Methods for Bioactive Compound Synthesis

生物活性化合物的合成方法

• 批准号: 7209463
• 负责人: PAUL R. HANSON
• 金额: $ 25.29万
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7209463
• 关键词: Acids; Address; Apoptosis; Area; Behavior; Biological; Biological Factors; Cancerous; Cell Adhesion; Cell Line; Cells; Characteristics; Chemicals; Chemistry; Cleaved cell; Complex; Coupled; Coupling; Cytoskeleton; Development; Disease; Exhibits; Family; Goals; Hematopoietic; Hematopoietic Cell Growth Factors; In Vitro; Interleukin-3; Laboratories; Left; Logic; Macrolides; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mediating; Methanol; Methodology; Methods; Molecular; Neoplasm Metastasis; Numbers; Pathway interactions; Phosphorus; Process; Property; Protein phosphatase; Protocols documentation; Purpose; Range; Reaction; Research Personnel; Role; Route; Scheme; Shunt Device; Silicon; Streptomyces; Sulfur; analog; base; cell growth; cytostatin; cytotoxicity; dolabelide A; fostriecin; in vivo; inhibitor/antagonist; innovation; inorganic phosphate; isomigrastatin; leustroducsin B; malignant breast neoplasm; member; migrastatin; neoplastic cell; novel; phosphatase inhibitor; phosphate ester; polyol; prevent; programs; small molecule

DESCRIPTION (provided by applicant): The purpose of this proposal is to implement phosphate triester tether methods for the synthesis of complex biologically relevant natural products. We have provided empirical evidence that counters historical and traditional views associated with the utilization of phosphates in synthesis. The logic of implementing phosphate-tethers is predicated in a number of salient features inherent to phosphorus, including: (i) facile multivalent coupling pathways (ii) chirality at phosphorus, (iii) multivalent activation to corresponding carbinol centers via innate leaving group ability within the phosphate tether, (iv) an orthogonal stability/reactivity profile that imparts protecting group features, and (v) inherent nucleophilic characteristics in pendant phosphate esters/acids that enable iodophosphonylation protocols. The proposed method will serve as the cornerstone in the asymmetric synthesis of (1) cytostatin, which is known to inhibit cell adhesion to the extra-cellular matrix by selectively inhibiting protein phosphatase 2A and has been shown to prevent metastasis, inhibit tumor cell growth, inhibit cell adhesion and cause apoptosis in certain cell lines; (2) 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; (3) fostriecin, a potent phosphatase inhibitor that displays in vitro activity against a broad range of cancerous cell lines including lung cancer, breast cancer, and ovarian cancer, as well as in vivo antitumor activity; (4) dolabelides A and B which are a family of recently isolated 22- and 24-membered macrolides that exhibit promising cytotoxicity properties against HeLaSa cells and (5) Iso-migrastatin, a natural product isolated from Streptomyces platens is and a member of the migrastatin family. Migrastatin is a shunt metabolite of iso-migrastatin and has been found to be a potent tumor cell migration inhibitor. The development of this innovative approach represents an integrated platform for the emergence of a new and powerful tether for small molecule synthesis. Overall, the phosphate tether will serve a multi- faceted role as a coupling agent, protecting group, latent leaving group and pendant nucleophile providing multivalent activation and ultimately dictating selective cleavage reactions within several bicyclic and monocyclic phosphate triesters.

描述（由申请人提供）：本提案的目的是实施磷酸三酯系链法合成复杂的生物相关天然产物。我们已经提供了经验证据，反驳历史和传统的观点与利用磷酸盐在合成。实施磷酸盐系绳的逻辑是基于磷固有的一些显著特征，包括：(i)容易的多价偶联途径（ii）磷的手性，（iii）通过磷酸盐系链内固有的离开基团能力对相应的甲醇中心进行多价活化，（iv）赋予保护基团特征的正交稳定性/反应性谱，以及(v)在悬置磷酸酯/酸中固有的亲核特性，使碘膦化方案成为可能。该方法将成为不对称合成(1)细胞抑制素的基础，已知细胞抑制素通过选择性抑制蛋白磷酸酶2A来抑制细胞对细胞外基质的粘附，并已被证明在某些细胞系中具有阻止转移、抑制肿瘤细胞生长、抑制细胞粘附和导致细胞凋亡的作用；(2) 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；(3) fostriecin，一种有效的磷酸酶抑制剂，在体外对多种癌细胞系（包括肺癌、乳腺癌和卵巢癌）具有活性，在体内也具有抗肿瘤活性；(4) dolabelides A和B是最近分离到的22-和24-成员的大环内酯类，它们对HeLaSa细胞具有良好的细胞毒性；(5)isomigrstatin，一种从平板链霉菌中分离到的天然产物，也是migrstatin家族的成员。迁移他汀是异迁移他汀的分流代谢物，已被发现是一种有效的肿瘤细胞迁移抑制剂。这种创新方法的发展代表了一个集成平台，为小分子合成提供了一个新的和强大的系绳。总的来说，磷酸系链将作为偶联剂、保护基团、潜在离开基团和悬垂亲核试剂发挥多方面的作用，提供多价活化，并最终决定几种双环和单环磷酸三酯的选择性裂解反应。