| The Retinoid X receptor alpha(RXRa),as a ligand-dependent transcriptional,plays a very important role in many physiological processes,such as regulation of cell growth and differentiation.Virtual screening can improve the efficiency of lead compound discovery and has become one of useful means for drug development.This project use Drugbank(2.0)because of old drugs’ Low cost and Proven safety.In this project,24 compounds were obtained from the DrugBank library through virtual screening,and 15 old drugs were purchased for testing their bioactivities.According to the reporter assay,we got two RXRa agonists:Domperidone(12),Rosiglitazone maleate(13),and two RXRα antagonists:Pitavastatin(1),Fluvastatin(4).The surface plasma resonance experiment was conducted,each compound can bind with RXRa-LBD well.The KD for these compounds binding to RXRa-LBD as follow:Pitavastatin(1)KD= 13.30 μM,Fluvastatin(4)KD= 11.04 μM,Domperidone(12)KD=8.80μM,Rosiglitazone maleate(13)KD= 15.01 μM.Finally,3 derivatives(compounds 25,26,27)of Pitavastatin(1)were obtained.The biological activity of derivatives was evaluated by reporter assay and BIAcore.The results showed that the carboxyl group on Pitavastatin was the necessary group to play its transcriptional repression activity,while the hydroxyl groups exhibit little effect.For the bisindolylmethanes project,Firstly,we established the HPLC quantitative method to optimize the reaction conditions.While the equivalent ratio of reactant(XS-0150)and PDC is 1:1.4,the equivalent ratio of reactant(XS-0150)and methanesulfonic acid is 1:5,methanol as solvent,the reaction time is 24 h,we obtained the highest yield of 87.66%(XS-0170).Then,we use the cation exchange resin to purify the product and made the separation yield reached 76.03%.Finally,using this new method,10 salt form of bisindolylmethane derivatives were synthesized,which indicated that this new method can be applied in this kind of reaction widely. |
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