INHIBITION OF THE ANTICANCER TARGET GLYOXALASE I

抗癌靶标乙二醛酶 I 的抑制

• 批准号: 6628300
• 负责人: Donald Creighton
• 金额: $ 31.57万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-02 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628300
• 关键词: active sites; antineoplastics; athymic mouse; carbon sulfur lyase; colon neoplasms; drug design /synthesis /production; enzyme inhibitors; glutathione; leukemia; mass spectrometry; melanoma; neoplasm /cancer pharmacology; prodrugs; prostate neoplasms; sulfoxide

DESCRIPTION: In this renewal application we propose to continue the development of novel new classes of antitumor agents that function by either reversibly or irreversibly inhibiting the enzymes of the glyoxalase pathway. In the previous funding period, we have demonstrated that enediol analog inhibitors (GSC(O)N(OH)R, where GS = glutathionyl) of the first enzyme in the pathway, glyoxalase I, inhibit the growth of murine and human tumors in vitro and in vivo. Growth inhibition appears to be due to the buildup of cytotoxic methylglyoxal, the substrate for the glyoxalase pathway. We have also discovered an efficient 'sulfoxide prodrug' for rapidly generating the enediol analog inside tumor cells. In addition, we have made major advances in our understanding of the structural biochemistry and mechanisms-of-action of glyoxalase I and the second enzyme in the pathway, glyoxalase II. We will now use this information to develop more potent antitumor agents. The specific aims are: 1.) To synthesize the sulfoxide prodrugs CH3(CH)nS(O)C(O)N(OH)C6H4Cl (n = 1,5,8,10), designed to rapidly diffuse into tumor cells and give rise to the enediol analogs via an acyl-interchange reaction with intracellular glutathione. 2.) To test for correlations between the structures of the sulfoxides and their ability to deliver enediol analog into L1210 leukemia and B16 melanoma cells, and to inhibit the growth of these tumors, in culture. 3.) To evaluate the pharmacokinetics and antitumor properties of the most promising sulfoxide prodrugs in mice bearing B16 melanotic melanoma. 4.) To determine the molecular basis of active-site directed irreversible inactivation of GlxI by S-(4-bromo-2,3-dioxobutyl)glutathione. 5.) To synthesize affinity labels of human GlxI, which target either Glu172 or Cys60 in the active site. Some of the affinity labels are designed to be hydrolyzed by GlxII, an enzyme activity that is high in normal cells but low in tumor cells.

在此更新申请中，我们建议继续开发

项目成果

Diffusion-dependent kinetic properties of glyoxalase I and estimates of the steady-state concentrations of glyoxalase-pathway intermediates in glycolyzing erythrocytes.

乙二醛酶 I 的扩散依赖性动力学特性以及糖酵解红细胞中乙二醛酶途径中间体的稳态浓度估计。

• DOI: 10.1111/j.1432-1033.1997.00852.x
• 发表时间: 1997
• 期刊: European journal of biochemistry
• 作者: Shih,MJ;Edinger,JW;Creighton,DJ
• 通讯作者: Creighton,DJ

A new method for rapidly generating inhibitors of glyoxalase I inside tumor cells using S-(N-aryl-N-hydroxycarbamoyl)ethylsulfoxides.

一种使用 S-(N-芳基-N-羟基氨基甲酰基)乙基亚砜在肿瘤细胞内快速生成乙二醛酶 I 抑制剂的新方法。

• DOI: 10.1021/jm980712o
• 发表时间: 1999
• 期刊: Journal of medicinal chemistry.
• 作者: Hamilton,DS;Kavarana,MJ;Sharkey,EM;Eiseman,JL;Creighton,DJ
• 通讯作者: Creighton,DJ

Bivalent transition-state analogue inhibitors of human glyoxalase I.

• DOI: 10.1021/ol035917s
• 发表时间: 2003-11
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Zhe-Bin Zheng;D. J. Creighton

Selective inhibition of MCF-7(piGST) breast tumors using glutathione transferase-derived 2-methylene-cycloalkenones.

使用谷胱甘肽转移酶衍生的 2-亚甲基环烯酮选择性抑制 MCF-7(piGST) 乳腺肿瘤。

• DOI: 10.1021/jm058245f
• 发表时间: 2005
• 期刊: Journal of medicinal chemistry.
• 作者: Joseph,Erin;Ganem,Bruce;Eiseman,JulieL;Creighton,DonaldJ
• 通讯作者: Creighton,DonaldJ

Pharmacokinetics and antitumor properties in tumor-bearing mice of an enediol analogue inhibitor of glyoxalase I.

乙二醛酶 I 烯二醇类似物抑制剂在荷瘤小鼠中的药代动力学和抗肿瘤特性。

• DOI: 10.1007/s002800000130
• 发表时间: 2000
• 期刊: Cancer chemotherapy and pharmacology.
• 作者: Sharkey,EM;O'Neill,HB;Kavarana,MJ;Wang,H;Creighton,DJ;Sentz,DL;Eiseman,JL
• 通讯作者: Eiseman,JL