Cascade Reactions for Biologically Active Natural Products

生物活性天然产物的级联反应

• 批准号: 10101401
• 负责人: CHRISTOPHER M BEAUDRY
• 金额: $ 24.52万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10101401
• 关键词: Alkaloids; Architecture; Asians; Binding; Binding Sites; Biological; Cancer cell line; Chemicals; China; Chronic Myeloid Leukemia; Clinical; Collaborations; Complex; Dependence; Development; Docking; Elements; Esterification; Evaluation; FDA approved; Goals; Harrington Plum Yew; Harringtonines; Health; Hematologic Neoplasms; Human; In Vitro; Investigation; Japanese Population; Lead; Leukemic Cell; Malignant Neoplasms; Medicine; Modeling; Molecular; Natural Products; Oxides; Patients; Peptides; Peptidyltransferase; Pharmaceutical Preparations; Pharmacologic Substance; Plum; Preparation; Process; Production; Property; Protein Engineering; Protein Synthesis Inhibition; Protein Synthesis Inhibitors; Proteins; Reaction; Recording of previous events; Research; Ribosomes; Role; Side; Site; Source; Specialist; Structural Biologist; Structure; Taxus; Testing; Text; Transfer RNA; Translations; Trees; analog; base; biological preparation; biological systems; cephalotaxine; chemical reaction; chemical synthesis; cost; cytotoxic; cytotoxicity; design; dimer; homoharringtonine; improved; inhibitor/antagonist; innovation; leukemia; leukemia treatment; nanomolar; novel; nucleobase; prevent

Homoharringtonine (HHT) is a clinically used protein translation inhibitor that is used to treat chronic myeloid leukemia. In addition to its FDA-approved role as a leukemia drug, HHT shows exciting promise for the treatment of other hematologic malignancies and tumors. Finally, it is a perfect molecule to use as a probe to investigate protein translation inhibition. HHT is currently prepared through semi-synthesis from naturally derived cephalotaxine. Cephalotaxine is obtained from Asian plum yew trees grown in China. The cost of HHT in particular, along with other leukemia treatments, has been described as “astronomical” and “harmful to patients” by a group of 100 leading cancer specialists. This cost results in part from a supply bottleneck reflecting its tree-based sourcing. This project will completely eliminate this supply problem, and provide cephalotaxine and HHT for our studies and those by other research groups. Natural products have been the source of the majority of drugs throughout history, and still are today. The field of chemical synthesis directly contributes to the application of natural products as medicines. Aromatic and heteroaromatic rings are indispensible motifs in biologically active compounds. Thus, chemical reactions that allow for the construction of molecular architectures containing substituted aromatic rings are particularly valuable to human health. Polycyclic nitrogenous molecules, exemplified by the Cephalotaxus alkaloids in this proposal, are also critically important as biologically active molecules and pharmaceuticals. However, polycyclic nitrogenous molecules, such as alkaloids, are notoriously difficult to prepare, often requiring arduous chemical syntheses for preparation. We will develop two new cascade reactions that efficiently prepare: 1. Substituted arenes, and 2. Complex polycyclic alkaloids. The innovativeness of this research is the strategic use of cascade reactions to assemble structures that previously required multiple steps to prepare. A distinguishing feature of this strategy is its inherent efficiency. Additionally, we will showcase these pericyclic cascades in syntheses of natural products and natural product analogs. More widely, this strategy will find immediate application in the preparation of biologically active molecules, such as HHT; chemical probes for biological systems, and related molecules.

高三尖杉酯碱（HHT）是一种临床上使用的蛋白质翻译抑制剂，用于治疗慢性粒细胞白血病。除了FDA批准的白血病药物作用外，HHT还显示出治疗其他血液恶性肿瘤和肿瘤的令人兴奋的前景。最后，它是一个完美的分子用作探针来研究蛋白质翻译抑制。 HHT目前通过天然来源的三尖杉碱的半合成制备。紫杉醇是从中国生长的亚洲李紫杉树中获得的。特别是HHT的成本，沿着其他白血病治疗，被一个由100名主要癌症专家组成的小组描述为“天文数字”和“对患者有害”。这一成本部分来自反映其基于树木的采购的供应瓶颈。本计画将彻底解决三尖杉碱及HHT的供应问题，并为我们及其他研究小组的研究提供三尖杉碱及HHT。 天然产物一直是历史上大多数药物的来源，今天仍然如此。化学合成领域直接有助于天然产物作为药物的应用。芳环和杂芳环是生物活性化合物中不可缺少的基序。因此，允许构建含有取代芳环的分子结构的化学反应对人类健康特别有价值。多环含氮分子，例如在该提议中的红豆杉生物碱，作为生物活性分子和药物也是至关重要的。然而，多环含氮分子，如生物碱，是众所周知的难以制备，往往需要艰苦的化学合成制备。我们将开发两个新的级联反应，有效地制备：1。取代的芳烃，和2.复杂的多环生物碱。这项研究的创新之处在于战略性地使用级联反应来组装以前需要多个步骤才能制备的结构。这一战略的一个显著特点是其固有的效率。此外，我们将展示这些周环级联在天然产物和天然产物类似物的合成。更广泛地说，这种策略将立即应用于制备生物活性分子，如HHT;生物系统的化学探针和相关分子。