Synthesis and Biology of Phorboxazole

佛波唑啉的合成及生物学

基本信息

批准号：
7756594
负责人：
Craig J. Forsyth
金额：
$ 25.16万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7756594
关键词：
Address Affect Affinity Apoptotic Architecture Binding Binding Proteins Biochemistry Biological Biological Assay Biological Factors Biology Cell Cycle Arrest Cell Cycle Progression Cell Cycle Regulation Cell Line Complex Coupled Critiques Cyclin-Dependent Kinase 4 Cytokeratin Cytostatics Data Development Ensure Evaluation Goals Hela Cells Human Indian Ocean Induction of Apoptosis Intermediate Filaments Laboratories Lead Length Ligands Light Macrolides Malignant Neoplasms Maps Methods Modification Molecular National Cancer Institute Organic Chemistry Outcome Oxazoles Porifera Principal Investigator Proteins Relative (related person)Research S Phase Screening procedure Serine Side Specificity Structure Study Section Testing Therapeutic Therapeutic Agents Toxicology Validation analog anti-cancer therapeutic cancer cell cellular targeting cytotoxic cytotoxicity drug development editorial high throughput screening innovation novel pharmacophore phorboxazole A premature programs receptor response small molecule

项目摘要

DESCRIPTION (provided by applicant): Phorboxazoles A and B are structurally complex natural products isolated from Indian Ocean sponges. These natural products display extraordinarily potent cytostatic activity towards the US National Cancer Institute's panel of 60 human cancer lines (mean GI50 values of < 1.6 x 10-9 M; most cell lines were 100% inhibited at this lowest test concentration) and represent an entirely new class of cytostatic agents, having been characterized as being "among the most potent cytostatic agents yet discovered." The phorboxazoles' mechanisms of action involve S phase cell cycle arrest and induction of apoptosis. Total synthesis has provided small amounts of the natural products and structural analogs that have been used to identify the importance of several structural features for potent activity and new lead compounds. Fluorescent derivatives of phorboxazole A have been developed and used to isolate phorboxazole analog binding proteins from HeLa cells. Phorboxazole analogs were independently found to bind to cyclin dependent kinase 4 (cdk4), cytokeratins, and several other proteins. The sequestration of cdk4 on cytokeratin intermediate filaments induced by phorboxazole analogs may cause S phase cell cycle arrest. However, the biological effects of phorboxazole interactions other targets needs to be fully elucidated. The overall goal of this proposal is to continue to develop the phorboxazole chemotype as a promising new class of anticancer therapeutic agents by innovating further synthetic organic and biological chemistry to uniquely and rapidly access structural analogs of the phorboxazoles, validate their cellular targets and define the essential biomolecular interactions, determine the essential phorboxazole pharmacophores, and provide mmole quantities of active analogs. A novel and rapid tricomponent approach to access the phorboxazole molecular architecture has been developed and will be coupled human cancer cell cytotoxicity and selectivity screens to map the natural product's essential pharmacophores and identify simpler molecules with favorable activity profiles. An array of biophysical studies will be used to detail ligand-receptor interactions and assist in target validation. The successful outcome of this project will completely define the mode and mechanisms of phorboxazoles' cytostatic and apoptotic activities, and will provide unique small molecule therapeutic candidates. This project seeks to identify and exploit novel cellular targets involved in the progression of the cell cycle of cancer cells using synthetic analogs of the phorboxazole natural products.

描述（由申请人提供）：佛波唑唑 A 和 B 是从印度洋海绵中分离出来的结构复杂的天然产物。这些天然产物对美国国家癌症研究所的 60 种人类癌细胞系（平均 GI50 值 < 1.6 x 10-9 M；大多数细胞系在此最低测试浓度下 100% 被抑制）显示出非常有效的细胞抑制活性，并且代表了完全新型细胞抑制剂，被称为“迄今为止发现的最有效的细胞抑制剂之一”。佛波唑类的作用机制涉及 S 期细胞周期停滞和诱导细胞凋亡。全合成提供了少量的天然产物和结构类似物，这些天然产物和结构类似物已被用来确定几种结构特征对有效活性和新先导化合物的重要性。佛波唑 A 的荧光衍生物已被开发并用于从 HeLa 细胞中分离佛波唑类似物结合蛋白。独立发现佛波唑唑类似物与细胞周期蛋白依赖性激酶 4 (cdk4)、细胞角蛋白和几种其他蛋白质结合。佛波唑类似物诱导的 cdk4 在细胞角蛋白中间丝上的隔离可能导致 S 期细胞周期停滞。然而，佛波唑唑与其他靶点相互作用的生物学效应需要充分阐明。该提案的总体目标是通过进一步创新合成有机化学和生物化学来继续开发佛波唑化学型作为一种有前途的新型抗癌治疗剂，以独特且快速地获得佛波唑的结构类似物，验证其细胞靶点并定义基本的生物分子相互作用，确定基本的佛波唑药效基团，并提供毫摩尔量的活性类似物。已经开发出一种新颖且快速的三组分方法来获取佛波唑唑分子结构，并将与人类癌细胞的细胞毒性和选择性筛选相结合，以绘制天然产物的基本药效团并鉴定具有有利活性特征的更简单的分子。一系列生物物理学研究将用于详细说明配体-受体相互作用并协助靶标验证。该项目的成功成果将彻底明确佛波唑类抑制细胞凋亡和细胞凋亡活性的模式和机制，并提供独特的小分子治疗候选药物。该项目旨在利用佛波唑唑天然产物的合成类似物来识别和开发参与癌细胞细胞周期进展的新细胞靶标。