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.

本应用的主要目标是1）开发铅抗癌β- 在体外和体内非常有效的lacTAMS以及2）为有效的学习经验 参加这项研究的少数族裔学生。长期目标是确定一个或多个类似物 临床评估。需要具有很高效力的新型和新颖的抗癌代理，对 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，对β-内酰胺的研究 由于新的化学治疗剂将非常及时且有用。 已经合成了许多具有多环状芳香族基团的新型β-内酰胺。其中一些 在体外表现出有希望的抗癌活性。在某些情况下，此活动超过了 知名和临床上有用的药物，顺铂。在初步实验中，这些β-内酰胺之一已显示 对卵巢和结肠癌细胞系的体内抗癌活性至中等程度。早点 搜索这些化合物的作用机理，初步研究表明 癌细胞系中G2/M检查点的极端积极封锁。 确定结构和机械关系，并更仔细地识别抗癌的选择性 活动是一系列经过精心设计的β-内酰胺类似物的一系列，与铅化合物有关 准备。这些包括由Staudinger和金属介导的综合外消旋和光学活跃的β-内酰胺， 并融合冷凝反应。作为另一种方法，这些β-内酰胺的合成 还将使用国内和自动微波炉。体外细胞毒性将用于 确定这些类似物的相对活性和逻辑结构基化学途径 将探索关系以增强他们的行动。化合物诱导G2细胞周期的能力 将研究用于测试机械目标和功效的封锁。另外，他们的活动反对 将研究DNA复制和诱导凋亡。在测试机制的后面 在作用中，将完成旨在检查凋亡的关键要素的选定基因阵列。这 同一数组也将用于检查已知在调节细胞中很重要的基因变化 循环。