RESUMO
A one-pot, transition-metal-free, domino Michael/SN Ar protocol of general applicability has been devised for the regioselective synthesis of polyfunctional naphthalenes by employing nitromethane and ortho-haloaryl ynones. Utilization of nitromethane as a one carbon carbanion source that is incorporated into a variety of ynones, ends up as an aromatic nitro substituent. The application of this domino process towards a total synthesis of the polycyclic alkaloid macarpine demonstrate for the efficacy of this methodology. The conceptually simple approach to affect regioselective, multifunctional benzoannulation of ynones displays wide substrate scope and functional-group tolerance and has been implemented with substituted nitromethanes, as well as with alicyclic o-haloynones.
RESUMO
Drawing inspiration from the impressive neurotrophic activity exhibited by the natural product paecilomycine A, we have designed a new natural product-like scaffold employing an intramolecular Pauson-Khand reaction. Several compounds based on the new designer scaffold exhibited promising neurotrophic activity and are worthy of further biological evaluation. Our findings also highlight the importance of a DOS strategy in creating useful therapeutical leads.
Assuntos
Produtos Biológicos/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/farmacologia , Fatores de Crescimento Neural/síntese química , Fatores de Crescimento Neural/farmacologia , Terpenos/química , Materiais Biomiméticos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fatores de Crescimento Neural/química , EstereoisomerismoRESUMO
Infiltration of arterial intima by foamy macrophages is a hallmark of early atherosclerotic lesions. Here, we investigated the potential role of Ser/Thr phosphatase PHLPP1 in foam cell development. PHLPP1 levels were elevated in OxLDL-exposed macrophages and high-fat diet (HFD)-fed zebrafish larvae. Using overexpression and knockdown approaches, we show that PHLPP1 promotes the accumulation of neutral lipids, and augments cellular total cholesterol and free fatty acid (FFA) levels. RNA-Seq analysis uncovered PHLPP1 role in lipid metabolism pathways. PHLPP1 interacted with and modestly increased ChREBP recruitment to Fasn promoter. PHLPP1-mediated lipid accumulation was attenuated by AMPK activation. Pharmacological inhibition or CRISPR/Cas9-mediated disruption of PHLPP1 resulted in lower lipid accumulation in the intersegmental vessels of HFD-fed zebrafish larvae along with a reduction in total cholesterol and triglyceride levels. Deficiency of phlp-2, C. elegans PHLPP1/2 ortholog, abolished lipid accumulation in high cholesterol-fed worms. We conclude that PHLPP1 exerts a significant effect on lipid buildup.
RESUMO
A new, one-pot domino benzannulation reaction between indole-3-ynones and various nitromethane derivatives has been explored for a general entry to diversely functionalized carbazole frameworks (28 examples). The scope of this new benzannulation has been extended to variants like 2-chloroindole-3-ynones to eventuate in chemo-differentiated 1,2,3,4-tetrasubstituted carbazoles with retention of the nitro group. The efficacy of this strategy has been demonstrated through concise total synthesis of natural products, viz. carbazomycin A, calothrixin B, and staurosporinone (K252c).
RESUMO
A "product control via substrate design" strategy has been conceptualized and implemented to harness the potential of aryne and activated alkyne insertions into oxindoles to readily and efficiently furnish pharmacophoric indano- and cyclopentannulated spirooxindole scaffolds in an operationally straightforward, one-pot, transition-metal-free protocol.
RESUMO
A general, transition-metal-free, one-pot, domino Michael-SNAr or AdNE substitution protocol was devised for spiroannulation of oxindoles with ortho-bromoaryl ynones, ß-bromoalkenyl ynones, and ß-bromoalkenyl enones in a convenient and efficient manner. As an application, a short synthesis of tetracyclic alkaloid spindomycin B was accomplished.
RESUMO
Following our recent discovery of a new scaffold exhibiting significant neurotrophic and neurogenic activities, a structurally tweaked analogue, embodying a 2-oxa-spiro [5.4]decane framework, has been conceptualised and found to be more potent and versatile. It exhibits enhanced neurotrophic and neurogenic action in in vitro, ex vivo and in vivo models and also shows robust neuroprotection in mouse acute cerebral stroke model. The observed attributes are traceable to the predominant activation of the TrkB-PI3K-AKT-CREB pathway. In addition, it also exhibits remarkable anti-neuroinflammatory activity by concurrently down-regulating pro-inflammatory cytokines IL-1α and IL-6, thereby providing a unique molecule with a trinity of neuroactivities, i.e. neurotrophic, neurogenic and anti-inflammatory. The new chemical entity disclosed here has the potential to be advanced as a versatile therapeutic molecule to treat stroke, depression, and possibly other neuropsychiatric disorders associated with attenuated neurotrophic/ neurogenic activity, together with heightened neuroinflammation.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Inflamação/patologia , Fatores de Crescimento Neural/metabolismo , Neurogênese/efeitos dos fármacos , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Isquemia/patologia , Masculino , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/genética , Neuritos/efeitos dos fármacos , Neuritos/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Compostos de Espiro/química , Transcrição Gênica/efeitos dos fármacos , Peixe-ZebraRESUMO
A general approach involving the insertion of in situ generated aryne into the C-C bond of cyclic 1,3-diketones for rapidly assembling functionalized benzo-fused medium ring carbocycles is delineated. The efficacy of the methodology has been demonstrated through a concise total synthesis of pentacyclic natural product radermachol.
RESUMO
An aryne insertion cascade reaction on oxindoles has been observed and constitutes a convenient "one pot" preparation of bioactive di- and triarylated oxindoles in good yields under mild conditions. A temperature controlled "reaction switch" enables ready access to dibenzo[b,e]azepin-6-one derivatives employing the same reaction regime. This tactic has been extended to a short synthesis of potent antiulcer agent darenzepine.
Assuntos
Alcinos/química , Antiulcerosos/uso terapêutico , Azepinas/uso terapêutico , Indóis/uso terapêutico , Úlcera/tratamento farmacológico , Antiulcerosos/síntese química , Antiulcerosos/química , Azepinas/síntese química , Azepinas/química , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , OxindóisRESUMO
In search for drugs to treat neuropsychiatric disorders wherein neurotrophic and neurogenic properties are affected, two neurotrophically active small molecules specially crafted following natural product leads based on 2-oxa-spiro[5.5]-undecane scaffold, have been thoroughly evaluated for their neurotrophic, neurogenic and neuroprotective potential in ex vivo primary culture and in vivo zebrafish and mouse models. The outcome of in vivo investigations suggest that one of these molecules is more neurotrophic than neurogenic while the other one is more neurogenic than neurotrophic and the former exhibits remarkable neuroprotection in a mouse acute ischemic stroke model. The molecular mechanisms of action of these compounds appear to be through the TrkB-MEK-ERK-CREB-BDNF pathway as pre-treatment with neurotrophin receptor TrkB inhibitor ANA-12 and MEK inhibitor PD98059 attenuates the neurotrophic action of compounds.
Assuntos
Transtornos Mentais/tratamento farmacológico , Fatores de Crescimento Neural/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Azepinas/farmacologia , Benzamidas/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Descoberta de Drogas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Flavonoides/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Transtornos Mentais/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/antagonistas & inibidores , Doenças Neurodegenerativas/prevenção & controle , Neurônios/metabolismo , Fármacos Neuroprotetores/antagonistas & inibidores , Receptor trkB/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Peixe-ZebraRESUMO
Starting from vinyl pyranoses an iron-catalyzed tandem isomerization-intramolecular aldolization reaction was developed to prepare cyclohexenone derivatives bearing substituents on the double bond, and it has been applied in a short synthesis of 4-epi-gabosines A and B, from d-glucose.