The Structure-activity Relationship Of Sulindac Derivatives Based On PPARγ-targeting And Nur77-dependent Paraptosis Induced By Diindolyimethane Derivatives

Nuclear receptors are a class of transcription factors which have genomic action and nongenomic action.They may play different role in disease because they are regulated by different ligands or modulators.Here,we have two chapters in our paper.The first chapter is focus on the sulindac derivates structure-activity studies base on regulation PPARγ activity and the effects on diabetes model.Proliferationactivated receptor gamma(PPARγ)is a valuable target for diabetic treatment.Here,we evaluated the PPARγ-based structure-activity relationship of sulindac derivatives.For PPARγ binding and transactivation,meta-substitution in sulindac’s benzylidene moiety was better than para-substitution.Z rather than E configuration of benzylidene double bond endowed derivatives with the selectivity of PPARγ modulation.Moreover,the indene fluorine was essential for binding and regulating PPARγ.Comparing to rosiglitazone,compound 6b with benzyloxy meta-substitution and Z benzylidene double bond slightly induced adipogenesis and moderately induced PPARγ-targeted gene expressions.However,6b potently improved glucose tolerance in the high-fat-diet induced diabetic mice model.Different from rosiglitazone,6b was devoid of apparent toxicity to osteoblastic differentiation.Thus,we provided some useful guidelines for PPARy-based optimization of sulindac and a potential lead for anti-diabetes drug with less side effect.In summary,this study reveals the structureactivity relationship between sulindac derivatives and PPARy.Sulindac derivatives may exert their anti-diabetes effects.This lays the foundation for the Drug development of sulindac derivates.The second chapter is mainly to study the role and mechanism of nuclear receptor Nur77 in paraptosis of breast cancer cells which is induced by Diindolylmethane derivative xs-861 and its oxidation salt xs-589.I3C can form into dimer under acidic condition,and the dimer of I3C is Diindolylmethane.Derivatives of diindolylmethane have been found to inhibit breast cancer cell proliferation by targeting nuclear receptor,but the ways and mechanisms are not clear.We treated breast cancer cells using the diindolylmethane derivative xs-861 and found that it induced cytoplasmic vacuolization of breast cancer cells,which eventually led to cell death.The function of its oxidation salt xs-589 is more powerful.We identified the vacuolization through the transmission electron microscope(TEM),immunofluocence and found that the vacuolization are mainly consisted of endoplasmic reticulum with mitochondria.The diindolylmethane derivatives induced cytoplasmic vacuolization and cell death,while the nucleus remained normal,and did not induce apoptosis nor depended on the activation of caspase.This is the first time to find induction paraptosis in breast cancer cells by diindolylmethane derivative.The paraptosis requires newly proteins.The paraptosis induced by diindolylmethane derivatives can be rescued by translation inhibitors but not transcription inhibitors.In addition to inhibition the new proteins,the translation inhibitors can also lead to a significant reduction of nuclear receptor Nur77.Therefore,we assumed that Nur77 may be involved in the paraptosis induced by the diindolylmethane derivative xs-861.Diindolylmethane derivatives led to Nur77 targeting to mitochondria in our experiment.Mitochondria associated membranes are the interconnection between the endoplasmic reticulum and mitochondria.Nur77 localized to mitochondria associated membranes which induced by diindolylmethane derivatives may affect the permeability of the calcium ions channel,IP3R,which resulted in damage to mitochondria and endoplasmic reticulum.