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，目前仅限量供应。特定的靶分子包括柱酰胺A、阿伯拉图内酰胺A、去甲软海绵素B的C29-C53亚基和去甲软海绵素B的C29-C54亚基。柱酰胺A和阿伯拉图内酰胺A是结构相关的四羧酸内酰胺，其特征是取代的双环[3.3.0]辛烷值核心和被包埋在内酰胺内的四羧酸部分。这两种化合物都具有强大的生物活性——圆柱酰胺在低微克/毫升IC[50]值下抑制B16黑色素瘤细胞的生长，而aburatubolactam A抑制P388小鼠白血病细胞的生长，并具有抑制超氧阴离子产生的能力。作为这类分子合成研究的一部分，将开发一种可以显示四羧酸内酰胺的简单支架，作为双环[3.3.0]辛烷核心的替代品。去甲软海绵素B和软海绵素B是一种复杂的海洋衍生聚醚，在体外和体内显示出显著的抗癌活性（对一系列细胞系的GI[50]值<lnM）。从天然来源获得合理数量的软海绵素似乎不太可能，而且目前它们复杂的结构似乎阻碍了合成提供可行的解决方案。截断的软海绵素结构已被观察到具有相当强的生物活性，而去甲软海绵素B的C29-C53亚基的简明合成和软海绵素B的C29-C54亚基的开发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.