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（由申请人提供）：该提案描述了奥西米喹和古库列宁的合成和研究，这两种天然产物分别具有有效的抗疟疾和抗增殖作用。奥西米喹是疟疾寄生虫的纳摩尔抑制剂，对药物敏感菌株和耐药菌株同样有效，并且在细胞培养中表现出高治疗指数。此外，它们在小鼠模型中显示出预防和治疗活性，且没有可测量的毒性。古库列宁是多种癌细胞系的低纳摩尔抑制剂，是治疗结直肠癌的非常有前景的候选药物，结直肠癌是美国癌症相关死亡的第二大原因。这两个天然产物家族都拥有独特的分子结构。奥西米喹含有嵌入五环碳骨架内的四取代氨基环丙烷，而古库列宁是含有六个碳环的二聚α-托酚酮天然产物。尽管这两个化合物家族在抗感染和抗增殖化合物中是独特的，并且显示出有效的和潜在的临床有用活性，但尚未报道合成或合成研究。此外，人们对它们的结构-功能关系知之甚少，其功效和选择性的机制仍然未知。该提案的目标是完成奥西米喹和古库列宁的简洁和收敛合成，并评估它们作为根治性抗疟疾药物和抗增殖药物的功效。我们在这两个代谢物家族的合成方面取得了重大进展，开发了化学方法来获取靶标的许多关键子结构。我们的合成工作开发了通过扩环-环收缩策略合成四取代氨基环丙烷和通过新型还原裂解反应合成3,5,6-三取代-α-托酚酮环的新方法。该提案的协作性质提供了评估奥米喹及其合成衍生物的抗疟预防和治疗活性以及阐明其生物靶点所需的基础设施。此外，我们将对古库列宁进行结构功能研究，测试天然产物与其靶标形成可逆共价键的假设，并鉴定候选结合蛋白。这些实验将导致鉴定出具有改进效力和活性的新型抗疟疾和抗癌药物，深入了解这些活性背后的生物学机制，并为其作为疟疾和结直肠癌新疗法的临床前评估奠定基础。