SAR Study Of Bis(3-indolyl)Methane(DIM)Compounds As Anticancer Agents Targeting Orphan Nuclear Receptor Nur77

DIM compounds derived from cruciferous vegetables are modulators of biological processes such as cell cycle arrest and apoptosis through multiple pathways and have remarkable anti-tumor effects.As intracellular molecular switches,nuclear receptors play a vital role in a variety of cellular pathways,including cell proliferation,differentiation and homeostasis.Nuclear receptors are also involved in a variety of pathological processes,including chronic inflammation,lipids disorders,atherosclerosis,diabetes and cancers.Many drugs targeting nuclear receptors have been used in clinical practice.Therefore,nuclear receptors still have been widely studied as drug targets in recent years.Literature search shows that DIM compounds can target the nuclear receptor Nur77 and induce apoptosis of cancer cells.Based on this mechanism,our group carried out a series of structural modifications and SAR studies of DIM compounds.In this thesis,we synthesized 33 novel DIM+derivatives for SAR studies based on structural diversity.The structures were characterized by 1H-NMR,13C-NMR and HR-MS.The purity of all compouds was above 98%by HPLC.All 33 compounds were biologically evaluated by an apoptotic assay and their SAR was analyzed.The structure-activity relationship can be summarized as follows:The antitumor activity is lost when the ortho position on the benzene ring is substituted;Substitution with electron withdrawing groups at the the meta or para position are preferred;The antitumor activity is positively correlated with the substituents'electron withdrawing ability;Replacing the H on the-NH group of one of the indole ring with alkyl chains results in the improvement in compounds',antitumor activity and the best activity is achieved when the alkyl chains is 1-3 carbon atoms long.XS-489 and compound XS-619 are the best compounds with 33 nM and 36 nM,respectively,which is about 5-fold improvement compared to the binding affinity of XS-170 to nuclear receptor Nur77.The structure-activity relationship of other potential candidate drugs is under further study.In Summary,The SAR of DIM+derivatives was studied and the evaluation of the compounds' apoptotic activity in triple negative breast cancer cells was carried out Couple of lead compounds with significant apoptotic activity against triple negative breast cancer were optimized.Furthermore,chemical synthses of this series of compounds were studied and more efficient and cost-effective synthetic route was identified.