Synthesis of Bioactive Complex Alkaloids

描述（由申请人提供）：本申请是对NIH通知编号NOT-OD-09-058的回应：NIH宣布恢复法案资金可用于竞争性修订申请。 该研究计划的重点是开发新的合成策略，用于生物活性复杂生物碱天然产物的全合成。在每一个全合成目标中，都隐含着发现和利用新反应的目标，这些反应推动了化学合成创新的边界。在这方面，新的策略，全合成几个含胍的复杂生物碱将进行探索。这些类别的靶标包括抗HIV/免疫调节batzelladine生物碱家族、抗癌和离子通道破坏crambescidin生物碱家族、强效细胞毒素cylindrospermopsin和强效免疫抑制剂帕劳'amine。所有这些天然产物表现出显着而独特的生物反应，但它们都是由至少一个胍部分嵌入在一个复杂的多环结构，合成的挑战，将通过调查新的成环策略和反应的氮杂环合成的结构特征。 增加的目的，构成了研究目标的扩展是C19-二萜生物碱的全合成的互补策略的发展。二萜生物碱的C19家族包括大量生物碱，其中的几个成员已经证明作为离子通道功能的调节剂的有效和选择性活性。因此，这些天然产物已被证明是非常有用的分子探针来剖析离子通道生物学。 这些靶分子的成功合成不仅为复杂生物碱合成的有效和实用策略奠定了基础，而且还提供了获得各种健康领域中具有生物学意义和治疗潜力的复杂天然产物的途径，包括小分子细胞毒性/抗癌剂、抗病毒剂和免疫调节剂，以及特异性破坏离子通道功能的独特杂环构建体。 公共卫生相关性：本研究计划的重点是开发新的合成策略，用于生物活性复合胍生物碱天然产物的全合成。这些靶分子的成功合成不仅为复杂分子合成的有效和实用策略奠定了基础，而且还提供了获得各种健康领域中具有生物学意义和治疗潜力的天然产物的途径，包括小分子细胞毒性/抗癌剂、抗病毒剂和免疫调节剂，以及特异性破坏离子通道功能的独特杂环构建体。

DESCRIPTION (provided by applicant): This application is in response to NIH Notice Number NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. This research program focuses on the development of new synthetic strategies for the total synthesis of biologically active complex alkaloid natural products. Within each total synthesis goal lies the implicit aim of discovering and exploiting new reactions that push the boundaries of chemical synthesis innovation. In this context, new strategies for the total synthesis of several guanidine-containing complex alkaloids will be explored. These classes of targets include the family of anti-HIV/immunomodulating batzelladine alkaloids, the family of anticancer and ion-channel disrupting crambescidin alkaloids, the potent cytotoxin cylindrospermopsin, and the powerful immunosuppressant palau'amine. All of these natural products exhibit significant yet distinct biological responses, yet they are all structurally characterized by at least one guanidine moiety embedded within a complex polycyclic architecture, a synthetic challenge that will be addressed by investigating novel annulation strategies and reactions for nitrogen-heterocycle synthesis. The added aim that constitutes the expansion of research objectives is the development of complementary strategies for the total synthesis of the C19-diterpenoid alkaloids. The C19 family of diterpene alkaloids comprises an expansive number of alkaloids, several members of which have demonstrated potent and selective activity as modulators of ion channel function. As such, these natural products have proven to be extremely useful molecular probes to dissect ion channel biology. Successful synthesis of these target molecules will not only lay the foundation of efficient and practical strategies for complex alkaloid synthesis, but also provide access to complex natural products of biological interest and therapeutic potential in a variety of health areas, including small molecule cytotoxic/anticancer, antiviral, and immunomodulating agents, as well as unique heterocyclic constructs that specifically disrupt ion channel function. PUBLIC HEALTH RELEVANCE: This research program focuses on the development of new synthetic strategies for the total synthesis of biologically active complex guanidine alkaloid natural products. Successful synthesis of these target molecules will not only lay the foundation of efficient and practical strategies for complex molecule synthesis, but also provide access to natural products of biological interest and therapeutic potential in a variety of health areas, including small molecule cytotoxic/anticancer, antiviral, and immunomodulating agents, as well as unique heterocyclic constructs that specifically disrupt ion channel function.