Methods for Bioactive Compound Synthesis

描述（由申请人提供）：本提案以开发新的系绳方法为中心，在复杂合成挑战的背景下支持，以帮助解决生物学相关问题，以推进当前药物发现工作，最终目标是开发新的治疗药物和探针来治疗人类疾病。虽然历史上和传统上对磷酸盐在有机合成中的使用持怀疑态度，但在上一个授权期内提供的大量证据突出了磷酸盐作为合成工具的多功能性。与以前的工作一致，其他栓系过程的发展将使这些方法成为天然产物全合成的实用和有利途径。该方法将作为(1)IKD-8344的不对称合成的基础，IKD-8344已显示出对不同细胞系的强驱虫药活性、细胞毒性和抗真菌活性；(2) Reidispongiolide A，一种结合肌动蛋白的26元大环内酯类药物，具有治疗多药耐药肿瘤的潜力；(3) Dictyostatin，已被证明对多种细胞系具有抗肿瘤/抗有丝分裂活性；(4) Leustroducsin B (LSN-B)，具有抗肿瘤活性，有望作为一种新型造血生长因子（HGF）应用于多种造血疾病；(5) Franklinolides A-C，对几种癌细胞具有细胞毒性。总的来说，这种方法的发展代表了一个集成平台，用于小分子合成的新型强大系绳系统的出现，将有助于生物研究类似物的分子设计和化学合成。

DESCRIPTION (provided by applicant): This proposal centers on the development of new tether methods to be championed in the context of complex synthetic challenges to aid in solving biologically relevant problems in order to advance current drug discovery efforts towards the ultimate goal of developing novel therapeutic agents and probes to treat human disease. While historical and traditional views toward the use of phosphates in organic synthesis were skeptical, the body of evidence provided in the last granting period has highlighted the versatilit of phosphates as synthetic tools. In tune with previous work, the development of additional tethered processes will establish these methods as practical and advantageous pathways to the total synthesis of natural products. The proposed method will serve as the cornerstone in the asymmetric synthesis of (1) IKD-8344, which has shown potent anthelmintic acvitivity, cytotoxicity and anti antifungal activity against different cell lines; (2) Reidispongiolide A, an actin-binding 26-membered macrolide that has potential in the treatment of multi- drug resistant tumors; (3) Dictyostatin, which has been shown to have antitumor/antimitotic activity against several cell lines; (4) Leustroducsin B (LSN-B), which has shown antitumor activity and has potential as a novel hematopoietic growth factor (HGF) with application to a number of hematopoietic diseases; and (5) Franklinolides A-C, which display cytotoxicity against several cancer cell lines. Taken collectively, the development of this approach represents an integrated platform for the emergence of new and powerful tether systems for use in small molecule synthesis that will aid in molecular design and chemical synthesis of analogs for biological investigations.