Rhodanine derivatives as novel peroxisome proliferator-activated receptor γ agonists  

作　　者：Qing LIU Yue-yun ZHANG Hui-li LU Qun-yi LI Cai-hong ZHOU Ming-wei WANG 

机构地区：[1]The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

出　　处：《Acta Pharmacologica Sinica》2007年第12期2033-2039,共7页中国药理学报（英文版）

基　　金：Project supported in part by grants from the Shanghai Municipality Science and Technology Development Fund(№ 05dZ22914 and 06DZ22907);the Ministry of Science and Technology(№ 2004CB518902)

摘　　要：Aim： To characterize the in vitro bioactivities of rhodanine derivatives as novel peroxisome proliferator-activated receptor （PPAR） Y modulators, based on a hit （SH0001267l） identified during high-throughput screening （HTS） of a diverse synthetic compound library, and to preliminarily elucidate the structure-activity relationship of this class of PPARYagonists. Methods： Full-length PPARY and retinoid X receptor tx （RXRtx）, biotinylated PPAR response element （PPRE）, [3H]BRL49653 （rosiglitazone）, and streptavidin-coated FlashPlate or microbeads were used to measure the receptor-binding properties of various compounds based on the scintillation proximity assay （SPA） technology. A recombinant PPRE vec- tor was transiently cotransfected with PPARY and RXRα plasmids into the African green monkey kidney （CV-l） cells, and the effects of BRL49653 and test com- pounds on transcription mediated by PPARY were determined by examining lu- ciferase （reporter） responses. 3T3-L1 cells were employed to determine whether the compounds facilitated adipogenesis upon PPAR,/activation. Results： Of the 16 000 samples screened with the SPA method, only l compound （SH00012671） displayed a similar binding affinity （Ki=186.7 nmol/L） to PPAR7 as BRL49653, but it was inactive in the cell-based assays. A series of rhodanine derivatives were synthesized based on the core structure of SH00012671 and 8 of them showed agonist activities in both cotransfection and pre-adipocyte differentiation assays. To reduce intrinsic cytotoxicities, the sulphur on the rhodanine was changed to oxygen. This alteration led to a decrease in receptor-binding affinities while modi- fied analogues generally maintained agonist efficacies in the cell-based assays. Of the analogues studied, compound 31 exhibited about 70% the efficacy exerted by BRL49653 in both cotransfection and pre-adipocyte differentiation assays. Conclusion： Through minor chemical modifications on the core structure of the initial HTS hit, SH00012Aim： To characterize the in vitro bioactivities of rhodanine derivatives as novel peroxisome proliferator-activated receptor （PPAR） Y modulators, based on a hit （SH0001267l） identified during high-throughput screening （HTS） of a diverse synthetic compound library, and to preliminarily elucidate the structure-activity relationship of this class of PPARYagonists. Methods： Full-length PPARY and retinoid X receptor tx （RXRtx）, biotinylated PPAR response element （PPRE）, [3H]BRL49653 （rosiglitazone）, and streptavidin-coated FlashPlate or microbeads were used to measure the receptor-binding properties of various compounds based on the scintillation proximity assay （SPA） technology. A recombinant PPRE vec- tor was transiently cotransfected with PPARY and RXRα plasmids into the African green monkey kidney （CV-l） cells, and the effects of BRL49653 and test com- pounds on transcription mediated by PPARY were determined by examining lu- ciferase （reporter） responses. 3T3-L1 cells were employed to determine whether the compounds facilitated adipogenesis upon PPAR,/activation. Results： Of the 16 000 samples screened with the SPA method, only l compound （SH00012671） displayed a similar binding affinity （Ki=186.7 nmol/L） to PPAR7 as BRL49653, but it was inactive in the cell-based assays. A series of rhodanine derivatives were synthesized based on the core structure of SH00012671 and 8 of them showed agonist activities in both cotransfection and pre-adipocyte differentiation assays. To reduce intrinsic cytotoxicities, the sulphur on the rhodanine was changed to oxygen. This alteration led to a decrease in receptor-binding affinities while modi- fied analogues generally maintained agonist efficacies in the cell-based assays. Of the analogues studied, compound 31 exhibited about 70% the efficacy exerted by BRL49653 in both cotransfection and pre-adipocyte differentiation assays. Conclusion： Through minor chemical modifications on the core structure of the initial HTS hit, SH00012

关 键 词：rhodanine derivatives peroxisome proliferator-activated receptor STRUCTURE-ACTIVITYRELATIONSHIP ADIPOGENESIS 

分 类 号：R96[医药卫生—药理学]