Synthesis and Study of Complex Antiproliferative and Antimalarial Natural Products

复杂的抗增殖和抗疟天然产物的合成与研究

• 批准号: 8885326
• 负责人: Seth B. Herzon
• 金额: $ 30.74万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-08 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885326
• 关键词: Address; Aldehydes; Alkylation; Anti-Infective Agents; Antimalarials; Antineoplastic Agents; Architecture; Artemisinins; Binding; Binding Proteins; Biological; Biological Assay; Biological Factors; Blood; Cancer Etiology; Cancer cell line; Carbon; Cell Culture Techniques; Cell Line; Cessation of life; Chemistry; Chloroquine; Chloroquine resistance; Clinical; Colorectal; Colorectal Cancer; Complex; Culicidae; Cyclization; Development; Diagnostic Neoplasm Staging; Drug-sensitive; Evaluation; Exhibits; Family; Fansidar; Foundations; Goals; Health; Human; In Vitro; Inhibitory Concentration 50; Investigation; Lead; Light; Liver; Malaria; Malignant Neoplasms; Measurable; Medicine; Methods; Mission; Molecular; Nature; New Agents; Operative Surgical Procedures; Outcome; Parasite resistance; Parasites; Proteins; Reaction; Recording of previous events; Reporting; Research; Research Infrastructure; Resistance; Resolution; Route; Safety; Skeleton; Southeastern Asia; Staging; Structure; Structure-Activity Relationship; Survival Rate; Synthesis Chemistry; Testing; Therapeutic; Therapeutic Index; Toxic effect; Tropolone; United States; United States National Institutes of Health; Work; analog; artemisinine; base; chemoradiation; covalent bond; flexibility; human disease; improved; in vivo; inhibitor/antagonist; insight; monomer; mouse model; novel; preclinical evaluation; prophylactic; public health relevance; quinoline; research clinical testing; research study; resistant strain; stereochemistry; transmission process

 DESCRIPTION (provided by applicant): This proposal describes the synthesis and studies of the ocimyquines and gukulenins, natural products that exhibit potent antimalarial and antiproliferative effects, respectively. Ocimyquines are nanomolar inhibitors of malaria parasites that are equally potent against drug-sensitive and -resistant strains, and have demonstrated high therapeutic indices in cell culture. In addition, they display prophylactic and curative activty in mouse models, without measurable toxicity. The gukulenins are low nanomolar inhibitors of several cancer cell lines and are very promising candidates for the treatment of colorectal cancer, the second-leading cause of cancer-related deaths in the United States. Both families of natural products possess molecular architectures that are unique. The ocimyquines contain a tetrasubstituted aminocyclopropane embedded within a pentacyclic carbon skeleton whereas the gukulenins are dimeric a-tropolone natural products containing six carbocyclic rings. Although these two families of compounds are unique among anti-infectives and anti-proliferative compounds, and show potent and potentially clinically-useful activities, no syntheses or synthetic studies have been reported. In addition, little is known about their structure-function relationships, and the mechanisms underlying their efficacy and selectivity remain unknown. The objectives of this proposal are to complete concise and convergent syntheses of the ocimyquines and gukulenins and evaluate their efficacy as radical cure anti-malarials and anti-proliferative agents. We have made significant progress toward the syntheses of both families of metabolites, having developed chemistry to access many of the key substructures of the targets. Our synthetic efforts have led to the development of new methods for the synthesis of tetrasubstituted aminocyclopropanes by a ring expansion-ring contraction strategy and 3,5,6-trisubsituted-a-tropolone rings by a novel reductive cleavage reaction. The collaborative nature of the proposal provides the infrastructure required to evaluate the antimalarial prophylactic and therapeutic activity of the ocimyquines and their synthetic derivatives and to elucidate their biological target. In addition, we will conduct structure-functin studies of the gukulenins, test the hypothesis that the natural products engage in reversible covalent bond formation with their target, and identify candidate binding proteins. These experiments will lead to the identification of new antimalarial and anticancer agents with improved potencies and activities, provide insights into the biological mechanisms underlying these activities, and lay the foundation for their preclinical evaluation as new treatments for malaria and colorectal cancer.

 描述（由适用提供）：该提案描述了胶囊和gukulenins的综合和研究，这些天然产物分别暴露了有效的抗疟药和抗增殖作用。 Ocimyquines是疟疾寄生虫的纳摩尔抑制剂，其对药物敏感和耐药性菌株的潜在潜力同样潜在，并且在细胞培养中表现出较高的治疗性。此外，它们在小鼠模型中显示出预防性和治愈活性，而无需可测量的毒性。古克林蛋白是几种癌细胞系的低纳摩尔抑制剂，是治疗结直肠癌的候选者，这是美国与癌症相关死亡的第二大原因。天然产品的两个家族都有独特的分子体系结构。圆柱素包含嵌入五边形碳骨架内的四抗氨基丙烷丙烷，而gukulenins却是二聚体，尽管这两个化合物家族在反感染和抗增殖化合物中是独一无二的，并且在抗化合物中均具有抗临床和潜在的临床活性，而不是综合研究，并且表现出了综合性研究。此外，对它们的结构功能关系知之甚少，其效率和选择性的基础机制仍然未知。该提案的目标是完成胶囊和gukulenins的简洁和收敛合成，并评估它们作为根本治疗抗癌症和抗增殖剂的有效性。我们已经开发了化学反应以访问靶标的许多关键子结构，从而取得了重大进展。我们的合成努力导致开发了通过环膨胀环收缩策略和3,5,6 triSubStantatization-a-Tropolone环的新方法开发了四叠取代的氨基丙烷丙烷，这是通过新颖的减少清洁反应。该提案的协作性质提供了评估胶囊及其合成衍生物的抗疟疾预防和治疗活性所需的基础设施，并阐明了其生物学靶标。此外，我们将对古克林蛋白进行结构 - 函数研究，检验天然产物与目标可逆的共价形成的假设，并鉴定候选蛋白质。这些实验将导致鉴定具有改进的电位和活性的新抗疟疾和抗癌药，并为这些活动的生物学机制提供见解，并为其临床前评估奠定基础，作为对疟疾和结肠癌的新疗法。