PLANT ANTITUMOR AGENTS

描述（由申请人提供）：我们持续项目的总体目标是确定和开发抗癌临床试验候选药物，基于先导化合物，这些先导化合物是通过对选定的药用植物进行聚焦疾病导向的细胞毒性、机制和分子靶标筛选而分离出来的，被选中的要么是用于治疗癌症的治疗用途，要么是其结构的新颖性和效力。这项研究的基本目的是发现新的抗癌药物，主要针对调节细胞分裂、死亡和分化的关键信号转导途径。为了实现我们的目标，我们将进行以下具体的研究。1)将继续对30种高优先级植物提取物进行生物活性定向分离和活性原理分离。我们的筛选方法已经改进到强调分子靶点和几个重要的信号转导途径和系统/细胞分化和凋亡的元素。两(2)种重要的生长因子受体酪氨酸激酶（EGFR和HER-2）作为一个新的和互补的研究倡议被添加。2)新的活性引线的结构表征将通过化学、物理和光谱技术来完成。3)将选择具有显著活性的先导物进行修饰和类似物合成，以确定结构-活性关系（SAR）并改善药理谱。传统的合成孔径雷达、分子建模和组合化学技术用于帮助先导物的生成和优化。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，加蓬番石榴的新活性成分），前列腺癌活性物质（新的姜黄素类似物）和分化/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和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）在美国国家癌症研究所（NCI）以及一些企业和学术合作者进行。我们的项目具有以下优势：1)高活性先导化合物和有前途的细胞毒性植物物种，包括来自NCI天然产物储存库计划（NCI- nprp）的热带雨林物种；(2)在分离和结构修饰方面具有优异的生产力，具有新的作用机制的新先导物作为临床试验候选物，这反过来可能导致癌症化疗的创新方法。(3)成功开发临床有用药物的良好前景，因为一些技术已经获得公司合作伙伴的许可，目前正在进行进一步的体外和体内临床前和临床评估。

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.