INHIBITION OF THE ANTICANCER TARGET GLYOXALASE I
INHIBITION OF THE ANTICANCER TARGET GLYOXALASE I
批准号:
6628300
负责人:
Donald Creighton
金额:
$31.57万
依托单位国家:
美国
项目类别:
财政年份:
1996
资助国家:
美国
项目状态:
已结题
起止时间:
1996-04-02 至 2005-01-31
中文摘要
在此更新申请中,我们建议继续开发
英文摘要
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.
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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
影响因子:
--
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.
影响因子:
--
作者:
[Hamilton,DS, Kavarana,MJ, Sharkey,EM, Eiseman,JL, Creighton,DJ]
通讯作者:
Creighton,DJ
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]
通讯作者:
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.
影响因子:
--
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.
影响因子:
--
作者:
[Sharkey,EM, O'Neill,HB, Kavarana,MJ, Wang,H, Creighton,DJ, Sentz,DL, Eiseman,JL]
通讯作者:
Eiseman,JL
共 10 条
GLUTATHIONE DEPENDENT GLYOXALASE PATHWAY
-
批准号:6977022
-
项目类别:
-
资助金额:$0.11万
-
财政年份:2003
-
负责人:Donald Creighton
-
依托单位:
INHIBITION OF THE ANTICANCER TARGET GLYOXALASE I
-
批准号:6497746
-
项目类别:
-
资助金额:$30.73万
-
财政年份:1996
-
负责人:Donald Creighton
-
依托单位:
INHIBITION OF THE ANTICANCER TARGET GLYOXALASE I
-
批准号:2683538
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项目类别:
-
资助金额:$28.57万
-
财政年份:1996
-
负责人:Donald Creighton
-
依托单位:
INHIBITION OF THE ANTICANCER TARGET GLYOXALASE I
-
批准号:6261174
-
项目类别:
-
资助金额:$33.44万
-
财政年份:1996
-
负责人:Donald Creighton
-
依托单位:
INHIBITION OF THE ANTICANCER TARGET GLYOXALASE I
-
批准号:2100208
-
项目类别:
-
资助金额:$26.96万
-
财政年份:1996
-
负责人:Donald Creighton
-
依托单位:
INHIBITION OF THE ANTICANCER TARGET GLYOXALASE I
-
批准号:2390774
-
项目类别:
-
资助金额:$27.26万
-
财政年份:1996
-
负责人:Donald Creighton
-
依托单位:
MECHANISM OF GLYOXALASE I AND FORMALDEHYDE DEHYDROGENASE
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批准号:3280215
-
项目类别:
-
资助金额:$7.64万
-
财政年份:1983
-
负责人:Donald Creighton
-
依托单位:
CATALYTIC MECH:GLYOXALASE I & FORMALDEHYDE DEHYDROGENASE
-
批准号:3280216
-
项目类别:
-
资助金额:$13.53万
-
财政年份:1983
-
负责人:Donald Creighton
-
依托单位:
CATALYTIC MECH:GLYOXALASE I & FORMALDEHYDE DEHYDROGENASE
-
批准号:3280217
-
项目类别:
-
资助金额:$11.59万
-
财政年份:1983
-
负责人:Donald Creighton
-
依托单位:
CATALYTIC MECH:GLYOXALASE I & FORMALDEHYDE DEHYDROGENASE
-
批准号:3280212
-
项目类别:
-
资助金额:$16.17万
-
财政年份:1983
-
负责人:Donald Creighton
-
依托单位:
海外基金