Synthetic Studies on the Antibiotic Saccharomicin B.

抗生素糖霉素B的合成研究。

• 批准号: 9118313
• 负责人: Clay Samuel Bennett
• 金额: $ 35.82万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118313
• 关键词: Address; Anhydrides; Antibiotic Resistance; Antibiotics; Bacteria; Biomedical Research; Chemicals; Chemistry; Complex; Deoxy Sugars; Development; Foundations; Glycobiology; Glycosides; Goals; Gram-Positive Bacteria; Health; Hydroxy Acids; Iodides; Lead; Learning; Length; Libraries; Methodology; Methods; Mission; Modification; Monosaccharides; Multi-Drug Resistance; Natural Products; Nature; Oligosaccharides; Outcome; Peptide Synthesis; Physical condensation; Production; Prosthesis; Public Health; Reaction; Reagent; Reporting; Research; Route; Structure; Structure-Activity Relationship; Technology; Testing; Therapeutic; Threonine; Time; Vertebral column; analog; antimicrobial; base; chemical synthesis; combat; drug development; drug resistant bacteria; flexibility; glycosylation; hemiacetal; human disease; improved; interest; next generation; novel; pathogen; programs; promoter; stereochemistry; success; sugar; technology development; tetrabutylammonium

 DESCRIPTION (provided by applicant): Synthetic Studies on the Antibiotic Saccharomicin B. Increasing incidents of antibiotic resistance in bacteria have created a need for new antimicrobials with novel modes of action. The saccharomicins are heptadecasaccharide antibiotics, which possess broad-spectrum activity against a range of pathogens. Although the saccharomicins possess a narrow therapeutic window, analogs could have the potential to serve as next-generation antibiotics. Before analogs can be developed, there is a need for a general and flexible route to the saccharomicins. The objective of this proposal is to address this need by developing a stereoselective approach to the total synthesis of saccharomicin B. This will require creating a general approach to the 2,6-dideoxy-sugars that make up much of the saccharomicin backbone, and uniting them in a stereoselective fashion. This will be accomplished by pursuing three specific aims. Specific Aim 1 will study an approach to 2,6- dideoxy-sugars based on Petasis-Ferrier union/rearrangements between hydroxy acids and orthoformates. This approach will allow for the production of a large number of 2,6-dideoxy-sugars starting from a handful of common starting materials, such as threonine. Specific Aim 2 will examine the synthesis of fragments of saccharomicin B. For the deoxy-sugar linkages, this approach will make use of reagent controlled dehydrative glycosylations promoted by either dihalocyclopropenes and tetrabutylammonium iodide (for a-selective glycosylations), or p-toluenesulfonic anhydride (for ß- specific glycosylations). An advantage to these chemistries is that they permit the direct stereoselective synthesis of deoxy-sugar glycosides without the need for temporary prosthetic groups. A portion of the fragments synthesized in this Aim will be converted to known saccharomicin degradation products to determine the absolute configuration of the sugars that make up the backbone. Specific Aim 3 will examine chemistries to assemble the fragments from Aim 2 into the heptadecasaccharide backbone of saccharomicin. The full length oligosaccharide will then be elaborated to saccharomicin B, thereby establishing the first total synthesis of this antibiotic. By providing a flexible route tothe saccharomicin B, this research will pave the way for developing next-generation antibiotics to help combat the growing threat of multidrug-resistant bacteria. Additionally, these studies will demonstrate that by using glycosylation chemistries where selectivity is entirely under control of the promoter, it is possible to synthesize extremely complex oligosaccharides. Lessons learned from these studies will help lay the foundation for the development of technologies that will permit the construction of complex oligosaccharides on rapid time scales. Thus, the research will also help accelerate discovery in chemical glycobiology.

 描述（由申请方提供）：抗生素西莫霉素B的合成研究。 越来越多的细菌抗生素耐药性事件产生了对具有新作用模式的新抗菌剂的需求。糖霉素是十七糖类抗生素，具有广谱抗病原体的活性。虽然糖霉素具有狭窄的治疗窗口，但类似物可能具有作为下一代抗生素的潜力。在开发类似物之前，需要糖霉素的通用和灵活的途径。本提案的目的是解决这一问题 需要通过开发立体选择性方法来全合成糖霉素B。这将需要创建一个通用的方法，以2，6-双脱氧糖，构成大部分的糖霉素骨干，并团结他们在一个立体选择性的方式。这将通过追求三个具体目标来实现。具体目标1将研究基于羟基酸和原甲酸酯之间的Petasis-Ferrier结合/重排的2，6-双脱氧糖的方法。这种方法将允许从少数常见的起始材料如苏氨酸开始生产大量的2，6-双脱氧糖。具体目标2将检查糖霉素B片段的合成。对于脱氧糖键，该方法将利用由二卤代环丙烯和四丁基碘化铵（用于α-选择性糖基化）或对甲苯磺酸酐（用于α-特异性糖基化）促进的试剂控制的脱水糖基化。这些化学的优点是它们允许脱氧糖苷的直接立体选择性合成，而不需要临时辅基。在该目的中合成的片段的一部分将被转化为已知的糖霉素降解产物，以确定构成主链的糖的绝对构型。特定目标3将检查将来自目标2的片段组装成糖霉素的十七糖骨架的化学。然后将全长寡糖加工成糖霉素B，从而建立该抗生素的首次全合成。通过为糖霉素B提供一个灵活的途径，这项研究将为开发下一代抗生素铺平道路，以帮助对抗日益增长的多重耐药细菌的威胁。此外，这些研究将证明，通过使用糖基化化学，其中选择性完全在启动子的控制下，有可能合成极其复杂的寡糖。从这些研究中吸取的经验教训将有助于为开发技术奠定基础，这些技术将允许在快速的时间尺度上构建复杂的寡糖。因此，这项研究也将有助于加速化学糖生物学的发现。