权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
7641064
负责人：
John James Letterio
金额：
$ 7.85万
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 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7641064
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 Cell Culture Techniques Cells Chemicals Chemistry Chemoprevention Chemopreventive Agent Chinese Herbs Cholesterol Clinical Clinical Research Colon Colon Carcinoma Colonic Neoplasms Communication Communities Couples 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 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 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 Skeleton Source Staging 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 design feeding functional group gastrointestinal human NOS2A protein improved in vivo inhibitor/antagonist knock-down knockout gene lung Carcinoma macrophage meetings men mouse model novel novel therapeutics oleanane prevent prototype response skeletal 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）：癌症化学预防领域为基础科学家和临床研究人员富有成效的合作提供了独特的机会，以解决迫切需要的问题。迄今为止，潜在癌症化学预防剂的最佳例子之一是半合成三萜类化合物 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic 酸 (CDDO)，它是由与天然产物齐墩果酸（来自中草药）的结构活性关系 (SAR) 产生的。本文描述的拟议工作将通过重点关注苔藓酸（一种在发芽的 Curcubita pepo L.（常见西葫芦）根部大量产生的天然产物）来扩展我们对三萜类化合物作为小分子化学预防剂的认识。我们的目标是研究该分子对关键炎症相关致癌标志物的影响，并确定其作为药物化学预防剂的潜力，特别是结肠癌。迄今为止，我们已经设计了该分子的纯化方法，产量为亚克级，并说明了其在细胞培养模型中抑制 iNOS 和 COX-2 表达的能力。我们目前正在纯化数克数量的苔藓酸，该提案的目标集中在探索该分子的化学和生物学。我们的两个具体目标是：1) 使用多样性导向合成 (DOS) 方法研究三萜类化合物活性（对于苔藓酸和整个三萜类化合物家族）的骨骼需求，2) 使用细胞培养和动物模型确定三萜类化合物是否是预防胃肠道癌变的有效药物。该提案具有战略意义，旨在潜在地确定可从丰富的饮食来源中获得的新化学预防剂，同时也回答有关三萜类化合物作为化学预防剂的更基本问题。该项目代表了合成有机化学家和癌症生物学家之间的合作努力，旨在解决癌症化学预防问题。所描述的目标将产生新的分子来测试其化学预防特性。