Novel Ribostamycins and SAR Study of Ring III Aminosugar

新型核霉素及环III氨基糖的SAR研究

• 批准号: 6770744
• 负责人: CHENG-WEI T CHANG
• 金额: $ 17.38万
• 依托单位: UTAH STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6770744
• 关键词: aminoglycoside antibiotics; aminosugar; antibacterial agents; binding sites; carbohydrate structure; chemical binding; chemical structure function; chemical substitution; chemical synthesis; combinatorial chemistry; drug design /synthesis /production; drug resistance; drug screening /evaluation; fluorescence; nuclear magnetic resonance spectroscopy; pharmacokinetics; ribosomal RNA

DESCRIPTION (provided by applicant): Carbohydrate research can contribute profound impacts in various fields although the synthesis of carbohydrate derivatives has been the major obstacle that impedes the progress in this area. Through our experience and effort, we have achieved our preliminary projected goals: synthesis of aminosugars/deoxysugars library, preparation of aminosugars/deoxysugars containing molecules with practical applications, and the studies of biological implications with these aminosugars/deoxysugars containing molecules. We are one of the few groups capable of creating such diverse unusual sugar and aminoglycoside libraries. After successfully achieving our initial goal of generating aminosugar/deoxysugar library, we have moved into one of the envisioned applications of unusual sugars: synthesizing a library of pyranmycin, novel aminoglycoside antibiotics. Compared to previous work, our pyranmycin designs provide the only examples with antibacterial activity close to neomycin (low micromole), and with much-improved acid stability. The later may potentially lead to the reduction of the cytotoxicity known to be associated with aminoglycoside antibiotics. Using synthetic approaches, we intend to synthesize two more structural entities coupled with a solid phase parallel synthesis of oligopeptides for the development of the general aminoglycoside designs against various strains of resistant bacteria, and with lower cytotoxicity. These are very challenging but interesting and important tasks. We have proposed several practical synthetic methods for our objectives. We have established our own facilities or collaborations for evaluating the antibacterial activity of our pyranmycin constructs in vivo and in whole cell based. We have learned solid knowledge in carbohydrate synthesis and aminoglycoside antibiotic design through our research. We wish to learn more regarding the influence of modulating the interactions, charge-charge and van der Waals, and apply the finding for future drug designs. It is our conviction that our proposed research will provide breakthroughs in carbohydrate-related fields, and pave the way to a broader research ranging from basic scientific studies like carbohydrates and receptors interaction to practical applications regarding the issues of public health and national security, such as, the development of clinically important unusual sugar-containing antibacterial (against anthrax, MDR-TB), antiviral (against HIV), antifungal, and anticancer agents.

描述（由申请人提供）：碳水化合物研究可以在各个领域产生深远的影响，尽管碳水化合物衍生物的合成一直是阻碍该领域进步的主要障碍。通过我们的经验和努力，我们实现了我们的初步投影目标：氨基糖/脱氧糖库的综合，准备具有实际应用的分子的氨基糖/脱氧糖，以及使用这些氨基糖/脱氧糖的生物学含义的研究。我们是能够创建如此不同寻常的糖和氨基糖苷库的少数小组之一。在成功实现了产生氨基加糖/脱氧库库的最初目标之后，我们进入了一种不寻常的糖的设想应用之一：合成pyranmycin库，新型氨基糖苷抗生素。与以前的工作相比，我们的吡喃霉素设计提供了唯一的抗菌活性的例子，接近新霉素（低微孔），并且具有重大改良的酸稳定性。后期可能导致降低已知与氨基糖苷抗生素有关的细胞毒性。使用合成方法，我们打算合成两个又有两个结构实体，并结合寡肽的固相平行合成，以开发一般的氨基糖苷设计，以针对各种抗性细菌的菌株和较低的细胞毒性。这些非常具有挑战性，但有趣而重要的任务。我们已经为我们的目标提出了几种实用的合成方法。我们已经建立了自己的设施或协作，以评估体内和整个细胞中的pyranmycin构建体的抗菌活性。通过我们的研究，我们已经学习了碳水化合物合成和氨基糖苷抗生素设计的坚实知识。我们希望了解有关调节相互作用，电荷收费和范德华的影响的更多信息，并将其应用于未来的药物设计。 It is our conviction that our proposed research will provide breakthroughs in carbohydrate-related fields, and pave the way to a broader research ranging from basic scientific studies like carbohydrates and receptors interaction to practical applications regarding the issues of public health and national security, such as, the development of clinically important unusual sugar-containing antibacterial (against anthrax, MDR-TB), antiviral (against HIV),抗真菌和抗癌药。