RESUMO
The perinucleolar compartment (PNC) is a dynamic subnuclear body found at the periphery of the nucleolus. The PNC is enriched with RNA transcripts and RNA-binding proteins, reflecting different states of genome organization. PNC prevalence positively correlates with cancer progression and metastatic capacity, making it a useful marker for metastatic cancer progression. A high-throughput, high-content assay was developed to identify novel small molecules that selectively reduce PNC prevalence in cancer cells. We identified and further optimized a pyrrolopyrimidine series able to reduce PNC prevalence in PC3M cancer cells at submicromolar concentrations without affecting cell viability. Structure-activity relationship exploration of the structural elements necessary for activity resulted in the discovery of several potent compounds. Analysis of in vitro drug-like properties led to the discovery of the bioavailable analogue, metarrestin, which has shown potent antimetastatic activity with improved survival in rodent models and is currently being evaluated in a first-in-human phase 1 clinical trial.
Assuntos
Núcleo Celular , Neoplasias , Biomarcadores/metabolismo , Nucléolo Celular/metabolismo , Nucléolo Celular/patologia , Núcleo Celular/metabolismo , Humanos , Neoplasias/metabolismo , Pirimidinas , PirróisRESUMO
We developed an electrochemical carboamidation sequence that affords either cyclic ß-amidoamine products via direct functionalization or linear hydroxybisamide products via a ring opening pathway. The reaction pathway was dependent on the nature of the N-acyl activating group, with carbamate groups favoring direct isocyanide addition to the N-acyliminium ion intermediate and the benzoyl activating group favoring the ring opening-functionalization pathway. Both protocols are one-pot reaction sequences, have general applicability, and lead to peptide-like products of greatly increased molecular complexity.
Assuntos
Carbamatos , Peptídeos , AminasRESUMO
Novel cellulose derivative CMC-Li was synthesized by cotton as raw material. The mechanism of the CMC-Li modified electrode materials by electrospinning was reported. CMC-Li/lithium iron phosphate (LiFePO4, LFP) composite fiber coated with LFP and CMC-Li nanofibers was successfully obtained by electrospinning. Then, CMC-Li/LFP nano-composite fiber was carbonized under nitrogen at a high temperature formed CNF/LFP/Li (CLL) composite nanofibers as cathode material. It can increase the contents of Li+, and improving the diffusion efficiency and specific capacity. The battery with CLL as cathode material retained close to 100% of initial reversible capacity after 200 cycles at 168 mAh g(-1), which was nearly the theoretical specific capacity of LFP. The cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), X-ray diffraction (XRD) and scanning electron microscope (SEM) were characterizing material performance. The batteries have good electrochemical property, outstanding pollution-free, excellent stability.
Assuntos
Celulase/química , Fibra de Algodão/métodos , Técnicas Eletroquímicas/métodos , Lítio/química , Difração de Raios XRESUMO
Me(3)SiI-promoted reaction of salicylic aldehydes with ketones via arylmethylation at the α-site of the carbonyl group and cyclodehydration of keto-diol provided a facile way to construct heteroannular ketals, furnishing benzopyranic [2,3-b]ketals and spiroketals in moderate to good yields.
Assuntos
Aldeídos/química , Benzopiranos/síntese química , Furanos/síntese química , Cetonas/química , Salicilatos/química , Compostos de Espiro/síntese química , Compostos de Trimetilsilil/química , Furanos/química , Metilação , Estrutura Molecular , Compostos de Espiro/químicaRESUMO
Me(3)SiI-promoted reaction of salicylic aldehydes with ß-dicarbonyl compounds provided a facile way to construct 4H-benzopyrans in moderate to good yields. This tandem reaction proceeds with high efficiency through nucleophilic addition, silyl enol ether formation, substitution, reduction, and intramolecular nucleophilic cyclization.