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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.

癌症化学预防领域为基础科学家和临床研究人员的富有成效的合作提供了一个独特的机会，以解决迫切需要的问题。迄今为止，潜在的癌症化学预防剂的最佳实例之一是半合成三萜类化合物2-氰基-3，12-二氧代齐墩果酸-1，9（11）-二烯-28-酸（CDDO），其产生于与天然产物齐墩果酸（来自中草药）的结构活性关系（SAR）。本文所述的拟议工作将扩大我们的知识，三萜类化合物作为小分子化学预防剂，通过专注于bryonolic酸，一种天然产物大量产生的根发芽西洋参。（common zucchini）.我们的目的是研究这种分子对关键炎症相关的致癌标志物的影响，并确定其作为药理学化学预防剂的潜力，特别强调结肠癌。到目前为止，我们已经设计了一种纯化这种分子，产生亚克数量，并说明了其抑制细胞培养模型中iNOS和考克斯-2表达的能力。我们目前正在纯化数克数量的bryonolic酸，这项提案的目标是集中在探索这种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）方法研究三萜类活性（对于苔藓酚酸和整个三萜类家族）的骨骼需求，和2）使用细胞培养和动物模型确定三萜类是否是用于预防胃肠道癌发生的有效药剂。这一建议的战略地位，以潜在地确定新的化学预防剂，可以从丰富的饮食来源，但也回答更基本的问题，三萜类化合物作为化学预防。该项目代表了一个合成有机化学家和癌症生物学家之间的合作奋进，以解决癌症化学预防的问题。所描述的目标将产生新的分子，以测试其化学预防特性。