title: Rhodium(III)-catalyzed regioselective C2-amidation of indoles with N-(2,4,6-trichlorobenzoyloxy)amides and its synthetic application to the development of a novel potential PPARγ modulator.
abstract: A new and efficient method for the direct regioselective C2-amidation of various functionalized indoles with several N-(2,4,6-trichlorobenzoyloxy)amides via Rh(iii)-catalyzed C-H activation/N-O cleavage/C-N formation using the pyrimidyl group as a readily installable and removable directing group has been developed. With this method, a variety of valuable 2-amido indoles can be easily prepared under mild conditions with broad functional group tolerance and excellent region-/site-specificities. Application of this strategy to the synthesis of target compound as a novel PPARγ modulator was also demonstrated. The results from biological evaluation showed that compound had a partial PPARγ agonistic activity and a strong PPARγ binding affinity with an IC50 value of 120.0 nM, along with a less pronounced adipocyte differentiation ability compared to the currently marketed anti-diabetic drug rosiglitazone, suggesting that further development of such a compound might be of great interest.
authors.affiliation: VARI/SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China. yiwei.simm@simm.ac.cn eric.xu@simm.ac.cn.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Shi
authors.forename: Guanguan
authors.initials: G
authors.lastname: Zhao
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000273:Adipose Tissue / Q000378:metabolism; D000577:Amides / Q000737:chemistry*; D000818:Animals; D019556:COS Cells; D002244:Carbon / Q000737:chemistry; D002384:Catalysis; D002454:Cell Differentiation; D002625:Chemistry, Organic / Q000379:methods; D002522:Chlorocebus aethiops; D015195:Drug Design; D006859:Hydrogen / Q000737:chemistry; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry; D010100:Oxygen / Q000737:chemistry; D047495:PPAR gamma / Q000737:chemistry*; D011485:Protein Binding; D012238:Rhodium / Q000737:chemistry*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000737:chemistry
chemical_list: D000577:Amides; D007211:Indoles; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D002244:Carbon; D006859:Hydrogen; D012238:Rhodium; D009584:Nitrogen; D010100:Oxygen