Novel beta-Lactams as New Anti-Cancer Agents

这项应用的主要目标是1)开发选择性的、有效的铅抗癌β-类似物- 在体外和体内都是高效的内酰胺类药物，以及2)创造有效的学习体验 参与本次研究的少数民族学生。长期目标是确定一个或多个类似物 临床评价。存在对新的和新型的抗癌剂的需求，该抗癌剂具有高效、有效地对抗 恶性细胞生长，对非肿瘤细胞的毒性降低。为了实现这一目标，对β-内酰胺类药物的研究 作为新的化疗药物将是非常及时和有用的。 许多具有多环芳香基团的新型β-内酰胺类化合物已被合成。其中一些人 在体外显示了良好的抗癌活性。在某些情况下，此活动超过了 众所周知的临床有用药物顺铂。在初步实验中，其中一种β-内酰胺类药物显示 体内对卵巢癌细胞和结肠癌细胞株具有中等程度的抗癌活性。在早期 为了探索这些化合物的作用机制，初步研究表明 极其活跃地阻断癌细胞株中的G2/M检查点。 确定结构和机理关系，更仔细地确定抗癌药物的选择性 活性，一系列精心设计的与先导化合物相关的β-内酰胺类似物将是 准备好了。其中包括用Staudinger和金属介导法合成外消旋和光学活性的β-内酰胺类， 和烯醇缩合反应。作为一种替代方法，合成这些β-内酰胺类药物 还将进行家用和自动微波炉的使用。体外细胞毒性将被用来 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 将对机械目标和效能测试的封锁进行调查。此外，他们针对 将研究DNA复制和诱导细胞凋亡。在对该机制的测试的稍后方面 在行动上，将完成旨在检查细胞凋亡关键要素的选定基因阵列。这个 同样的阵列也将用于检查已知对调节细胞具有重要作用的基因的变化 周而复始。

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.