Synthesis and Study of Natural and Non-natural Antiproliferative Agents

描述(申请人提供)：我们研究的主要重点仍然是合成和研究具有已证实或潜在的抗癌活性的复杂分子。开发了高效的实验室合成路线，为研究和生物评价提供了获得具有潜在改进性能的新材料的途径。阐明我们研究的试剂的生物(抗增殖)活性背后的详细化学过程是我们研究的一个主要目标。具体的合成靶标包括天然抗增殖剂艾维菌胺、千金藤素B、盐孢子酰胺、喹诺卡菌素、N1999A2、克达西丁发色团和马多肽素发色团。此外，我们还将进行固相裂解池合成，包括约1,000个安全霉素类似物的文库，具有3-亚烷基3-H-吲哚-1-氧化物功能的小分子文库(~200个化合物)，一类新型的潜在酶(蛋白酶)抑制剂，以及一些喹诺卡星、阿维菌胺和千金藤素B的结构类似物。我们将合成大量天然蛋白酶体抑制剂和抗增殖剂Salinosporide的类似物。根据设计，正在开发的合成路线包括三个结构不同的地点；路线也非常短和有效。我们实验室正在进行一项重大的工作，以阐明沙维菌素的分子靶点(S)，以及分别以阿维菌胺和千金藤素B为代表的一类新的天然抗增殖剂。我们将继续进行研究，以阐明蛋白质靶标3-磷酸甘油醛脱氢酶与双链DNA和金丝桃素的二元复合体相互作用的细节，以及这种相互作用在金丝桃素的抗增殖活性中可能发挥的作用。

DESCRIPTION (provided by applicant): The primary focus of our research continues to be the synthesis and study of complex molecules with proven or potential anti-cancer activity. Efficient laboratory synthetic routes are developed that provide access to new materials with potentially improved properties for study and biological evaluation. The elucidation of the detailed chemical processes that underlie the biological (antiproliferative) activity of the agents we study is a principal goal of our research. Specific synthetic targets include the natural antiproliferative agents avrainvillamide, stephacidin B, salinosporamides, quinocarcin, N1999A2, kedarcidin chromophore, and maduropeptin chromophore. In addition, we will execute a solid-phase split-pool synthesis of a library of ~1,000 saframycin analogs, a small library (~200 compounds) of molecules bearing the 3-alkylidene 3-H- indole-1-oxide function, a novel class of potential enzyme (protease) inhibitors, and a number of structural analogs of quinocarcin, avrainvillamide, and stephacidin B. We will synthesize a large number of analogs of the natural proteasomal inhibitor and antiproliferative agent salinosporamide. By design, the synthetic route under development incorporates three sites of structural variability; the route is also notably short and efficient. A major effort is underway in our laboratory to elucidate the molecular target(s) of the saframycins and, separately, the new class of natural antiproliferative agents represented by avrainvillamide and stephacidin B. We will continue to pursue studies designed to elucidate the details of the interaction of the protein target glyceraldehyde 3-phosphate dehydrogenase (GAPDH) with binary complexes of duplex DNA and saframycins, and the role this interaction may play in the antiproliferative activity of saframycins.