Novel Chromone Compound Induces The Apoptosis Of Gastric Cancer Cells By Targeting Dyskerin:Design、Synthesis And Evaluation

Telomerase up-regulation is found in most of human cancer specimens and provides actively to carcinogenesis.It is formed by reverse transcriptase(TERT),nucleic acid(TERC)and other binding proteins that together work as an active complex.Among these binding ones dyskerin plays an essential role.Dyskerin was found to be associated with both ribosome biogenesis and telomerase complex stabilization and its over-expression has been linked to unfavorable prognosis in a variety of tumor types.Present studies suggest that in one hand losing of dyskerin function decrease TERC and telomerase activity which induce the telomere attrition.In the other hand,lack of dyskerin altered m RNA translation and synthesis of antiapototic factors such as bcl-2and bcl-xl.These finally lead to cell cycle arrest or cell death.Besides,other studies also point out that this gene may play additional roles in nucleo-cytoplasmic shuttling,DNA damage response,and cell adhesion.Since dyskerin plays a vital role in both cellular and individual processes,targeting these processes has been explored for the development of drugs to selectively or preferentially kill cancer cells.Purpose:Design and synthesis Dyskerin inhibitors for selectively or preferentially kill cancer cells.Meanwhile,study their mechanism in oncotherapy.Methods:1.Based on the active site of Dyskerin protein,we screened skeleton structure of active compound via molecular docking and synthesis a series of novel compounds.2.Evaluation of novel compounds via MTT assay,apoptosis analyses,MMP detection and cell cycle analyses.3.To study the mechanism of apoptosis inducing by compound 8 by detecting the levels of associated proteins via western blot.4.To study the target of novel compound via western blot and immunofluorescence assay to verify our design.5.To study whether novel chromone compound 8 is a telomerase inhibitor via TRAP-ELISA-PCR assay.Results: With the help of computer-aided drug design,a series of novel compound as potential dyskerin inhibitors were designed and synthesized.After evaluated of anticancer activity,we found compound 8 is a preferable one that inducing gastric cancer cells SGC-7901 apoptosis by arresting cell cycle,breaking mitochondria function and inhibiting telomerase activity.Meanwhile,western blot and immunofluorescence detection exhibited dramatically decrease of dyskerin expression.All the above suggest that compound 8 is an efficient Dyskerin inhibitor and have significant anticancer activity.Conclusion: These results support dyskerin as a new target for anticancer drug design and encourage our further exploration to the development of new drugs by targeting dyskerin and other telomerase related proteins.