Anticancer Agents--Structure and Synthesis

描述(由申请人提供)：这项研究计划(CA-19033)，现已进入第28个年头，体现了我们对完整的结构表征和高效的、对映选择性合成具有建筑挑战性的抗癌药物的长期承诺。29-31年的主要目标可以分为两个主要冲刺。在(+)-环糊精方面，我们将：(A)采用我们现在有效的第二代方法至少释放一克(+)-环磷唑A，以便将这种重要的药物用于临床前评估；(B)利用先进的环唑类中间体进行详细的构效关系研究；(C)以结构活性结果为指导，设计和合成较不复杂的类似物；以及(D)制备氯乙酸酯、荧光和放射性标记的光亲和类似物，以确定这种重要的抗癌药物的蛋白受体(S)、结合位点(S)和分子作用机制(S)。 在新的靶分子/类似物合成方面，我们将：(E)完成骨苷A的合成策略；(F)在模型研究的基础上设计和合成一系列(+)-骨苷A类似物，以确定这种新的微管蛋白稳定抗肿瘤药物的作用方式和结合部位(S)；(G)完成利特林A、B和C的全合成，采用非羟醛范型构建聚酮结构单元；以及(H)启动一项新的计划，旨在全面合成非常有效的抗肿瘤药物(+)-irciniastatin A和B。在每种情况下，最终目标都将是为未来的生物学研究提供足够的合成材料。 在新的反应/合成方法领域，具体目标包括：(I)开发和探索非羟醛策略的范围，以获得对复杂分子合成重要的各种聚酮片段；以及(J)展示非羟醛策略的效用，以便在已知的具有生物学意义的天然产物支架的基础上，随时构建聚焦文库。 除了这些特定的合成目标之外，这个项目的一个总体的、长期的目标是识别负责生物活性的分子结构。因此，当我们开发每个目标结构的方法时，我们也将准备模型化合物，以允许阐明结构-活性关系。

DESCRIPTION (provided by applicant): This research program (CA-19033), now in the twenty-eighth year, embodies our long-term commitment to the complete structural characterization and efficient, enantioselective synthesis of architecturally challenging anticancer agents. The principle goals for the 29-31 years can be divided into two major thrusts. In the (+)-phorboxazole area, we will: (A) deliver a minimum of one gram of (+)-phorboxazole A employing our now effective second-generation route, in order to make this important agent available for pre-clinical evaluation; (B) exploit the advanced phorboxazole intermediates for a detailed structure-activity study; (C) design and synthesize, guided by the structural activity results, less complex analogs; and (D) prepare chloroacetate, fluorescent, and radiolabeled photoaffinity analogs to define the protein receptor(s), binding site(s), and molecular mechanism(s) of action of this important antitumor agent. In the area of new target molecule/analog synthesis, we will: (E) complete our synthetic strategy for peloruside A; (F) design and synthesize, based on modeling studies, a series of (+)-peloruside A analogs to define the mode of action and binding site(s) of this new tubulin stabilizing antitumor agent; (G) complete the total synthesis of lituarines A, B and C, exploiting a non-aldol paradigm for the construction of polyketide structural units; and (H) initiate a new program directed at the total synthesis of the remarkably potent antitumor agents, (+)-irciniastatin A and B. In each case, the ultimate goal will be to deliver sufficient synthetic material for future biological study. In the area of new reactions/synthetic methods, the specific goals include: (I) develop and explore the scope of the non-aldol tactic to access diverse polyketide fragments of importance to complex molecule synthesis; and (J) demonstrate the utility of the non-aldol tactic for the ready construction of focused libraries based on known natural product scaffolds of biological interest. Beyond these specific synthetic objectives, a general, long-range goal of this program is the identification of the molecular architecture responsible for biological activity. Thus, as we develop an approach to each target structure, we will also prepare model compounds designed to permit the elucidation of structure-activity relationships.