Synthesis of Biologically Active Natural Products

生物活性天然产物的合成

基本信息

批准号：
7333310
负责人：
BARRY B. SNIDER
金额：
$ 28.6万
依托单位：
BRANDEIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-12-01 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7333310
关键词：
Adhesions Aldehydes Alkaloids Amines Anhydrides Anti-Bacterial Agents Antibiotics Antifungal Agents Biological Biological Factors Biomimetics Candida albicans Cells Chemistry Cyclohexane Cyclohexanes DNA Primase Depth Development Diamines Diels Alder reaction Dinophyceae Drug resistance Epoxy Compounds Esters Evaluation Face Gram-Positive Bacteria HL-60 Cells Hand Human Hydrazine Hydrazines Imides Inhibitory Concentration 50 Japanese Population K-562 Ketones Lanosterol synthase Lead Ligands Liver Macrolides Malignant Neoplasms Marines Methods Modeling Mono-S NP 25302 Object Attachment One-Step dentin bonding system Osteoclasts Osteoporosis Penicillium Pharmaceutical Preparations Postmenopause Preparation Prevention Proline Protons Rattus Reaction Reporting Route Saccharomyces cerevisiae Salts Sch 642305 Sea Sodium Chloride Source Sparteine Squalene Squalene Synthetase Standards of Weights and Measures Streptomyces Structure System Woman Yeasts analog azine base bohemamine catalyst citronellal desire epimerization epohelmin A inhibitor/antagonist interest jenamidine A leukemia lipoprotein-associated phospholipase A(2)meter methyl group novel phospholipase A2 inhibitor stereochemistry

项目摘要

This proposal consists of five unrelated projects to prepare structurally novel, biologically active natural products of potential interest as drugs and, in carrying out these syntheses, to develop newsynthetic methods that will be of general interest and utility. (1) Symbioimine, which inhibits osteoclast differentiation and may therefore be of value in the treatment of osteoporosis, will be synthesized using the novel Diels- Alder reaction of a dihydropyridinium salt as the key step. (2) The proline-derived alkaloids jenamidine A, SB-311099, and epohelmins A and B were recently isolated from a variety of sources and have potent biological activity. New chemistry will be developed to synthesize these natural products to confirm the assignments and provide material for further biological evaluation. (3) An unusual bicyclic macrolide, Sch 642305 inhibits bacterial DMAprimase with an EC50 of 70 micromolar making it a lead for the development of new antibacterial agents. A stereochemically simpler macrolide precursor will be prepared and converted to Sch 642305 by a trans-annular Michael reaction as a novel and potentially very efficient route to this type ring system. (4) Abyssomicin C shows antibiotic activity against a variety of Gram-positive bacteria including pathogenic Staphyloccocus aureus strains and drug-resistant strains. A biomimetic synthesis will be carried out using an intramolecular Diels-Alder reaction to form the cyclohexane ring. Epoxidation and ring opening of the epoxide will complete the synthesis. (5) Bisabosqual A inhibits the microsomal squalene syntheses from Saccharomyces cerevisiae, Candida albicans, HepG2 cell and rat liver with IC50 valuesof 0.43, 0.25, 0.95 and 2.5 microgram/mL, respectively, and has broad antifungal activities against various yeasts. The tetracyclic framework and stereochemistry make the synthesis a challenging problem which will be carried out using chemistry developed in our synthesis of the tetracyclic core. (6) A C2-Symmetric hydrazine and the derived C2-symmetric diamine have been prepared in multi-gram quantities from the azine of citronellal their utility in asymmetric synthesis will be explored. These natural product targets are leads for the treatment of osteoporosis and cancer and for the development of new antibiotics. In the course of these studies new methods will be developed that are of general utility for preparing drugs more economically.

该提案由五个不相关的项目组成，旨在制备结构新颖、具有生物活性的天然物质作为药物具有潜在兴趣的产品，并在进行这些合成时开发新合成物具有普遍意义和实用性的方法。 (1)共生亚胺，抑制破骨细胞分化因此可能对骨质疏松症的治疗有价值，将使用新型狄尔斯- 二氢吡啶鎓盐的Alder反应是关键步骤。 (2)脯氨酸衍生生物碱杰那脒A， SB-311099 以及 epohelmins A 和 B 最近从多种来源中分离出来，具有有效的生物活性。将开发新的化学方法来合成这些天然产物，以确认作业并为进一步的生物学评估提供材料。 (3) 一种不寻常的双环大环内酯，Sch 642305 抑制细菌 DMAprimase，EC50 为 70 微摩尔，使其成为该开发的领先者新型抗菌剂。将制备并转化立体化学更简单的大环内酯前体通过跨环迈克尔反应获得 Sch 642305，这是一种新颖且可能非常有效的途径环系统。 (4) Abyssomicin C 对多种革兰氏阳性菌表现出抗生素活性包括致病性金黄色葡萄球菌菌株和耐药菌株。仿生合成将可以使用分子内狄尔斯-阿尔德反应来进行以形成环己烷环。环氧化和环氧化物的开环将完成合成。 (5) Bisabosqual A抑制微粒体角鲨烯由酿酒酵母、白色念珠菌、HepG2 细胞和大鼠肝脏合成，IC50 值为分别为 0.43、0.25、0.95 和 2.5 微克/mL，对多种真菌具有广泛的抗真菌活性酵母。四环骨架和立体化学使合成成为一个具有挑战性的问题，这将可以使用我们在四环核合成中开发的化学方法来进行。 (6) C2 对称肼和衍生的 C2 对称二胺已以数克的量由将探讨香茅醛的吖嗪在不对称合成中的用途。这些天然产物的目标是导致骨质疏松症和癌症的治疗以及新抗生素的开发。在课程中这些研究将开发出对于制备药物具有普遍用途的新方法经济上。