Synthesis of Anti-Trypanosomal Terpenoid Oligomers

抗锥虫萜类低聚物的合成

• 批准号: 8721181
• 负责人: Ruben Martin Martinez
• 金额: $ 2.97万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721181
• 关键词: Acids; Alder plant; American; Back; Biological; Biological Products; Breathing; Chagas Disease; Chemicals; Chemistry; Chronic; Chronic Phase; Collaborations; Communities; Complex; Country; Cyclization; Data; Development; Diels Alder reaction; Disease; Family; Family member; Foundations; Genomics; Goals; Hand; Head; Health; Human; In Vitro; Infection; Institutes; Investigation; Kilogram; Lead; Literature; Mediating; Methods; Mind; Morbidity - disease rate; Outcome; Parasites; Parasitic infection; Pharmaceutical Preparations; Phase; Plants; Polyenes; Process; Prodrugs; Research; Route; Side; Skeleton; Source; Structure; Structure-Activity Relationship; System; Tail; Terpenes; Testing; Therapeutic; Therapeutic Agents; Trypanosoma cruzi; Variant; analog; base; cytotoxic; cytotoxicity; disorder prevention; drug discovery; improved; in vivo; insight; member; milligram; monomer; mortality; neglect; novel; oxidation; public health relevance; solid solution

DESCRIPTION (provided by applicant): The goal of this proposal is synthesize a class of structurally novel oligomeric terpenoids which are presented here to have previously unreported potent and selective anti-trypanosomal activity, and to determine their biological target and structure-activity relationship (SAR.) Our long-term goal is to produce new drug leads for the treatment of chronic infections of Trypanosoma cruzi (T. cruzi,) the causative agent of Chagas disease, and demonstrate their therapeutic value through in-vitro and in-vivo testing. The proposed research comprises the development of a new class of polyene capable of rapid, highly regio- and diastereo-selective formation of fused polycyclic polyene monomers; new methods for the controlled oligomerization of these monomeric species; and application of this chemistry to short, scalable and modular syntheses of the family of terpenoids presented herein. This chemistry will be used to explore the biological impact of various moieties within the context of their terpenoid frameworks through SAR discovery, to determine how the unique chemical reactivities of these polycyclic and macrocyclic systems are related to their resulting biological activities (including the possibility of prodrug degradation into reactive intermediates within T. cruzi,) and to determine the target(s) of these compounds in collaboration with the Genomics Institute of Novartis Research Foundation (GNF.) The first phase of research concerns the streamlined development of a novel chiral dienophile, as well as a new application of the polarized dendritic polyenes - Danishefsky Dendralenes - developed in our lab which undergo highly regio- and stereoselective Diels-Alder reactions to rapidly construct the polycyclic skeleton of these monomeric terpenoids. All available literature precedent indicates that these monomeric species will have widespread utility in the rapid construction of larger complex carbocycles. The second phase of research draws inspiration from a hypothesis regarding the biogenetic origin of this complex family of terpenoids being traced back to variations on a single monomeric unit. We will explore regioselective and stereoselective strategies of controlled oligomerization of the monomeric terpenoids into the desired poly- and macrocyclic oligomers, employing a strongly substrate-directed Diels-Alder approach as well as an unprecedented formal head-to-tail macrocyclization. To achieve these cyclizations, we will investigate thermal, photochemical, and Lewis-base mediated strategies as well as solid and solution phase approaches. The third phase of research, conducted in collaboration with GNF/Novartis, involves the elucidation of the structural basis for anti-trypanosomal activity within this class of terpenoid oligomers and the determination of their mechanism of action. We present preliminary data that show the potent and selective cytotoxicity of these compounds against T. cruzi parasites.

描述（由申请人提供）：本课题的目标是合成一类结构新颖的低聚萜类化合物，这些化合物具有以前未报道的强效和选择性抗锥虫活性，并确定它们的生物学靶点和构效关系（SAR）。我们的长期目标是生产新的药物先导物，用于治疗恰加斯病的病原体克氏锥虫（T. cruzi）的慢性感染。并通过体外和体内试验证明其治疗价值。提出的研究包括开发一种新型多烯，这种多烯能够快速、高度区域选择性和非对映选择性地形成熔融多环多烯单体；这些单体的控制寡聚化的新方法并将该化学应用于本文介绍的萜类化合物家族的短时间、可扩展和模块化合成。通过SAR发现，该化学将用于探索萜类框架内各种部分的生物影响，以确定这些多环和大环系统的独特化学反应性与它们产生的生物活性（包括前药降解为活性中间体的可能性）之间的关系