Synthesis of Biologically Active Natural Products

生物活性天然产物的合成

• 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
• 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

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.

该提案由五个无关的项目组成，以准备结构新颖的生物活性自然 潜在兴趣作为药物的产品，并在执行这些合成时开发新闻合成 将具有普遍关注和效用的方法。 （1）共生生物胺，抑制破骨细胞分化 因此，可能在骨质疏松症的治疗中具有价值 二氢吡啶盐盐作为关键步骤的alder反应。 （2）脯氨酸衍生的生物碱jenamidine a， 最近将SB-311099和epohelmins A和B从各种来源分离出来，并具有有效性 生物活性。将开发新的化学反应以合成这些天然产品，以确认 分配并提供材料以进行进一步的生物学评估。 （3）不寻常的双环大环内酯，SCH 642305用70个微摩尔的EC50抑制细菌Dmaprimase，使其成为发展的领先 新的抗菌剂。立体化学上更简单的大花环前体将准备并转换 通过反式隔开的迈克尔反应作为一种新颖的，潜在非常有效的途径到SCH 642305 环系统。 （4）深渊C显示针对多种革兰氏阳性细菌的抗生素活性 包括金黄色葡萄球菌菌株和抗药性菌株。仿生合成将 可以使用分子内多尔德尔 - 奥尔德反应进行形成环己烷环。环氧化和 环氧化物的环开口将完成合成。 （5）Bisabosqual a抑制微斑鳞状 酿酒酵母，白色念珠菌，HEPG2细胞和大鼠肝脏的合成，具有IC50值 分别为0.43、0.25、0.95和2.5微克/ml，并且具有广泛的抗真菌活性 酵母。四环素框架和立体化学使综合成为一个具有挑战性的问题 使用在我们的四环核心合成中开发的化学作用。 （6）C2对称 肼和衍生的C2-对称二氨酸已经以多克数量制备 将探索其在不对称合成中的偶然甲苯甲烷。这些天然产品目标是 铅治疗骨质疏松和癌症以及新抗生素的发展。在课程中 在这些研究中，将开发新方法，这些方法是为更多准备药物准备的一般效用 经济上。