Novel cyclophilin D inhibitors derived from quinoxaline exhibit highly inhibitory activity against rat mitochondrial swelling and Ca2+ uptake/release

doi:10.1111/j.1745-7254.2005.00189.x

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第三研究室

	Novel cyclophilin D inhibitors derived from quinoxaline exhibit highly inhibitory activity against rat mitochondrial swelling and Ca2+ uptake/release
	Guo, HX ; Wang, F ; Yu, KQ; Chen, Y; Bai, DL; Chen, KX; Shen, X; Jiang, HL
刊名	ACTA PHARMACOLOGICA SINICA
	2005-10
卷号	26 期号:10 页码:1201-1211
关键词	cyclophilin quinoxalines surface plasmon resonance mitochondrial permeability transition fluorescence titration inhibitor
ISSN号	1671-4083
DOI	10.1111/j.1745-7254.2005.00189.x
文献子类	Article
英文摘要	Aim: To investigate methods for identifying specific cyclophilin D(CypD) inhibitors derived from quinoxaline, thus developing possible lead compounds to inhibit mitochondrial permeability transition (MPT) pore opening. Methods: Kinetic analysis of the CypD/inhibitor interaction was quantitatively performed by using surface plasmon resonance (SPR) and fluorescence titration (FT) techniques. IC50 values of these inhibitors were determined by PPIase inhibition activity assays. Results: All the equilibrium dissociation constants (K-D) of the seven compounds binding to CypD were below 10 mu mol/L. The IC50 values were all consistent with the SPR and FT results. Compounds GW2, 5, 6, and 7 had high inhibition activities against Ca2+-dependent rat liver mitochondrial swelling and Ca2+ uptake/release. Compound GW5 had binding selectivity for CypD over CypA. Conclusion: The agreement between the measured IC50 values and the results of SPR and FT suggests that these methods are appropriate and powerful methods for identifying CypD inhibitors. The compounds we screened using these methods (GW1-7) are reasonable CypD inhibitors. Its potent ability to inhibit mitochondrial swelling and the binding selectivity of GW5 indicates that GW5 could potentially be used for inhibiting MPT pore opening.
WOS关键词	CIS-TRANS-ISOMERASE ; INTERMEMBRANE JUNCTIONAL COMPLEXES ; PERMEABILITY TRANSITION ; CELL-DEATH ; CRYSTAL-STRUCTURE ; CYCLOSPORINE-A ; CYTOCHROME-C ; BINDING-SITE ; PROTEIN ; APOPTOSIS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000232346000008
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/273791]
专题	药理学第三研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物发现与设计中心
通讯作者	Shen, X
作者单位	1.Chinese Acad Sci, Grad Sch, Shanghai Inst Biol Sci,Shanghai Inst Mat Med, State Key Lab Drug Res,Drug Discovery & Design Ct, Shanghai 201203, Peoples R China 2.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China
推荐引用方式 GB/T 7714	Guo, HX,Wang, F,Yu, KQ,et al. Novel cyclophilin D inhibitors derived from quinoxaline exhibit highly inhibitory activity against rat mitochondrial swelling and Ca2+ uptake/release[J]. ACTA PHARMACOLOGICA SINICA,2005,26(10):1201-1211.
APA	Guo, HX.,Wang, F.,Yu, KQ.,Chen, Y.,Bai, DL.,...&Jiang, HL.(2005).Novel cyclophilin D inhibitors derived from quinoxaline exhibit highly inhibitory activity against rat mitochondrial swelling and Ca2+ uptake/release.ACTA PHARMACOLOGICA SINICA,26(10),1201-1211.
MLA	Guo, HX,et al."Novel cyclophilin D inhibitors derived from quinoxaline exhibit highly inhibitory activity against rat mitochondrial swelling and Ca2+ uptake/release".ACTA PHARMACOLOGICA SINICA 26.10(2005):1201-1211.