SYNTHESIS OF BIOACTIVE COMPLEX ALKALOIDS

生物活性复合生物碱的合成

基本信息

批准号：
7372447
负责人：
David Y Gin
金额：
$ 39.9万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-10 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7372447
关键词：
Acute Address Alder plant Alkaloids Antifungal Agents Antiviral Agents Architecture Area Binding Biological Biological Factors Cancer cell line Carbodiimides Cells Class Colon Carcinoma Complex Cyclopentane Cytotoxic Antibiotics Cytotoxin DNA Sequence Rearrangement Development Dissociation Evaluation Exhibits Facility Construction Funding Category Family Family member Foundations Generations Goals Guanidines HIV HIV Envelope Protein gp120 Health Human Human Biology Imidates Imidazole Imines Immunosuppressive Agents Inhibitory Concentration 50 Investigation Ion Channel Lethal Dose 50 Malignant Epithelial Cell Medicine Methods Mus Nitrogen Organic Chemistry Palau&apos amine Principal Investigator Process Protein Tyrosine Kinase Pyrimidine Pyrimidines Pyrroles Reaction Research Therapeutic Therapeutic Agents Toxic effect chemical synthesis crambescidin 816 cycloaddition cylindrospermopsin cytotoxic cytotoxicity guanidinium immunoregulation innovation interest ion channel blocker leukemia marine natural product member novel programs response small molecule

项目摘要

DESCRIPTION (provided by applicant): 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. These proposed goals will involve investigation of diastereoselective [4+2]-annulation of vinyl carbodiimides with chiral imine and imidate derivatives for dihydropyrimidine and pyrimidine synthesis, as well as other convergent cycloaddition strategies for the construction of fully substituted all-cis cyclopentanes. 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.

描述（由申请人提供）：该研究计划的重点是开发新的合成策略，以全合成生物活性复杂的生物碱天然产物。在每个总合成目标中，目标是发现和利用推动化学合成创新边界的新反应的隐含目的。在这种情况下，将探讨几种含鸟嘌呤复合体生物碱的总合成的新策略。这些目标类别包括抗HIV/免疫调节的蝙蝠碱生物碱，抗癌家族和离子通道家族，破坏了crambesscidin生物碱，有效的细胞毒素cylindrospermopsin，以及强大的免疫抑制剂palau'amamine。所有这些天然产物都表现出显着但不同的生物学反应，但它们在结构上的特征都至少具有嵌合在复杂的多环结构中的鸟胺部分，这是一种合成的挑战，该挑战将通过研究氮基因核合成的新型环状策略和反应来解决。这些提出的目标将涉及对二氢酰亚胺和二氢吡啶的合成以及其他融合的环载策略的非对映选择性[4+2]的乙烯基碳二酰亚胺的施加，并拟胺的衍生物用于二氢吡啶胺和吡啶胺的合成。 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.