Total Synthesis of Bioactive Compounds

描述（由申请人提供）：本提案的主要目标是开发几种具有强效药理活性的海洋衍生天然产物的合成，这些天然产物目前仅以有限的数量提供。特异性靶分子包括柱酰胺A、阿武拉土内酰胺A和去甲软海绵素B的C29-C53亚基以及软海绵素B的C29-C54亚基。阿苯酰胺A和阿武拉土内酰胺A是结构上相关的特特拉姆酸大环内酰胺，其特征在于取代的双环[3.3.0]辛烷核和包埋在大环内酰胺内的特特拉姆酸部分。两种化合物均具有有效的生物活性-柱酰胺在低微克/毫升IC[50]值下抑制B16黑色素瘤细胞的生长，阿武拉土内酰胺A抑制P388小鼠白血病细胞的生长，同时沿着抑制超氧阴离子生成的能力。作为这类分子的合成研究的一部分，将开发一种可以显示特特拉姆酸大环内酰胺的简单支架，作为双环[3.3.0]辛烷核心的替代物。去甲软海绵素B和软海绵素B是复杂的海洋来源的聚醚，其显示出显著有效的体外和体内抗癌活性（GI[50]值<InM，相对于一系列细胞系）。从天然来源获得合理量的软海绵素似乎是不可能的，并且目前它们的复杂结构似乎排除了提供可行解决方案的合成。已观察到截短的软海绵素结构具有相当有效的生物活性，并且将开发去甲软海绵素B的C29-C53亚基和软海绵素B的C29-C54亚基的简明合成，这将为进一步的生物学研究提供材料。

DESCRIPTION (provided by applicant): The principal objectives of this proposal are to develop syntheses of several marine-derived natural products that possess potent pharmacological activity, and that are currently available only in limited amounts. Specific target molecules include cylindramide A, aburatubolactam A, and the C29-C53 subunit of norhalichondrin B, and the C29-C54 subunit of halichondrin B. Cylindramide A and aburatubolactam A are structurally related tetramic acid macrolactams characterized by a substituted bicyclo[3.3.0]octane core and a tetramic acid moiety entrapped within a macrolactam. Both compounds possess potent biological activity - cylindramide inhibits the growth of B16 melanoma cells at low microgram per milliliter IC[50] values, and aburatubolactam A inhibits the growth of P388 murine leukemia cells along with the ability to inhibit superoxide anion generation. As part of synthetic studies on this class of molecules a simple scaffold that can display the tetramic acid macrolactam will be developed as a surrogate for the bicyclo[3.3.0]octane core. Norhalichondrin B and halichondrin B are complex marine-derived polyethers that display remarkably potent in vitro and in vivo anti-cancer activity (GI[50] values of <lnM vs a range of cell lines). Obtaining the halichondrins in reasonable amounts from the natural source seems unlikely, and at present their complex structures seem to preclude synthesis providing a workable solution. Comparably potent biological activity has been observed for truncated halichondrin structures, and concise syntheses of the C29-C53 subunit of norhalichondrin B, and the C29-C54 subunit of halichondrin B will be developed that will provide material for further biological study.