Synthesis and Study of Complex Antiproliferative and Antimalarial Natural Products

 描述(由申请人提供)：本提案描述了ocimyquines和gukulenins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。Ocimyquines是疟疾寄生虫的纳米分子抑制剂，对药物敏感和耐药菌株同样有效，并在细胞培养中显示出高治疗指数。此外，它们在小鼠模型中表现出预防和治疗活性，没有可测量的毒性。Gukulenins是几种癌细胞株的低纳米分子抑制剂，非常有希望用于治疗结直肠癌，结直肠癌是美国与癌症相关的死亡的第二大原因。这两个天然产品家族都拥有独特的分子结构。阿基咪喹含有嵌入五环碳骨架的四取代氨基环丙烷，而古库兰素是含有六个碳环的二聚体阿托洛酮天然产物。虽然这两类化合物在抗感染和抗增殖化合物中是独一无二的，并显示出强大的和潜在的临床有用活性，但尚未有合成或合成研究的报道。此外，人们对它们的结构-功能关系知之甚少，其有效性和选择性的机制也尚不清楚。这项建议的目的是完成简明和聚合的合成，并评价其作为根治、抗疟疾和抗增殖剂的疗效。我们在合成这两个代谢物家族方面取得了重大进展，发展了化学来获得目标的许多关键亚结构。我们的合成工作导致了通过扩环-缩环策略合成四取代氨基环丙烷和通过一种新的还原裂解反应合成3，5，6-三取代-a-托洛普隆环的新方法的发展。该提案的协作性质为评价奥西喹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标提供了所需的基础设施。此外，我们还将对古苦素进行结构与功能的研究，检验天然产物与其靶标进行可逆共价键形成的假设，并确定候选结合蛋白。这些实验将导致发现新的具有更高效力和活性的抗疟疾和抗癌药物，为了解这些活性的生物学机制提供见解，并为它们作为疟疾和结直肠癌新疗法的临床前评估奠定基础。

 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.