Methods for Bioactive Compound Synthesis

描述(由申请人提供)：这项建议的中心是开发新的系绳方法，在复杂的合成挑战的背景下支持，以帮助解决与生物相关的问题，以推动当前的药物发现努力，朝着开发治疗人类疾病的新型治疗剂和探针的最终目标迈进。虽然历史和传统观点对磷酸盐在有机合成中的使用持怀疑态度，但上一次授权期提供的大量证据突显了磷酸盐作为合成工具的多功能性。与以前的工作相一致，附加系留过程的开发将使这些方法成为通向天然产物全合成的实用和有利的途径。该方法将作为以下不对称合成的基石：(1)IKD-8344，它对不同的细胞系具有很强的驱虫活性、细胞毒性和抗真菌活性；(2)Reidispongiolide A，一种肌动蛋白结合的26元大环内酯，具有治疗多药耐药肿瘤的潜力；(3)Dictyostatin，已被证明具有抗肿瘤/抗有丝分裂活性；(4)Leustroducsin B(LSN-B)，它已显示出抗肿瘤活性，并有可能成为一种新的造血生长因子(HGF)，应用于多种血液系统疾病；和(5)富兰克林内酯A-C，对几种癌细胞具有细胞毒性。总而言之，这种方法的发展代表了一个综合平台，用于小分子合成的新的和强大的系绳系统的出现，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.