b-Lactones: Bioactive Target and Vehicles for Synthesis

b-内酯：生物活性靶标和合成载体

基本信息

批准号：
7584710
负责人：
DANIEL ROMO
金额：
$ 30.06万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7584710
关键词：
3-hydroxybutanal Amides Anti-Bacterial Agents Anti-Inflammatory Agents Biological Biological Factors Biological Process Biomimetics Cell Line Cembranes Clinical Research Collaborations Complex Coupling Cyclization Development Evaluation Exhibits Family Funding Future Generations Goals Grant Health Human Hyperlipidemia Hypertriglyceridemia Intervention Keto Acids Lactams Lactones Malignant Neoplasms Marines Medical Methods Norditerpenoids Phase Physical condensation Preparation Process Proteasome Inhibitor Proteins Reaction Reporting Roentgen Rays Route Serine Structure System Testing Therapeutic Agents Time TimeLine Variant Virus Diseases Work anticancer activity antineoplastic antibiotics base belactosin A cellular targeting cembrane design flexibility human disease improved interest member multicatalytic endopeptidase complex omuralide salinosporamide A tetrahydrofuran tool

项目摘要

This proposal seeks to exploit diastereoselective routes to bicyclic-¿-lactones to access antitumor, antibacterial and anti-inflammatory agents of interest for human health and as tools for studying basic biological processes. In this grant period, we will continue to exploit the potential of various methods developed in our group that enable concise and versatile total syntheses of several bioactive natural products including salinosporamides, scabrolides/ineleganolide, oxazolomycins, and haterumalides/biselides. These compounds all exhibit potent effects on various cell lines thus this project will also ultimately target the identification of their cellular targets where this is unknown or alternatively develop variants of these protein-reactive natural products as activity-based cellular probes to identify off-targets. The particular aims are: (1) Building on work from the previous grant period, optimization studies directed toward improved yields and diastereoselectivity of a concise (9 steps from serine) enantioselective synthesis of the potent proteasome inhibitor, salinosporamide A are proposed. Hypothesis-directed derivatives that may have increased potency are proposed based on the reported X-ray structures of the salino A- and belactosin-20S proteasome complexes (to be tested at Genzyme). (2) Building on our work toward the salinosporamides, we propose a synthesis of the oxazolomycin and neooxazolomcyin ¿- lactam core involving modified bis-cyclizations. (3) We will exploit our recently developed, diastereoselective bis-cyclization reaction of keto acids to access the cyclopentyl core common to the scabrolide/ineleganolide family of marine cembranes. To construct, the bicyclic-¿-lactone macrocyclic core, we propose a transannular CH insertion that would be of fundamental interest for the synthesis of this growing family of bicyclic "-lactone macrocycles and related targets. (4) We propose double- diastereoselective, bis-cyclizations for the synthesis of ¿-lactone-fused tetrahydrofurans to access THFs found in the haterumalides(Hat)/biselides(Bise).

该提案旨在探索非映选择路线，以访问生物学 - lactones 人类健康感兴趣的抗肿瘤，抗菌和抗炎药以及研究基本生物学过程的工具。在这个赠款期间，我们将继续利用我们小组中开发出的各种方法的潜力，以简化和多种生物活性天然产品的多功能总合成盐孢胺，scabrolides/ineleganolide，oxazolomycins和oxazolycins和 Haterumalides/Biselides。这些化合物都对各种细胞系都暴露了有效作用该项目还将最终针对其细胞靶标的识别这是这些蛋白质反应性天然的未知或开发的变体产品作为基于活动的细胞问题，以识别脱靶。特定目的是：（1）基于上一个赠款期的工作，优化研究针对简洁的提高的产量和非对映选择性（距串行9步）有效蛋白酶体抑制剂的对映选择性合成，盐酸盐盐A为建议的。可能增加效力的假设指导的衍生物是根据所报道的Salino A-和Belactosin-20的X射线结构提出的提议蛋白酶体复合物（在Genzyme进行测试）。（2）在我们的工作迈向盐氧化盐，我们提出了奥甲唑霉素和Neooxazolomcyin�-的合成 - LACTAM核心涉及修饰的双囊化。（3）我们将利用最近的开发的，酮酸的非映选择性双基环化反应 scabrolide/Ineleganolide sarine Cembranes家族常见的环戊烯核心。为了构建，双乳酮大环核心，我们提出了一个跨性别CH 插入这个不断增长的家庭的基本利益将是基本的利益 bilic“ - 乳酮大环和相关靶标。（4）我们提出双重非映选择性，用于合成的双乳糖融合四氢呋喃的双囊肿访问在Haterumalides（HAT）/Biselides（Bise）中发现的THF。