DIVERSE NATURAL PRODUCTS FROM ISOLATION AND CHEMICAL MODIFICATION

癌症可以被认为是一种细胞间信号改变的疾病。 这些研究的目标是识别和开发新的天然 产物对癌基因信号转导通路的抑制作用 癌症的治疗和预防。信令目标将是 包括磷脂信号转导酶(磷脂酰肌醇 磷脂酶C、磷脂酰肌醇-3-激酶和磷脂酶D)， 蛋白丝氨酸/苏氨酸激酶(Raf-1、MEK和MAP-1) 和调节细胞周期的酶(cdc26磷酸酶和 CDK4激酶)。天然产品的来源将是用于 传统中药、美洲原住民药用植物、真菌 萃取物和天然产物的组合文库 分子(“前体”)。《中国》中确定的合作者将 经香港提供覆盖草药主要栖息地的植物 成长在中国身上。易于获得的天然产品，具有趣味性 生物活性，将作为“生物支架”来准备 产品的不同混合物(“前体”)通过使用非选择性 试剂、反应和/或反应条件。有效的销售线索将是 使用高性能生物测定定向指纹进行鉴定 对每一种粗提物或混合物进行高效液相色谱分离 “前体”，96孔微滴定板中的馏分，将被 已提交进行筛选。每一组分的指纹将会是 以二极管收集的紫外/可见光光谱的形式提供 阵列探测器，并存储在数据库中。论现役人员的认定 分数，原始参照板将被检索和质量 波谱和核磁共振等波谱数据将被收集在活跃的 威尔斯来完成指纹识别。这个指纹将被用来 重新收集所需的材料以进行进一步的提纯和测试 将通过最先进的方法在有机化合物中进行结构解析 化学反应。与已发现的活性化合物结构相似的化合物 将通过合成或在可行的情况下从其他来源获得， 已经检查过了。在生化反应中表现出活性的纯化合物 将对目标筛选的生长抑制活性进行评估 体外肿瘤细胞及体外活性较高的化合物 将在体内进行进一步的评估。前景看好的临床前研究进展 先导化合物将由我们的商业合作伙伴进行。

Cancer can be considered a disease of altered intercellular signalling. The goal of these studies is to identify and develop novel natural product inhibitors of oncogene signalling pathways for the effective treatment and prevention of cancer. The signalling targets which will be used include enzymes of phospholipid signaliing (phosphatidylinositol phospholipase C, phosphatidylinositol-3-kinase and phospholipase D), protein serine/threonine kinases (Raf-1 kinase, MEK kinase and MAP- kinase) and enzymes that regulate the cell Cycle (cdc26 phosphatase and cdk4 kinase). The sources of the natural products will be plants used in traditional Chinese medicine, native Americans' medicinal plants, fungal extracts, and combinatorial libraries of natural product derived molecules ("progenomers"). Identified collaborators in China will provide, via Hong Kong, plants which cover the major habitats of herbal growth in China. Readily available natural products with interesting biological activities, will be used as "biological scaffolds" to prepare diverse mixtures of products ("progenomers") by use of non-selective reagents, reaction and/or reaction conditions. Active leads will be identified by bioassay-directed fingerprinting using high performance liquid chromatography to obtain for each crude extract or mixture of "progenomers", fractions in 96 well microtiter plates, which will be submitted for screening. Fingerprints of each of these fractions will be available in the form of ultraviolet/visible spectra collected by a diode array detector and stored in a data bank. On identification of active fractions, the original reference plate will be retrieved and mass spectra and NMR and other spectral data will be collected on the active wells to complete the fingerprinting. This fingerprint will be used to recollect the desired material for further purification and testing Structure elucidation will be done by state of the art methods in organic chemistry. Compounds of analogous structures to those found to be active will be obtained by synthesis or from other sources, where practical, and screened. The pure compounds exhibiting activity in the biochemical target screens will be evaluated for growth inhibitory activity against tumor cells in vitro and those compounds of sufficient in vitro activity will be further evaluated in vivo. Preclinical development of promising lead compounds will be carried out by our commercial collaborator.