New Strategies for the Synthesis of Bioactive Molecules

生物活性分子合成新策略

• 批准号: 6752144
• 负责人: RAYMOND L. FUNK
• 金额: $ 31.72万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6752144
• 关键词: alkenes; antifungal antibiotics; antimetabolites; antineoplastic antibiotics; biological products; carbopolycyclic compound; chemical addition; cyclization; cytotoxicity; diene; drug design /synthesis /production; indoles; marine toxins; neurotransmitter antagonist; nicotinic receptors

DESCRIPTION (provided by applicant): The primary objective of this research is to continue to discover new strategies for the construction of complex carbocyclic or heterocyclic ring systems. A theme throughout this proposal is the further development and exploitation of new, reactive dienophiles and/or heterodienes derived from retrocycloaddition reactions. The new reactants derived from these retrocycloaddition reactions can also be utilized in additional types of cyclization reactions such as intramolecular conjugate addition reactions, olefin metathesis reactions, internal Wittig reactions, etc. It is expected that this new methodology will expedite the syntheses of biologically active natural products and/or analogs. Thus, the architecturally complex cytotoxin communesin B will be assembled by an intramolecular cycloaddition reaction of an indole with an aza-orthoxylylene. The potent anti-microtubule agent welwistatin will be assembled using our newly developed bridged bicycloalkane and indole annulation methodologies. This will permit structure-activity studies of this anticancer agent that has certain pharmacological properties that are superior to the clinically used vinca alkaloids. A related fused bicycloannulation strategy will be used to assemble the perhydroazulene core ring system of the potent antifungal/anticancer natural product pseudolaric acid. The mechanism of action of this compound may be novel and upon completion of the total studies collaborative biological work will be directed toward the identification of the cellular protein target. The potent neuronal nictotinic acetylcholine receptor antagonist dihydro-beta-erythroidine will be assembled using a novel intramolecular cycloaddition of an amidoacrolein. Subsequent analog work will hopefully define the structure activity relationship for this compound and lead to an antagonist with improved subtype selectivity, of potential therapeutic value in smoking cessation and psychostimulant abuse. Finally, the cytotoxic xenicanes, isolated from soft coral, will be prepared from Z-2-acylenal hetero cycloadducts and thence direct metal mediated ring closure of the strained cyclononene. The total synthesis will provide larger quantities of these compounds for biological studies than has heretofore been available.

描述（由申请人提供）：这项研究的主要目的是继续发现建造复杂碳环或杂环环系统的新策略。整个提案中的主题是对从倒角载载反应得出的新的反应性二烯和/或异源的进一步发展和开发。从这些倒角载载反应中得出的新反应物也可以用于其他类型的环化反应，例如分子内结合物添加反应，烯烃的元理解反应，内部wittig反应等。可以预期，这种新方法将加快生物活性活跃的天然产物和/或类似物的生物活跃的生物活性的合成。因此，结构复杂的细胞毒素nimeresin B将由吲哚与AZA-异氧基苯甲酸的分子内环载反应组装。有效的抗微管剂Welwistatin将使用我们新开发的桥接双环烷和吲哚环状方法组装。这将允许对具有某些药理学特性的这种抗癌剂进行结构活性研究，这些药理特性优于临床使用的VINCA生物碱。相关的融合双环策略将用于组装有效的抗真菌/抗真菌/抗癌天然产物伪酸的perhydrozulene Core环系统。该化合物的作用机理可能是新颖的，并且在完成全面研究后，协作生物学工作将针对细胞蛋白靶标的鉴定。有效的神经元胺乙酰胆碱受体拮抗剂二氢β-甲状腺素将使用新型的分子内环载蛋白组装。随后的模拟工作有望定义该化合物的结构活动关系，并导致对拮抗剂的拮抗剂，具有提高亚型的选择性，具有潜在的戒烟和精神刺激性滥用方面的治疗价值。最后，将从Z-2-酰基异源环载体中制备从软珊瑚中分离出来的细胞毒性异种，然后直接直接的金属介导的环形环闭合环闭合。总合成将为生物学研究提供比迄今为止可用的更多这些化合物。