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

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解决迫切需要的问题提供了一个富有成效的合作的独特机会。迄今为止，潜在癌症化学预防的最佳例子之一是半合成三萜2-氰基-3,12-二氧齐墩酸-1,9(11)-二烯-28-果酸（CDDO），它与天然产物齐墩果酸（来自中草药）形成了结构活性关系（SAR）。本文提出的工作将扩大我们对三萜作为小分子化学预防剂的认识，重点关注发芽西葫芦（Curcubita pepo L.，普通西葫芦）根部大量产生的天然产物——苔藓酸。我们的目标是研究该分子对癌症发生的关键炎症相关标志物的影响，并确定其作为药物化学预防的潜力，特别强调结肠癌。到目前为止，我们已经设计出了这种分子的纯化方法，产量为亚克，并在细胞培养模型中证明了它抑制iNOS和COX-2表达的能力。我们目前正在提纯数克数量的苔藓酸，本提案的目标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)使用多样性定向合成（DOS）方法研究三萜活性（对苔藓酸和整个三萜家族）的骨骼需求；2)通过细胞培养和动物模型确定三萜是否是预防胃肠道癌变的有效药物。这一建议具有战略意义，可以从丰富的饮食来源中找到新的化学预防剂，但也可以回答有关三萜化合物作为化学预防剂的更基本问题。这个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，以解决癌症化学预防的问题。所描述的目标将产生用于测试其化学预防性能的新分子。

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.