Cascade Reactions for Biologically Active Natural Products

生物活性天然产物的级联反应

• 批准号: 10475216
• 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/10475216
• 关键词: Alkaloids; Architecture; Asian; 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; 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; 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.

同杉碱（HHT）是一种临床使用的蛋白质翻译抑制剂，用于治疗慢性髓性白血病。除了fda批准的白血病药物作用外，HHT在治疗其他血液恶性肿瘤和肿瘤方面也显示出令人兴奋的前景。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。