Methods for Bioactive Compound Synthesis

生物活性化合物的合成方法

• 批准号: 8460397
• 负责人: PAUL R. HANSON
• 金额: $ 27.75万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460397
• 关键词: A549; Actins; Alkylation; Anthelmintics; Antifungal Agents; Antimitotic Agents; Binding; Biological; Biological Factors; Biology; Breast; Cancer cell line; Candida albicans; Cell Line; Cell Proliferation; Cells; Chemicals; Colon; Complex; Coupled; DU145; Development; Diploidy; Disease; Exhibits; Goals; Grant; HT29 Cells; Health; Helminths; Hematopoietic; Hematopoietic Cell Growth Factors; Human; Immunocompromised Host; Investigation; Lung; MEL Gene; Macrolides; Mediating; Methodology; Methods; Microfilaments; Molecular; Multi-Drug Resistance; Mus; Organic Synthesis; Ovary; Pathway interactions; Prevention; Process; Property; Prostate; Reaction; Route; Scheme; Silicon; Skin; System; Therapeutic Agents; Trichinella spiralis; Work; analog; cancer cell; chemical synthesis; cytotoxicity; design; dictyostatin; drug discovery; human disease; inorganic phosphate; interest; leukemia; leustroducsin B; novel; novel therapeutics; pathogen; polymerization; public health relevance; reidispongiolide A; small molecule; tool; tumor

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.

描述（由申请人提供）：该提案集中于开发新的系链方法，该方法将在复杂的合成挑战背景下得到支持，以帮助解决生物学相关问题，从而推动当前的药物发现工作，以实现开发新型治疗剂和探针以治疗人类疾病的最终目标。虽然对磷酸盐在有机合成中的使用的历史和传统观点持怀疑态度，但在最后一个授权期提供的证据突出了磷酸盐作为合成工具的重要性。与以前的工作相一致，其他栓系过程的发展将建立这些方法作为实用和有利的途径，以全合成天然产物。所提出的方法将作为不对称合成（1）IKD-8344的基础，IKD-8344对不同的细胞系显示出有效的驱虫活性、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）网丝菌素，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），已显示出抗肿瘤活性，并有潜力作为一种新型造血生长因子（HGF）应用于多种造血系统疾病;和（5）Franklinolides A-C，其对几种癌细胞系显示细胞毒性。总的来说，这种方法的发展代表了一个综合平台，用于出现新的和强大的系链系统，用于小分子合成，这将有助于分子设计和化学合成类似物的生物学研究。