INHIBITION OF THE ANTICANCER TARGET GLYOXALASE I

抗癌靶标乙二醛酶 I 的抑制

• 批准号: 6497746
• 负责人: Donald Creighton
• 金额: $ 30.73万
• 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 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497746
• 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.

描述：在此更新申请中，我们建议继续开发 新型的抗肿瘤药物，通过可逆或 不可逆地抑制谷胱甘肽酶途径的酶。上一 在资助期间，我们已经证明， （GSC（O）N（OH）R，其中GS =谷胱甘肽）， glycoproteinase I在体外和体内抑制鼠和人肿瘤的生长， vivo.生长抑制似乎是由于细胞毒性的积累， 甲基乙二醛，glycoprotein酶途径的底物。我们还 发现了一种有效的“亚砜前药”， 肿瘤细胞内的类似物。此外，我们还在我们的 了解结构生物化学和作用机制， 途径中的第二种酶是谷胱甘肽酶I和谷胱甘肽酶II。我们现在将 利用这些信息来开发更有效的抗肿瘤药物。具体目标 是：1.）合成了亚砜类前药CH_3（CH）_nS（O）C（O）N（OH）C_6H_4Cl（n = 1，5，8，10），旨在快速扩散到肿瘤细胞中，并产生 通过与细胞内的酰基交换反应， 谷胱甘肽2.）的情况。为了测试这些结构之间的相关性， 亚砜及其将恩替卡韦类似物递送到L1210白血病中能力， B16黑色素瘤细胞，并抑制这些肿瘤的生长。3.）第三章 评价最有前途的药物的药代动力学和抗肿瘤特性， 亚砜前药在携带B16黑色素瘤的小鼠中的作用。4.）确定 GlxI活性位点定向不可逆失活的分子基础 S-（4-溴-2，3-二氧代丁基）谷胱甘肽。5.）合成亲和标记物 人GlxI，其靶向活性位点中的Glu 172或Cys 60。一些 亲和标记物被设计为被GlxII水解，GlxII是一种酶活性， 在正常细胞中高，但在肿瘤细胞中低。