DISCOVERY AND EVALUATION OF NOVEL TRITERPENOID CHEMOPREVENTIVES IN A NEW COLON CA

新型三萜化学预防剂在新结肠 CA 中的发现和评价

基本信息

批准号：
7545051
负责人：
John James Letterio
金额：
$ 7.84万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-18 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7545051
关键词：
1-Phosphatidylinositol 3-Kinase 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid Acute Address Adverse effects Animal Model Anti-Inflammatory Agents Anti-inflammatory Antihypertensive Agents Antineoplastic Agents Biological Factors Biological Markers Biology Cancer Death Rates Cancer Patient Cancer cell line Carcinoma Cardiovascular Diseases Cardiovascular system Cells Chemicals Chemistry Chemoprevention Chemopreventive Agent Chinese Herbs Cholesterol Class Clinical Clinical Research Colon Colon Carcinoma Colonic Neoplasms Communication Communities Couples Cultured Cells Data Death Rate Detection Development Diet Disease Doctor of Medicine Dose Drug Delivery Systems Early Diagnosis Employee Strikes Enhancers Enzymes Epigenetic Process Epithelial Epithelial Cells Esters Evaluation Event Family Future Gastrointestinal tract structure Gene Expression Genes Genetic Transcription Genus Cola Germination Goals Growth Factor Hamartomatous Polyp Heart Diseases Human Hydroxyprostaglandin Dehydrogenases Imidazole Immune In Vitro Infarction Inflammation Inflammatory Institution Intestinal Neoplasms Intraperitoneal Injections Janus kinase Knowledge Laboratories Leucine Zippers Link Lymphocytic Infiltrate MADH4 gene Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Mediating Modeling Molecular Mus Mutagenesis Mutation Newly Diagnosed Non-Steroidal Anti-Inflammatory Agents Nuclear Numbers Oleanolic Acid Oncogenic Oral Administration Oxidative Stress PTGS2 gene Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phase I Clinical Trials Phenotype Plant Roots Pre-Clinical Model Prevention Primary carcinoma of the liver cells Process Property Recurrence Refractory Research Research Personnel Risk Role STAT protein STAT3 gene Safety Scientist Serum Signal Transduction Signaling Molecule Skeletal system Skeleton Source Staging Standards of Weights and Measures Steroids Stress Structure-Activity Relationship Syndrome System T-Lymphocyte TNF gene Techniques Testing Therapeutic Time Transforming Growth Factors Translations Tumor Suppressor Proteins Universities Vascular Endothelial Growth Factors Woman Work anticancer research bryonolic acid cancer chemoprevention cancer prevention carcinogenesis celecoxib cyclooxygenase 2 cytokine day design feeding functional group gastrointestinal human NOS2A protein improved in vivo inhibitor/antagonist knock-down knockout gene lung Carcinoma macrophage men mouse model novel novel therapeutics oleanane prevent prototype response small molecule small molecule libraries transcription factor tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): The field of cancer chemoprevention represents a unique opportunity for the fruitful cooperation of basic scientists and clinical researchers to tackle a problem of acute need. One of the best examples to date of a potential cancer chemopreventive is the semisynthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), which was born out of a structure activity relationship (SAR) with the natural product oleanolic acid (from Chinese herbs). The proposed work described herein will expand our knowledge of triterpenoids as small molecule chemopreventives by focusing on bryonolic acid, a natural product abundantly produced in the roots of germinating Curcubita pepo L. (common zucchini). We aim to study the effect of this molecule on key inflammation-related markers of carcinogenesis and determine its potential as a pharmacologic chemopreventive with a special emphasis on colon cancer. To date we have devised a purification of this molecule yielding sub-gram quantities and illustrated its ability to inhibit the expression of iNOS and COX-2 in cell culture models. We are currently purifying multi-gram quantities of bryonolic acid and the goals of this proposal are centered on exploring the chemistry and biology of this molecule. Our two specific aims are: 1) to study the skeletal requirement of triterpenoid activity (for bryonolic acid and the entire triterpenoid family) using a diversity oriented synthesis (DOS) approach, and 2) determine whether triterpenoids are effective agents for the prevention of gastrointestinal carcinogenesis using cell culture and animal models. This proposal is strategically placed to potentially identify new chemopreventive agents which could be obtained from an abundant dietary source, but also to answer more fundamental questions about triterpenoids as chemopreventives. This project represents a collaborative endeavor between a synthetic organic chemist and a cancer biologist to address problems of cancer chemoprevention. The described aims will yield new molecules to be tested for their chemopreventive properties.

描述（由申请人提供）：癌症化学预防的领域是基础科学家和临床研究人员富有成果的合作来解决急需问题的独特机会。迄今为止潜在癌症化学预防的最好的例子之一是半合成三萜2-苯甲酸-3,12-12-12-二氧化碳-1,9（11）-dien-28- oic酸（CDDO），它们与与天然产物硫化硫酸（来自中国植物的硫化产物）的结构活性关系（SAR）出生。本文所述的提议的工作将通过关注bryonolocic酸来扩展我们对三萜类化学的知识，这是一种在发芽的姜黄素的根源中产生的天然产物（常见的西葫芦）。我们旨在研究该分子对癌变的关键炎症相关标记的影响，并确定其作为药理学化学预防的潜力，并特别强调结肠癌。迄今为止，我们已经设计了该分子产生子格的量的纯化，并说明了其在细胞培养模型中抑制iNOS和COX-2表达的能力。我们目前正在净化多克甲酸的数量，该提案的目标集中在探索该分子的化学和生物学上。我们的两个具体目的是：1）研究三萜活性的骨骼需求（对于肌酸和整个三萜类家族），使用以多样性为导向的合成（DOS）方法和2）确定三萜类化合物是否是使用细胞培养和动物模型预防胃肠道癌作用的有效药物。该提案在战略上旨在识别可从丰富的饮食来源获得的新化学预防剂，但也可以回答有关三萜类化学抗化的更多基本问题。该项目代表了合成有机化学家与癌症生物学家之间的合作努力，以解决癌症化学预防问题。所述的目的将产生新的分子，以测试其化学预防特性。