A General Approach to the Core of the Anti-tumor 6, 7 seco-ent-Kauranes

抗肿瘤核心的一般方法 6, 7 seco-ent-Kauranes

• 批准号: 8077254
• 负责人: Johnathan Edward DeLorbe
• 金额: $ 4.84万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-19 至 2012-07-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8077254
• 关键词: Affinity; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antineoplastic Agents; Architecture; Area; Back; Biological; Biological Factors; Breast; Breathing; Carbon; Chemistry; Cyclization; Development; Disease; Diterpenes; Esterification; Exhibits; Family; Goals; Human; Infection; Isodon; K-562; Ligands; MCF7 cell; Malignant Neoplasms; Methanol; Methodology; Methods; Molecular; Ovarian; Palladium; Pattern; Pharmaceutical Preparations; Phosphines; Play; Preparation; Reaction; Research; Role; Scheme; Screening procedure; Source; Structure; System; Therapeutic; Therapeutic Agents; Toxic effect; Tumor Cell Line; analog; base; catalyst; chemical synthesis; design; drug candidate; feeding; fight against; leukemia; novel; novel therapeutics; ovarian neoplasm; public health relevance; scaffold; small molecule; tumor; undecane

DESCRIPTION (provided by applicant): The goal of the research outlined in this proposal is to investigate the scope and utility of a tandem intramolecular asymmetric Heck cyclization / carbonylation / nucleophile trapping reaction as a general entry to the 2-oxaspiro[5.5]undecane core. Further chemistry, such as transmetallation, heteroatom and hydride addition to the acyl-palladium intermediate will be investigated to determine the scope of the nucleophile trapping. The 2-oxaspiro[5.5]undecane core is an underlying molecular architecture present in greater than 100 compounds belonging to the 6,7-seco-ent-kaurane diterpenoids, which are known to possess antibacterial, anti-tumor, anti-inflammatory, and anti-feeding activity. Initial efforts will focus on the successful development of the Heck cyclization / carbonylation reaction sequence, which could involve an elaborate screening of palladium precatalysts as well as chiral bidentate phosphine ligands. Following the realization of this goal, an efficient chemical synthesis will allow elaboration of the properly functionalized 2- oxaspiro[5.5]undecane core into the natural product maoecrystal Z, a compound exhibiting micromolar affinity against the human tumor cell lines K562 leukemia, MCF7 breast, and A2780 ovarian. This will establish the necessary synthetic groundwork needed for access to this biologically active family of diterpenoids. The challenging structure as well as the exciting biological profile makes this diterpene an intriguing compound for asymmetric total synthesis. PUBLIC HEALTH RELEVANCE: The battle against cancer is ongoing, and small molecules still play a very important role as therapeutics and treatment options. Many of the ent-kaurane diterpenes, including maoecrystal Z, are recognized for their anti-tumor activity and low toxicity, making them attractive anticancer drug candidates. A general approach to these compounds that allows access to analogues is a worthwhile endeavor.

描述(由申请人提供)：本提案中概述的研究目标是调查串联的分子内不对称Heck环化/羰化/亲核试剂捕获反应作为进入2-氧杂螺[5.5]十一烷核心的一般入口的范围和用途。进一步的化学，如跨金属，杂原子和氢化物加成的酰基钯中间体将被研究，以确定亲核捕获的范围。2-氧杂螺[5.5]十一烷核是一种基本的分子结构，存在于100多个化合物中，属于6，7-二烯-金刚烷二萜类化合物，已知具有抗菌、抗肿瘤、抗炎和拒食活性。最初的工作将集中在Heck环化/羰化反应序列的成功开发上，这可能涉及到精心筛选钯前催化剂和手性双齿膦配体。在实现这一目标后，有效的化学合成将使适当功能化的2-氧杂螺[5.5]十一烷核心精制成天然产品毛晶Z，这是一种对人类肿瘤细胞系K562白血病、MCF7乳腺和A2780卵巢表现出微摩尔亲和力的化合物。这将为获得这个具有生物活性的二萜类化合物家族奠定必要的合成基础。具有挑战性的结构和令人兴奋的生物学特性使这种二萜化合物成为不对称全合成的一个有趣的化合物。 与公共卫生相关：与癌症的斗争正在进行中，小分子作为治疗和治疗选择仍然发挥着非常重要的作用。许多对位金刚烷二萜，包括毛晶Z，因其抗肿瘤活性和低毒性而被公认，使它们成为有吸引力的抗癌药物候选者。对于这些化合物，允许获得类似物的一般方法是一项值得努力的努力。