IngentaConnect Novel cyclophilin D inhibitors derived from quinoxaline exhibit h...

Authors: GUO, Hong-xia; WANG, Feng; YU, Kun-qian¹; CHEN, Jing¹; BAI, Dong-lu¹; CHEN, Kai-xian¹; SHEN, Xu²; JIANG, Hua-liang¹

Source: Acta Pharmacologica Sinica, Volume 26, Number 10, October 2005 , pp. 1201-1211(11)

Publisher: Blackwell Publishing

Abstract:

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

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.

Keywords: cyclophilin; quinoxalines; surface plasmon resonance; mitochondrial permeability transition; fluorescence titration; inhibitor

Document Type: Research article

DOI: 10.1111/j.1745-7254.2005.00189.x

Affiliations: 1: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 2: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai

The full text electronic article is available for purchase. You will be able to download the full text electronic article after payment.

$50.16 plus tax Refund Policy

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

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