PLANT ANTITUMOR AGENTS

植物抗肿瘤剂

• 批准号: 6965604
• 负责人: KUO-HSIUNG LEE
• 金额: $ 33.45万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-10 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6965604
• 关键词: analog; antineoplastics; biological signal transduction; breast neoplasms; cell death; cell differentiation; cell growth regulation; chemical models; chemical structure function; chromatography; combinatorial chemistry; computer simulation; drug discovery /isolation; drug screening /evaluation; growth factor receptors; medicinal plants; neoplasm /cancer pharmacology; plant extracts; prostate neoplasms; protein tyrosine kinase; tissue /cell culture

DESCRIPTION (provided by applicant): Overall goals of our continuing program are to identify and develop anticancer clinical trial candidates, based on lead compounds that are isolated by using focused disease-oriented cytotoxicity, mechanistic, and molecular target based screening of selected medicinal plants, chosen either for their therapeutic use to treat cancer(s) or their structural novelty and potency. The fundamental aim of the proposed research is to discover novel anticancer drugs targeted primarily at key signal transduction pathways that regulate cell division, death, and differentiation. The following specific studies will be carried out to accomplish our goals. 1) Bioactivity-directed fractionation and isolation of the active principles from 30 high priority plant extracts will be continued. Our screening approach has been refined to stress molecular targets and several important signal transduction pathways and systems/elements of cellular differentiation and apoptosis. Two (2) important growth factor receptor tyrosine kinases (EGFR and HER-2) have been added as a new and complementary research initiative. 2) Structural characterization of new active leads will be done by chemical, physical, and spectral techniques. 3) Leads with significant activity will be selected for modification and analog synthesis to determine structure-activity relationships (SAR) as well as to improve pharmacological profiles. Conventional SAR, molecular modeling, and combinatorial chemistry techniques are used to aid lead generation and optimization. Compounds/plants of priority interest for investigation include breast cancer actives (e.g., neotanshinlactone and analogs, new active constituents of Quassia gabonensis), prostate cancer actives (new curcumin analogs), and differentiation/apoptosis inducers (new water-soluble dithiophene derivatives). 4) Subsequent in-depth mechanism of action studies and additional in vitro and in vivo antitumor evaluation will be performed by the National Institutes of Health (NIH) at the National Cancer Institute (NCI) as well as several corporate and academic collaborators. Our program has advantages of 1) an excellent supply of highly active lead compounds and promising cytotoxic plant species, including rainforest species from the NCI Natural Product Repository Program (NCI-NPRP), (2) excellent productivity in isolation and structural modification of new leads with new mechanisms of action as clinical trials candidates, which in turn could lead to innovative methods for cancer chemotherapy, and (3) a superior prospect for the successful development of a clinically useful drug, as several technologies have been licensed by corporate collaborators and are now undergoing further in vitro and in vivo preclinical and clinical assessment.

描述（由申请人提供）：我们持续计划的总体目标是基于先导化合物来识别和开发抗癌临床试验候选药物，这些先导化合物是通过对选定的药用植物进行重点疾病导向的细胞毒性、机制和分子靶点筛选而分离出来的，选择它们要么是因为它们用于治疗癌症的治疗用途，要么是因为它们的结构新颖性和效力。该研究的根本目的是发现主要针对调节细胞分裂、死亡和分化的关键信号转导途径的新型抗癌药物。为了实现我们的目标，将进行以下具体研究。 1) 将继续从 30 种高优先级植物提取物中进行生物活性导向的分馏和活性成分分离。我们的筛选方法已经过改进，以适应应激分子靶点和几个重要的信号转导途径以及细胞分化和凋亡的系统/元件。作为一项新的补充研究计划，添加了两 (2) 个重要的生长因子受体酪氨酸激酶（EGFR 和 HER-2）。 2) 新活性先导化合物的结构表征将通过化学、物理和光谱技术来完成。 3) 将选择具有显着活性的先导化合物进行修饰和类似物合成，以确定构效关系（SAR）并改善药理学特征。传统的 SAR、分子建模和组合化学技术用于帮助潜在客户生成和优化。优先研究的化合物/植物包括乳腺癌活性物质（例如新丹参内酯和类似物、加蓬苦木的新活性成分）、前列腺癌活性物质（新姜黄素类似物）和分化/细胞凋亡诱导剂（新的水溶性二噻吩衍生物）。 4）后续深入的作用机制研究以及额外的体外和体内抗肿瘤评估将由美国国立卫生研究院（NIH）、美国国家癌症研究所（NCI）以及一些企业和学术合作者进行。我们的计划具有以下优势：1) 大量供应高活性先导化合物和有前景的细胞毒性植物物种，包括来自 NCI 天然产物存储库计划 (NCI-NPRP) 的雨林物种，(2) 在新先导化合物的分离和结构修饰方面具有出色的生产力具有新的作用机制作为临床试验候选者，这反过来又可能导致癌症化疗的创新方法，以及（3）成功开发临床有用药物的良好前景，因为多项技术已获得企业合作者的许可，并且正在开发中。现在正在进行进一步体外和体内临床前和临床评估。