ABSTRACT
Fourteen bergenin/cinnamic acid hybrids were synthesized, characterized and evaluated for their antitumour activity both in vitro and in vivo. The most potent compound, 5c, arrested HepG2 cells (IC50 = 4.23 ± 0.79 µM) in the G2/M phase and induced cellular apoptosis. Moreover, compound 5c was also found to suppress the tumour growth in Heps xenograft-bearing mice with low toxicity. In the mechanistic study, 5c administration ignited a mitochondria-mediated apoptosis pathway of HepG2 cell death. Furthermore, 5c activated Akt-dependent pathways and further decreased the expression of the Bcl-2 family of proteins. The downstream mitochondrial p53 translocation was also significantly activated, accompanied by an increase of the caspase-9, caspase-3 activation. These data imply that bergenin/cinnamic acid hybrids could serve as novel Akt/Bcl-2 inhibitors for further preclinical studies.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Benzopyrans/chemistry , Benzopyrans/therapeutic use , Cinnamates/chemistry , Cinnamates/therapeutic use , Liver Neoplasms/drug therapy , Liver/drug effects , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Benzopyrans/pharmacology , Caspase 3/metabolism , Caspase 9/metabolism , Cinnamates/pharmacology , Esterification , Female , G2 Phase , Hep G2 Cells , Humans , Liver/metabolism , Liver/pathology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Mice , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolismABSTRACT
Esculetin, synonymous with 6,7-dihydroxycoumarin, is the main active ingredient of the traditional Chinese medicine Cortex Fraxini. The twig skin or trunk bark of Cortex Fraxini are used by herb doctors as a mild, bitter liver and gallbladder meridians' nontoxic drug as well as dietary supplement. Recently, with a variety of novel esculetin derivatives being reported, the molecular mechanism research as well as clinical application of Cortex Fraxini and esculetin are becoming more attractive. This mini-review will consolidate what is known about the biological activities, the mechanism of esculetin and its synthetic derivatives over the past decade in addition to providing a brief synopsis of the properties of esculetin.
Subject(s)
Umbelliferones/chemical synthesis , Umbelliferones/pharmacology , Animals , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/pharmacology , Antioxidants/chemical synthesis , Antioxidants/pharmacology , Drugs, Chinese Herbal , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Medicine, Chinese Traditional , Molecular StructureABSTRACT
An effective synthesis of nucleosides using glycosyl chlorides as glycosyl donors in the absence of Lewis acid has been developed. Glycosyl chlorides have been shown to be pivotal intermediates in the classical silyl-Hilbert-Johnson reaction. A possible mechanism that differs from the currently accepted mechanism advanced by Vorbrueggen has been proposed and verified by experiments. In practice, this catalyst-free method provides easy access to Capecitabine in high yield.
