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）：本提案描述了分别表现出强效抗疟和抗增殖作用的天然产物ocimyquines和gukulenins的合成和研究。罗咪喹是疟疾寄生虫的纳摩尔抑制剂，其对药物敏感株和耐药株同样有效，并且在细胞培养物中已证明具有高治疗指数。此外，它们在小鼠模型中显示出预防和治疗活性，没有可测量的毒性。gukulenins是几种癌细胞系的低纳摩尔抑制剂，并且是治疗结直肠癌的非常有希望的候选物，结直肠癌是美国癌症相关死亡的第二大原因。这两类天然产物都具有独特的分子结构。ocimyquines含有嵌入在五环碳骨架内的四取代的氨基环丙烷，而gukulenins是含有六个碳环的二聚α-环庚三烯酚酮天然产物。虽然这两个家族的化合物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的活性，但尚未报道合成或合成研究。此外，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。本提案的目的是完成罗咪喹类和古枯菌素类的简明和收敛的合成，并评价它们作为根治性抗疟疾和抗增殖剂的功效。我们在合成这两个代谢物家族方面取得了重大进展，开发了化学方法来获得目标的许多关键子结构。我们的合成工作已经导致了新的方法的发展，用于合成四取代的氨基环丙烷的扩环-缩环策略和3，5，6-三取代的-a-环酚酮环的一种新的还原裂解反应。该提案的协作性质提供了评价ocimyquines及其合成衍生物的抗疟疾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，我们将进行gukulenins的结构-功能研究，测试的假设，天然产物从事可逆共价键形成与其目标，并确定候选结合蛋白。这些实验将导致新的抗疟和抗癌药物的鉴定，提高效力和活动，提供这些活动的生物学机制的见解，并奠定了基础，为他们的临床前评价作为疟疾和结直肠癌的新疗法。