Synthesis of Biologically Active Natural Products

生物活性天然产物的合成

基本信息

批准号：
7155541
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/7155541
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 Research Personnel 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 epohelmin B inhibitor/antagonist interest jenamidine A leukemia lipoprotein-associated phospholipase A(2)meter methyl group novel phospholipase A2 inhibitor programs stereochemistry

项目摘要

DESCRIPTION (provided by applicant): 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 new synthetic 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 DMA primase 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 values of 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.

描述（由申请人提供）：该提案由五个不相关的项目组成，旨在制备具有潜在药物用途的结构新颖、具有生物活性的天然产物，并在进行这些合成的过程中，开发具有普遍兴趣和实用性的新合成方法。 (1) 以二氢吡啶鎓盐的新型 Diels-Alder 反应为关键步骤合成 Symbioimine，它能抑制破骨细胞分化，因此可能对骨质疏松症的治疗有价值。 (2) 脯氨酸衍生的生物碱 jenamidine A、SB-311099 和 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，以确认分配并为进一步的生物学评估提供材料。 (3) Sch 642305 是一种不寻常的双环大环内酯，可抑制细菌 DMA 引物酶，EC50 为 70 微摩尔，使其成为新型抗菌剂开发的先导者。将制备立体化学更简单的大环内酯前体，并通过跨环迈克尔反应将其转化为 Sch 642305，这是一种新颖且可能非常有效的此类环系统途径。 (4) Abyssomicin C 对多种革兰氏阳性菌显示出抗生素活性，包括致病性金黄色葡萄球菌菌株和耐药菌株。将使用分子内狄尔斯-阿尔德反应进行仿生合成以形成环己烷环。环氧化物的环氧化和开环将完成合成。 (5) Bisabosqual A 抑制酿酒酵母、白色念珠菌、HepG2 细胞和大鼠肝脏的微粒体角鲨烯合成，IC50 值分别为 0.43、0.25、0.95 和 2.5 微克/mL，并对多种酵母具有广泛的抗真菌活性。四环骨架和立体化学使合成成为一个具有挑战性的问题，将使用我们在四环核心合成中开发的化学来进行。 (6) 由香茅醛的吖嗪制备了数克数量的C2对称肼和衍生的C2对称二胺，将探讨它们在不对称合成中的应用。这些天然产物目标是治疗骨质疏松症和癌症以及开发新抗生素的先导化合物。在这些研究过程中，将开发出更经济地制备药物的通用新方法。