RESUMEN
Raptor, a regulatory-associated protein of mTOR, has been genetically proved to be an important regulator in lipogenesis. However, its druggable potential is rarely investigated, largely due to the lack of an inhibitor. In this study, the antiadipogenic screening of a daphnane diterpenoid library followed by target fishing led to the identification of a Raptor inhibitor, 1c (5/7/6 carbon ring with orthoester and chlorine functionalities). Pharmacodynamic studies verified that 1c is a potent and tolerable antiadipogenic agent in vitro and in vivo. Mechanistic studies revealed that the targeting of Raptor by 1c could block the formation of mTORC1 and then downregulate the downstream S6K1- and 4E-BP1-mediated C/EBPs/PPARγ signaling, eventually retarding adipocyte cell differentiation at the early stage. These findings suggest that Raptor can be explored as a novel therapeutic target for obesity and its related complications, and 1c as the first Raptor inhibitor may provide a new therapeutic option for these conditions.
Asunto(s)
Complejos Multiproteicos , Fosfoproteínas , Proteína Reguladora Asociada a mTOR/metabolismo , Fosfoproteínas/metabolismo , Fosforilación , Complejos Multiproteicos/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Euphohyrisnoids A (1) and B (2), two highly rearranged lathyrane diterpenoids featuring a unique tetracyclo[10.2.2.01,10.03,7]cetane and tricyclo[8.4.1.03,7]pentadecane skeleton, respectively, were isolated from the seeds of Euphorbia lathyris. Their structures were determined by detailed spectroscopic analysis and were further confirmed by single-crystal X-ray diffraction. 1 significantly inhibited adipogenesis in 3T3-L1 adipocytes by retarding cell differentiation at the early stage.
Asunto(s)
EuphorbiaRESUMEN
Phytochemical investigation of the leaves and twigs of Croton yanhuii led to the isolation of seven highly modified nor-clerodane diterpenoids (1-7), including three new ones, croyanoids A-C (1-3), along with four known analogues (4-7). Compound 1 incorporates a 5,12-epoxy ring, forming a unique cage-like, 6/6/6/5-fused tetracyclic ring system. Their structures were established by extensive spectroscopic analysis, and the absolute configurations of 1-4 were determined by a combination of circular dichroism (CD) analysis and single-crystal X-ray diffraction. All compounds were tested in an array of bioassays, but were inactive. Crotoeurin A (7), a nor-clerodane dimer with a high yield of 0.2 isolated in current study, was considered as a chemotaxonomic marker for this species.
Asunto(s)
Croton/química , Diterpenos de Tipo Clerodano/química , Células 3T3-L1 , Células A549 , Animales , China , Diterpenos de Tipo Clerodano/aislamiento & purificación , Humanos , Ratones , Estructura Molecular , Óxido Nítrico , Fitoquímicos/química , Fitoquímicos/aislamiento & purificación , Hojas de la Planta/química , Células RAW 264.7RESUMEN
Crotonpenoids A (1) and B (2), two highly modified clerodane diterpenoids featuring a new 10-(butan-2-yl)-1,6,12-trimethyltricyclo[7.2.1.02,7]dodecane skeleton, were isolated from the leaves and twigs of Croton yanhuii. Their structures including the absolute configurations were determined by spectroscopic analysis, single-crystal X-ray diffraction, and biomimetic semisynthesis. Compounds 1 and 2 exhibited an agonistic effect on pregnane X receptor at 10 µM.
