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1.
J Am Chem Soc ; 144(41): 18823-18828, 2022 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-36198113

RESUMO

The first total synthesis of daphgraciline has been achieved, which also represents the first example of the synthesis of Daphniphyllum yuzurine-type alkaloids (∼50 members). The unique bridged azabicyclo[4.3.1] ring system in the yuzurine-type subfamily was efficiently and diastereoselectively assembled via a mild type II [5+2] cycloaddition for the first time. The compact tetracyclic [6-7-5-5] skeleton was installed efficiently via an intramolecular Diels-Alder reaction, followed by a benzilic acid-type rearrangement. The synthetically challenging spiro tetrahydropyran moiety in the final product was installed diastereoselectively via a TiIII-mediated reductive epoxide coupling reaction. Potential access to enantioenriched daphgraciline is presented.


Assuntos
Alcaloides , Estrutura Molecular , Reação de Cicloadição , Compostos de Epóxi , Estereoisomerismo
2.
Int J Pharm ; 578: 119177, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32105724

RESUMO

Bacterial therapy is emerging for the treatment of cancers though some scientific and clinical problems have not been addressed. Here, a live drug-loaded carrier, paclitaxel-in-liposome-in-bacteria (LPB), was prepared for inhalation treatment of primary lung cancer, where liposomal paclitaxel (LP) was highly effectively internalized into bacteria (E. coli or L. casei) to get LP-in-E. coli (LPE) or LP-in-L. casei (LPL) by electroporation that had no influence on the growth of these bacteria. Bacteria, LP, the simple mixture of LP and bacteria, and LPB remarkably inhibited the proliferation of A549 lung cancer cells, where LPE was the strongest one. Drug-loaded bacteria delivered the cargos into the cells more quickly than the mixture of drugs and bacteria and the cargos alone. LPE also showed the highest anticancer effect on the rat primary lung cancer among them with the downregulation of VEGF and HIF-1α and the improvement of cancer cell apoptosis after intratracheal administration. Moreover, the bacterial formulations significantly enhanced the expressions of immune markers (TNF-α, IL-4, and IFN-γ) and immune cells (leukocytes and neutrophils). LPB showed much higher bacterial distribution in the lung than other organs after intratracheal administration. LPB is a promising medicine for inhalation treatment of primary lung cancer.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Escherichia coli/metabolismo , Lipossomos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Células A549 , Administração por Inalação , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ratos , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Int J Exp Pathol ; 100(4): 234-243, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31464029

RESUMO

CHARGE syndrome is a congenital disorder with multiple malformations in the craniofacial structures, and cardiovascular and genital systems, which are mainly affected by neural crest defects caused by loss-of-function mutations within chromodomain helicase DNA-binding protein 7 (CHD7). However, many patients with CHARGE syndrome test negative for CHD7. Semaphorin 3E (sema3E) is a gene reported to be mutated in patients with CHARGE syndrome. However, its role in the pathogenesis of CHARGE syndrome has not been verified experimentally. Here, we report that the knockdown of sema3E results in severe craniofacial malformations, including small eyes, defective cartilage and an abnormal number of otoliths in zebrafish embryos, which resemble the major features of CHARGE syndrome. Further analysis reveals that the migratory cranial neural crest cells are scattered in the region of the hindbrain, and the postmigratory neural crest cells are reduced in the pharyngeal arches upon sema3E knockdown. Notably, immunostaining and time-lapse imaging analyses of a neural crest cell-labelled transgenic fish line, sox10:EGFP, show that the migration of cranial neural crest cells is severely impaired, and many of these cells are misrouted upon sema3E knockdown. Furthermore, the sox10-expressing cranial neural crest cells are scattered in chd7 homozygous mutants, which phenocopied the phenotype in sema3E morphants. Overexpression of sema3E rescues the phenotype of scattered cranial neural crest cells in chd7 homozygotes, indicating that chd7 may control the expression of sema3E to regulate cranial neural crest cell migration. Collectively, our data demonstrate that sema3E is involved in the pathogenesis of CHARGE syndrome by modulating cranial neural crest cell migration.


Assuntos
Síndrome CHARGE/genética , Síndrome CHARGE/metabolismo , Movimento Celular , DNA Helicases/genética , DNA Helicases/metabolismo , Semaforinas/genética , Semaforinas/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Síndrome CHARGE/patologia , Técnicas de Silenciamento de Genes , Humanos , Modelos Animais , Crista Neural , Peixe-Zebra/embriologia
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