PLANT ANTITUMOR AGENTS

描述(申请人提供)：我们持续计划的总体目标是确定和开发抗癌临床试验候选化合物，基于通过对选定的药用植物进行集中的疾病导向细胞毒性、机械和基于分子靶标的筛选而分离出来的先导化合物，选择用于治疗癌症的药物(S)或其结构新颖性和有效性。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，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定向分离和有效成分的分离。我们的筛选方法已经被改进，以适应分子靶标和几个重要的信号转导途径和系统/元件的细胞分化和凋亡。两(2)个重要的生长因子受体酪氨酸激酶(EGFR和HER-2)作为一项新的和互补的研究计划被增加。2)利用化学、物理和光谱技术对新的活性引线进行结构表征。3)将选择具有显著活性的先导化合物进行修饰和模拟合成，以确定结构-活性关系(SAR)以及改善药理图谱。传统的合成孔径雷达、分子模拟和组合化学技术被用来辅助铅的产生和优化。优先研究的化合物/植物包括乳腺癌活性物质(例如新丹参酮及其类似物、新的加本花活性成分)、前列腺癌活性物质(新的姜黄素类似物)和分化/凋亡诱导剂(新的水溶性二硫吩衍生物)。4)随后的深入作用机制研究和额外的体外和体内抗肿瘤评估将由国家卫生研究院(NIH)在国家癌症研究所(NCI)以及几个企业和学术合作者进行。我们的计划具有以下优势：1)大量高效的先导化合物和前景看好的细胞毒性植物物种，包括来自NCI天然产品储存库计划(NCI-NPRP)的热带雨林物种；(2)作为临床试验候选者的新的作用机制，在分离和结构修饰方面具有极高的生产力，这反过来可能导致癌症化疗的创新方法；以及(3)由于几项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，因此我们有很好的前景开发出一种临床有用的药物。

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.