Design, Synthesis, and Interaction Study of Quinazoline-2(1H)-thione Derivatives as Novel Potential Bcl-xL Inhibitors

被引:49
作者
Feng, Yu [2 ]
Ding, Xiao [3 ]
Chen, Tao [1 ]
Chen, Lili [2 ]
Liu, Fang [4 ]
Jia, Xu [2 ]
Luo, Xiaomin [3 ]
Shen, Xu [2 ]
Chen, Kaixian [3 ]
Jiang, Hualiang [3 ]
Wang, Hui [1 ]
Liu, Hong [3 ]
Liu, Dongxiang [2 ]
机构
[1] Chinese Acad Sci, Inst Nutr Sci, Shanghai Inst Biol Sci, Grad Sch, Shanghai 200031, Peoples R China
[2] Chinese Acad Sci, Dept Mol Pharmacol, Shanghai 201203, Peoples R China
[3] Chinese Acad Sci, Ctr Drug Design & Discovery, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
[4] Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Shenyang 110016, Liaoning, Peoples R China
基金
中国国家自然科学基金;
关键词
SMALL-MOLECULE INHIBITOR; BCL-2; APOPTOSIS; PROTEINS; EXPRESSION; CANCER; FORMS;
D O I
10.1021/jm901004c
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Development of inhibitors to antagonize the activities of antiapoptotic Bcl-2 family proteins is of particular interest in cancer chemotherapy. We discovered a quinazoline-2(1H)-thione derivative (DCBL55) as a new Bcl-x(L), Bcl-2, and Mcl-1 inhibitor by virtual database screening. We systematically modified the structure of compound 1 by chemical synthesis. The interactions of the compounds with Bcl-x(L), were predicted by molecular modeling simulations, which were confirmed by structure activity relationship analysis and protein mutation studies. Three locations at the hydrophobic groove of Bcl-x(L), referred to as P2, P4, and P5, were found to contribute to the ligand interactions. Although the compounds induced mitochondrial potential reduction, caspase activation, and ROS generation, the cytotoxicities and the ultrastructural changes of outer mitochondrial membrane suggested that the compounds may target additional proteins outside the Bcl-2 family. Altogether, the present study provides new lead compounds and critical structural information for further development of more potent and specific inhibitors of antiapoptotic Bcl-2 family proteins.
引用
收藏
页码:3465 / 3479
页数:15
相关论文
共 28 条
[1]   Critical upstream signals of cytochrome c release induced by a novel Bcl-2 inhibitor [J].
An, J ;
Chen, YM ;
Huang, ZW .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (18) :19133-19140
[2]   Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL [J].
Degterev, A ;
Lugovskoy, A ;
Cardone, M ;
Mulley, B ;
Wagner, G ;
Mitchison, T ;
Yuan, JY .
NATURE CELL BIOLOGY, 2001, 3 (02) :173-182
[3]   Apoptosis and immaturity in acute myeloid leukemia [J].
Del Principe, MI ;
Del Poeta, G ;
Venditti, A ;
Buccisano, F ;
Maurillo, L ;
Mazzone, C ;
Bruno, A ;
Neri, B ;
Consalvo, MI ;
Lo Coco, F ;
Amadori, S .
HEMATOLOGY, 2005, 10 (01) :25-34
[4]  
EPSTEIN AL, 1978, CANCER-AM CANCER SOC, V42, P2379, DOI 10.1002/1097-0142(197811)42:5<2379::AID-CNCR2820420539>3.0.CO
[5]  
2-4
[6]   Bcl-xL forms two distinct homodimers at non-ionic detergents:: Implications in the dimerization of Bcl-2 family proteins [J].
Feng, Yu ;
Lin, Zhaohu ;
Shen, Xu ;
Chen, Kaixian ;
Jiang, Hualiang ;
Liu, Dongxiang .
JOURNAL OF BIOCHEMISTRY, 2008, 143 (02) :243-252
[7]   ORAL GOSSYPOL IN THE TREATMENT OF METASTATIC ADRENAL CANCER [J].
FLACK, MR ;
PYLE, RG ;
MULLEN, NM ;
LORENZO, B ;
WU, YW ;
KNAZEK, RA ;
NISULA, BC ;
REIDENBERG, MM .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1993, 76 (04) :1019-1024
[8]   Surface plasmon resonance analysis of dynamic biological interactions with biomaterials [J].
Green, RJ ;
Frazier, RA ;
Shakesheff, KM ;
Davies, MC ;
Roberts, CJ ;
Tendler, SJB .
BIOMATERIALS, 2000, 21 (18) :1823-1835
[9]  
KERR JFR, 1994, CANCER-AM CANCER SOC, V73, P2013, DOI 10.1002/1097-0142(19940415)73:8<2013::AID-CNCR2820730802>3.0.CO
[10]  
2-J