Synthesis and Biology of Phorboxazole

佛波唑啉的合成及生物学

基本信息

批准号：
7373001
负责人：
Craig J. Forsyth
金额：
$ 22.45万
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 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7373001
关键词：
Address Affinity Antineoplastic Agents Apoptosis Apoptotic Architecture Binding Binding Proteins Biochemistry Biological Biological Assay Biological Factors Biological Testing Biology Cancer cell line Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Death Cell Line Class Complement component C1s Complex Coupled Cyclin-Dependent Kinase 4 Cytokeratin Cytostatics Development Evaluation Family Fluorescence Anisotropy Generations Goals Hela Cells Human In Vitro Indian Ocean Induction of Apoptosis Intermediate Filaments Laboratories Lead Length Ligands Macrolides Malignant Neoplasms Maps Methodology Molecular National Cancer Institute Nuclear Magnetic Resonance Organic Chemistry Outcome PC3 cell line Phase Porifera Proteins Recruitment Activity Relative (related person)Source Structure Surface Plasmon Resonance Testing Therapeutic Therapeutic Agents Validation Variant X-Ray Crystallography analog anti-cancer therapeutic anticancer activity cancer cell cancer therapy cell growth cellular targeting chemotherapeutic agent cytotoxic cytotoxicity design functional group in vitro Assay in vivo innovation macromolecule neoplastic cell novel pharmacophore phorboxazole A pre-clinical receptor receptor binding 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）：phorboxazoles A和B是从印度洋海绵中分离出的结构复杂的天然产品。这些天然产品对美国国家癌症研究所的60种人类癌症系列（平均GI50值<1.6 x 10-9 m;在最低的测试浓度下抑制了100％），并代表了完全新的细胞抑制剂，并且在最有效的细胞稳定剂中被描述为“最有效的细胞抗细胞剂”。 phorboxazoles的作用机理涉及S相细胞周期停滞和凋亡的诱导。总合成提供了少量的天然产物和结构类似物，这些产品用于确定几种结构特征对于有效活性和新铅化合物的重要性。已经开发并使用了phorboxazole A的荧光衍生物，用于分离phorbacazole模拟结合蛋白与HeLa细胞分离。独立发现凤凰类似物与细胞周期蛋白依赖性激酶4（CDK4），细胞角蛋白和其他几种蛋白质结合。 CDK4对phorboxazole类似物诱导的细胞角蛋白中间丝的隔离可能会导致S相细胞周期停滞。然而，凤梨唑相互作用的生物学效应需要完全阐明其他目标。该提案的总体目标是继续开发phorbasazole化学型，作为一种有希望的新型抗癌治疗剂，通过创新进一步的合成有机和生物化学，以独特，快速访问phorboxazazoles的结构类似物，从而验证其细胞量的量化量，并确定必不可少的生物分子量，并确定了必不可少的phosoper量，并确定了量子元素的量。类似物。已经开发了一种新颖而快速的三个成分方法来访问凤凰分子结构，并将耦合到人类癌细胞细胞毒性和选择性筛选，以绘制天然产物的必需药理，并鉴定出具有良好活性特征的简单分子。一系列生物物理研究将用于详细说明配体 - 受体相互作用并有助于靶向验证。该项目的成功结果将完全定义phorboxazoles的细胞抑制和凋亡活性的模式和机制，并将提供独特的小分子治疗候选者。该项目旨在使用phorboxazole天然产物的合成类似物来识别和利用与癌细胞细胞周期进展有关的新型细胞靶标。