Synthesis of the Phosphatidylinositol 3-Kinase Inhibitor

磷脂酰肌醇 3-激酶抑制剂的合成

• 批准号: 6789834
• 负责人: BRIAN A LANMAN
• 金额: $ 4.11万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-20 至 2007-08-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6789834
• 关键词: alkylation; androstane compound; chemical reaction; chemical synthesis; epoxides; intermolecular interaction; kinase inhibitor; method development; phosphatidylinositol 3 kinase; postdoctoral investigator

DESCRIPTION (provided by applicant): Phosphatidylinositol 3-phosphates (PIPs) are intracellular secondary messengers whose aberrant production contributes to the aggressive growth of a wide range of cancers. The fungal secondary metabolite wortmannin is a widely employed phosphatidylinositol 3-kinase (PI3K) inhibitor (IC50 4.2 nM), which represents a promising starting point for the design of isoform-selective PI3K inhibitors which are anticipated to be valuable biochemical and clinical tools for the study and regulation of PIP production. A convergent total synthesis of this structurally intriguing compound is proposed which can provide access to analogues of wortmannin suitable for the development of isoform-selective PI3K inhibitors. Key features of the proposed synthetic route include a novel Stilie coupling between an a-stannyl epoxide and a vinyl triflate and the FriedeI-Crafts alkylation of an acyl furan.

描述（由申请人提供）：磷脂酰肌醇3-磷酸盐（PIPS）是细胞内次级信使，其异常产生有助于广泛的癌症的积极生长。真菌次生代谢产物麦芽醇是一种广泛采用的磷脂酰肌醇3-激酶（PI3K）抑制剂（IC50 4.2 nm），它代表了同类型PI3K抑制剂设计的有希望的起点，预计该研究是有价值的生物化学和临床工具的有价值的生产和临床工具的。提出了该结构上有趣化合物的收敛性总合成，该化合物可以提供适合于开发同工型选择PI3K抑制剂的磨砂蛋白的类似物。所提出的合成路线的关键特征包括a甘南环氧化物和三面乙烯基乙烯基和乙烯基乙烯基烷基化的新型Stilie耦合。