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铅化合物来识别和开发抗癌临床试验候选者，这些化合物是通过使用聚焦疾病的细胞毒性，机械和分子靶标的筛查所选药用植物的筛查来隔离的，该筛查是为了治疗癌症（S）或其结构和陶器的治疗方法。拟议的研究的基本目的是发现针对细胞分裂，死亡和分化的关键信号转导途径的新型抗癌药物。将进行以下具体研究以实现我们的目标。 1）将继续从30个高优先植物提取物中进行生物活性指导的分级和分离活性原理。我们的筛选方法已被完善，以应对分子靶标以及几种重要的信号转导途径以及细胞分化和凋亡的系统/元素。两（2）个重要的生长因子受体酪氨酸激酶（EGFR和HER-2）已被添加为一项新的互补研究计划。 2）新活性导线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铅进行修改和模拟合成，以确定结构活性关系（SAR）并改善药理特征。常规的SAR，分子建模和组合化学技术用于帮助潜在客户产生和优化。研究优先兴趣的化合物/植物包括乳腺癌活性分子（例如，新丙酮酮和类似物，Quassia gabonensis的新活性成分），前列腺癌活性（新的姜黄素类似物）以及分化/凋亡诱导剂（新的水分含量二含双含量）。 4）随后的动作研究以及额外的体外和体内抗肿瘤评估的深入机理将由美国国家癌症研究所（NCI）的国家卫生研究院（NIH）以及几位公司和学术合作者进行。我们的计划具有1）优势供应高度活跃的铅化合物和有希望的细胞毒性植物物种，包括NCI天然产品储备计划（NCI-NPRP）的雨林物种（NCI-NPRP），（2）（2）在隔离和结构性修饰方面出色的生产力和新铅的结构性修饰具有新的动作机制，以进行临床试验的新机制，这是临床试验的最高效果，这是临床竞争的一种象征和癌症的方法（癌症），而癌症是癌症的，而癌症是癌症的，这是一种癌症，而癌症是癌症的，并且是癌症的方法。临床上有用的药物，因为几种技术已获得公司合作者的许可，现在正在进行进一步的体外和体内临床前和临床评估。