PLANT ANTITUMOR AGENTS

描述（由申请人提供）：我们持续项目的总体目标是基于先导化合物来鉴定和开发抗癌临床试验候选药物，所述先导化合物通过使用针对疾病的细胞毒性、机制和基于分子靶标的筛选来分离选定的药用植物，选择所述药用植物是因为其治疗癌症的治疗用途或其结构新奇和效力。这项研究的基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。为实现我们的目标，将开展以下具体研究。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级分离和活性成分的分离。我们的筛选方法已被完善，以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。增加了两种重要的生长因子受体酪氨酸激酶（EGFR和HER-2），作为一项新的补充研究计划。2)将通过化学、物理和光谱技术对新活性电极导线进行结构表征。3)将选择具有显著活性的先导化合物进行修饰和类似物合成，以确定结构-活性关系（SAR）以及改善药理学特征。传统的SAR，分子建模和组合化学技术用于帮助铅的产生和优化。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/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价将由美国国立卫生研究院（NIH）在美国国家癌症研究所（NCI）以及几个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的优质供应，包括来自NCI天然产品储存库计划的雨林物种（2）在作为临床试验候选物的具有新作用机制的新先导物的分离和结构修饰方面的优异生产率，这反过来可以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上级前景，因为几种技术已经被公司合作者许可，并且现在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.