Novel beta-Lactams as New Anti-Cancer Agents

新型 β-内酰胺作为新型抗癌药物

• 批准号: 7163260
• 负责人: Bimal K Banik
• 金额: $ 18.41万
• 依托单位: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7163260
• 关键词: analog; antineoplastics; apoptosis; aromatic hydrocarbon receptor; beta lactam antibiotic; cell cycle; chemical synthesis; cisplatin; drug discovery /isolation; health science research potential; heterocyclic compounds; microarray technology

The principal goals of this application are 1) to develop selective, potent analogues of lead anticancer beta- lactams that are highly effective in vitro and in vivo and 2) to create an effective learning experience for the minority students who participate in this research. The long-term goal is to identify one or more analogues for clinical evaluation. A need exists for new and novel anticancer agents with high potency, efficacy against malignant cell growth yet with reduced toxicity to non-cancerous cells. Toward this goal, studies of beta-lactams as new chemotherapeutic agents would be very timely and useful. A number of novel beta-lactams that have multicyclic aromatic groups have been synthesized. Some of them have demonstrated promising anticancer activity in vitro. In some instances this activity exceeded that of a well-known and clinically useful drug, cisplatin. In preliminary experiments one of these beta-lactams has shown anticancer activity in vivo against ovarian and colon cancer cell lines to a moderate degree. In an early search for the mechanism of action of these compounds, preliminary studies have demonstrated an extremely active blockade of the G2/M checkpoint in cancer cell lines. To identify the structural and mechanistic relationships and to more carefully identify selectivity of anticancer activity, an extended series of carefully designed beta-lactams analogues, related to lead compounds will be prepared. These include synthesis of racemic and optically active beta-lactams by Staudinger- and metal-mediated, and enolate condensation reactions. As an alternative approach, synthesis of these beta-lactams using domestic and automated microwave oven will also be performed. In vitro cytotoxicity will be utilized to determine the relative activity of these analogues and logical structural-stereochemical based pathway relationships will be explored to enhance their action. The ability of compounds to induce G2 cell cycle blockade for tests of mechanistic targets and efficacy will be investigated. In addition, their activity against DNA replication and induction of apoptosis will be studied. In a later aspect of the testing for the mechanism of action, a selected gene arrays designed to examine key elements of apoptosis will be accomplished. The same array will also be used to examine changes in genes known to be of importance in regulating the cell cycle.

本申请的主要目标是 1) 开发先导抗癌β-的选择性、有效类似物 内酰胺在体外和体内都非常有效，2) 为学生创造有效的学习体验 参与这项研究的少数民族学生。长期目标是确定一种或多种类似物 临床评价。需要具有高效能、功效的新型抗癌剂 恶性细胞生长，但对非癌细胞的毒性降低。为了实现这一目标，β-内酰胺的研究 因为新的化疗药物将是非常及时和有用的。 已经合成了许多具有多环芳香基团的新型β-内酰胺。其中一些 已在体外表现出有前景的抗癌活性。在某些情况下，这种活动超过了 众所周知的临床上有用的药物，顺铂。在初步实验中，其中一种β-内酰胺显示 对卵巢癌细胞系和结肠癌细胞系具有中等程度的体内抗癌活性。在早期 为了寻找这些化合物的作用机制，初步研究表明 极其积极地阻断癌细胞系中的 G2/M 检查点。 确定结构和机制关系并更仔细地确定抗癌的选择性 活性，一系列精心设计的与先导化合物相关的β-内酰胺类似物将被 准备好了。这些包括通过施陶丁格和金属介导合成外消旋和光学活性β-内酰胺， 和烯醇缩合反应。作为一种替代方法，合成这些 β-内酰胺 还将使用家用和自动化微波炉进行。体外细胞毒性将用于 确定这些类似物的相对活性和基于逻辑结构-立体化学的途径 将探索关系以加强他们的行动。化合物诱导 G2 细胞周期的能力 将调查机械目标和功效测试的封锁。此外，他们的活动针对 将研究DNA复制和细胞凋亡的诱导。在稍后的机制测试方面 在行动中，将完成设计用于检查细胞凋亡关键要素的选定基因阵列。这 相同的阵列还将用于检查已知对调节细胞具有重要意义的基因的变化 循环。