Synthesis of Leucascandrolide A: Supplement

描述（由申请人提供）：Leucascandrolide A是一种海洋天然产物，由于其独特的分子结构、强大的细胞毒性和生物起源的模糊性，引起了人们的广泛关注。我们的R01 CA93457拨款的竞争性补充的目的是建立细胞培养设施和环境，以便对芥子糖素内酯A进行全面的基于细胞的评估，旨在确定这种高细胞毒性天然产物的作用方式。这些目标超出了我们最初的应用范围，我们的应用主要集中在开发亮色木糖内酯A的高效化学合成，合成类似物的构建和几种新的合成方法的开发。我们的初步研究已经证明了高度有效和广泛的细胞毒性谱。此外，亮色木犀内酯A对破坏微管蛋白或肌动蛋白微丝没有明显的影响，这强烈提示了另一种作用机制。在这个项目的范围内，我们将进行(a)广泛的细胞毒性和毒性评估，(b)确定结构活性谱，以及(c)设计试剂，以亲和为基础分离亮色candrolide a的细胞靶点。

DESCRIPTION (provided by applicant): Leucascandrolide A is a marine natural product, which attracted considerable attention due to the unique molecular constitution, potent cytotoxic properties and ambiguity of the biogenetic origin. The objective of this competitive supplement to our grant R01 CA93457 is to establish the cell culture facility and the environment in order to conduct comprehensive cell-based evaluation of leucascandrolide A aimed at the determination of the mode of action of this highly cytotoxic natural product. These objectives are beyond the scope of our original application, which was centered on the development of efficient chemical synthesis of leucascandrolide A, construction of synthetic analogs and development of several new synthetic methods. Our preliminary studies have demonstrated highly potent and broad cytotoxicity profile. Furthermore, leucascandrolide A had no noticeable effect on disrupting either tubulin or actin microfilaments, strongly suggesting an alternative mechanism of action. Within the scope of this project we will pursue (a) broad evaluation of cytotoxicity and toxicity of leucascandrolide A. (b) determination of the structure activity profile, and (c) design of reagents for affinity-based isolation of the cellular target of leucascandrolide A.