Synthesis of the Apoptosis-Inducing Alkaloid Monanchocidin

诱导细胞凋亡的生物碱Monanchocidin的合成

• 批准号: 8256495
• 负责人: Ryan Lloyd Patman
• 金额: $ 4.92万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-23 至 2014-08-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256495
• 关键词: Address; Adverse effects; Alkaloids; Alkylation; Alkynes; Apoptosis; Biological; Biological Factors; Cell Nucleus; Complex; Coupling; Cyclization; Development; Disease; Family; Family member; Fatty Acids; Goals; Guanidines; Inhibition of Cancer Cell Growth; Lead; Malignant Neoplasms; Marines; Metals; Methodology; Methods; Natural Resources; Nature; Palladium; Production; Public Health; Reaction; Reagent; Relative (related person); Research; Resources; Route; Scheme; Side; Structure; Synthesis Chemistry; Testing; Transition Elements; analog; cancer therapy; cancer type; chemotherapy; combat; flexibility; improved; innovation; member; novel; stereochemistry

DESCRIPTION (provided by applicant): Many medicinal reagents for the treatment of cancer originate from natural resources. To obtain sufficient quantities of these molecules and to improve their biological profile it is often necessary to produce these compounds synthetically. Monanchocidin, a member of the crambescidin family, is an attractive target for synthesis due to its complex structure and promising inhibition of cancer cell growth. An innovative strategy is proposed to address the synthesis of this molecule employing palladium catalyzed asymmetric allylic alkylation (AAA) and a novel hydroguanidination/cyclization sequence. The objective of this proposal is to develop a concise enantioselective synthesis of monanchocidin using newly developed reactions. We hypothesize that the pentacyclic guanidine can be rapidly assembled stereoselectively by developing a transition metal catalyzed hydroguanidination reaction. The specific aims of this project are; (1) to utilize palladium-catalyzed asymmetric allylic alkylation to construct the pyrolidine core of monanchocidin and other crambescidin family members, (2) develop and implement a novel transition-metal catalyzed hydroguanidination-spirocyclization method to assemble the pentacyclic guanidine, (3) develop an expedient synthetic route to access the fatty acid side chain in monanchocidin, and (4) develop a fragment coupling strategy that provides an efficient and modular route toward the first total synthesis of monanchocidin. The proposed research will be executed in an efficient manner by synthesizing key fragments enantioselectively and coupling them to the pyrolidine core of monanchocidin; assembled via palladium catalyzed asymmetric allylic alkylation (AAA). A novel method for construction of the pentacyclic guanidine of monanchocidin will be developed using a transition metal catalyzed hydroguanidination. An examination of transition metals typically used in hydroamination reactions will be conducted and the most efficient of these will be further optimized and employed in the proposed synthesis. PUBLIC HEALTH RELEVANCE: During the last half century, many of the current treatments for various types of cancer have been inspired by nature. Obtaining sufficient quantities of these compounds for proper testing remains a major limitation for their use as chemotherapies. Synthetic chemistry is one resource that enables the production of these molecules and the flexibility of this approach typically enables the synthesis of analogs that in many cases show improved activities or fewer side effects critical for their development as medicinal reagents to improve public health.

描述（由申请人提供）：许多用于治疗癌症的药物试剂都源自自然资源。为了获得足够数量的这些分子并改善它们的生物学特征，通常需要合成生产这些化合物。 Monanchocidin 是 Crambescidin 家族的一员，由于其复杂的结构和有望抑制癌细胞生长，因此成为一个有吸引力的合成靶点。提出了一种创新策略，利用钯催化的不对称烯丙基烷基化 (AAA) 和新型氢胍化/环化序列来合成该分子。该提案的目的是利用新开发的反应开发一种简明的对映选择性合成莫南乔丁的方法。我们假设五环胍可以通过过渡金属催化的氢胍反应快速立体选择性地组装。该项目的具体目标是： (1)利用钯催化的不对称烯丙基烷基化构建monanchocidin和其他crambescidin家族成员的吡咯烷核心，(2)开发并实施一种新型过渡金属催化的氢胍化-螺环化方法来组装五环胍，(3)开发一种获取莫南乔丁中脂肪酸侧链的便捷合成途径，以及 (4) 开发一种片段偶联策略，提供首次全合成莫南乔丁的高效模块化路线。拟议的研究将以对映选择性合成关键片段并将其与莫南乔丁的吡咯烷核心偶联的方式有效地进行；通过钯催化的不对称烯丙基烷基化（AAA）组装。将使用过渡金属催化的氢胍化来开发一种构建莫南乔菌素五环胍的新方法。将对通常用于加氢胺化反应的过渡金属进行检查，并且将进一步优化其中最有效的过渡金属并将其用于所提出的合成中。 公共健康相关性：在过去的半个世纪中，当前针对各种类型癌症的许多治疗方法都是受到大自然的启发。获得足够数量的这些化合物进行适当的测试仍然是它们用作化疗的主要限制。合成化学是能够生产这些分子的一种资源，这种方法的灵活性通常能够合成类似物，这些类似物在许多情况下表现出改善的活性或更少的副作用，这对于将其开发为改善公众健康的医用试剂至关重要。