product (+)-laurencin has been developed. The methodology employs ring-opening of an ephedrine-based spiro-epoxide with a chiral secondary alcohol, hemiacetal allylation and ring closing metathesis as the key steps for elaboration of the functionalized medium-ring ether moiety in laurencin.