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: 7912932
• 负责人: Bimal K Banik
• 金额: $ 19.27万
• 依托单位: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7912932
• 关键词: American; Amides; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Apoptosis; Apoptotic; Binding; Biochemical Pharmacology; Biological Models; Cancer cell line; Cancerous; Cell Cycle; Cells; Cholesterol; Chrysenes; Cisplatin; Classification; DNA Repair; DNA Replication Induction; Data; Diamide; Elements; Enzymes; Exhibits; G2/M Transition; Genes; Goals; Human; Human Cell Line; In Vitro; Induction of Apoptosis; Journals; Lactams; Lead; Learning; Mediating; Metals; Methods; Minority; Monitor; Normal Cell; Normal tissue morphology; Ovarian; Pan Genus; Pathway interactions; Pharmaceutical Preparations; Physical condensation; Plasma; Publishing; Reaction; Relative (related person); Research; Resistance; Screening procedure; Series; Side; Structure-Activity Relationship; Students; System; Testing; Texas; Toxic effect; Tumor Cell Line; Universities; analog; anticancer activity; antitumor agent; base; beta-Lactams; biological systems; cancer cell; cell growth; chemotherapeutic agent; colon cancer cell line; cytotoxicity; design; enolate; experience; flexibility; improved; in vitro activity; in vivo; microwave electromagnetic radiation; novel; phenanthrene; research clinical testing; research study; tumor

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）开发选择性的、有效的先导抗癌β-受体类似物， 在体外和体内都非常有效的内酰胺类药物，以及2）为 参加这项研究的少数民族学生。长期目标是鉴定一种或多种类似物， 临床评价存在对具有高效力、抗肿瘤功效和抗肿瘤活性的新的和新颖的抗癌剂的需要。 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-内酰胺类药物的研究 作为新的化疗剂将是非常及时和有用的。 已经合成了许多具有多环芳族基团的新型β-内酰胺。他们中的一些 已经在体外证明了有希望的抗癌活性。在某些情况下，这一活动超过了 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， 对卵巢癌和结肠癌细胞系的体内抗癌活性达到中等程度。在早期 为了寻找这些化合物的作用机制，初步研究表明， 在癌细胞系中G2/M检查点的极其活跃的阻断。 为了确定结构和机制关系，并更仔细地确定抗癌药物的选择性， 活性，一个扩展系列的精心设计的β-内酰胺类似物，有关的铅化合物将 制备这些包括通过施陶丁格和金属介导的外消旋和光学活性β-内酰胺的合成， 和烯醇化物缩合反应。作为替代方法，这些β-内酰胺的合成 使用家用和自动微波炉也将进行。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 将探讨各种关系，以加强它们的行动。化合物诱导G2细胞周期的能力 将研究用于测试机制目标和功效的封锁。此外，他们反对 将研究DNA复制和细胞凋亡的诱导。在测试该机制的稍后方面中， 为了发挥作用，将完成一个选定的基因阵列，用于检测细胞凋亡的关键因素。的 同样的阵列也将用于检测已知在调节细胞中起重要作用的基因的变化 周期