RESUMEN
Three new tetrahydrobenzocyclooctabenzofuranone lignan glucosides, longipedunculatins A-C (1-3), a new dibenzocyclooctadiene lignan glucoside, longipedunculatin D (4), a new dibenzocyclooctadiene lignan (5), five new tetrahydrobenzocyclooctabenzofuranone lignans (6-10), and two new simple lignans (11, 12) were isolated from the roots of Kadsura longipedunculata. Their structures and absolute configurations were established using a combination of MS, NMR, and experimental and calculated electronic circular dichroism data. Compound 7 showed moderate hepatoprotective activity against N-acetyl-p-aminophenol-induced toxicity in HepG2 cells with a cell survival rate at 10 µM of 50.8%. Compounds 2, 7, and 12 showed significant in vitro inhibitory effects with an inhibition rate of 55.1%, 74.9%, and 89.8% on nitric oxide production assays at 10 µM.
Asunto(s)
Kadsura/química , Lignanos/aislamiento & purificación , Hígado/efectos de los fármacos , Dicroismo Circular , Ciclooctanos/química , Ciclooctanos/aislamiento & purificación , Ciclooctanos/farmacología , Células Hep G2 , Humanos , Lignanos/química , Lignanos/farmacología , Espectroscopía de Resonancia Magnética , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Raíces de Plantas/química , Sustancias Protectoras/química , Sustancias Protectoras/aislamiento & purificación , Sustancias Protectoras/farmacologíaRESUMEN
Histone deacetylases (HDAC) are being targeted for a number of diseases such as cancer, inflammatory disease, and neurological disorders. Within this family of 18 isozymes, HDAC4 is a prime target for glioma, one of the most aggressive brain tumors reported. Thus, the development of HDAC4 inhibitors could present a novel therapeutic route for glioma. In this work, molecular docking studies on cyclopropane hydroxamic acid derivatives identified five novel molecular interactions to the HDAC4 receptor that could be harnessed to enhance inhibitor binding. Thus, design guidelines for the optimization of potent HDAC4 inhibitors were developed which can be utilized to further the development of HDAC4 inhibitors. Using the developed guidelines, eleven novel cyclopropane hydroxamic acid derivatives were designed that outcompeted all original cyclopropane hydroxamic acids HDAC4 inhibitors studied in silico. The results of this work will be an asset to paving the way for further design and optimization of novel potent HDAC4 inhibitors for gliomas.
