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海洋来源的天然产物的合成，这些天然产物具有强大的药理活性，目前仅限量供应。特定的靶分子包括圆柱酰胺A、阿魏酸内酰胺A和去甲软骨素B的C29-C53亚基，以及野牡丹素B的C29-C54亚基。环丙氨酰胺A和阿布他内酰胺A是结构上相关的四酸大内酰胺类药物，其特征是取代的双环[3.3.0]辛烷核和包埋在大内酰胺中的四酸部分。这两个化合物都具有很强的生物活性-圆锥胺在每毫升低微克IC[50]值下抑制B16黑色素瘤细胞的生长，而阿布妥拉坦A抑制P388小鼠白血病细胞的生长以及抑制超氧阴离子的产生。作为对这类分子的合成研究的一部分，将开发一种能够显示四酸大内酰胺的简单支架，作为双环[3.3.0]辛烷核的替代品。去甲软骨素B和去甲软骨素B是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(与一系列细胞系相比，其GI[50]值为&lt；LNM)。从自然来源获得合理数量的灯盏花素似乎不太可能，而且目前它们的复杂结构似乎排除了合成提供可行解决方案的可能性。已经观察到截短的延胡索乙素结构具有相对较强的生物活性，并将开发去甲灯盏花素B的C29-C53亚基和去甲灯盏花素B的C29-C54亚基的简明合成，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.