Novel Ribostamycins and SAR Study of Ring III Aminosugar

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展的主要障碍。通过我们的经验和努力，我们已经实现了初步的预期目标：氨基糖/脱氧糖文库的合成，具有实际应用的含氨基糖/脱氧糖分子的制备，以及这些含氨基糖/脱氧糖分子的生物学意义的研究。我们是少数能够创建如此多样化的不寻常糖和氨基糖苷库的团队之一。在成功实现生成氨基糖/脱氧糖文库的最初目标后，我们已经进入了不寻常糖的设想应用之一：合成吡喃霉素（新型氨基糖苷类抗生素）文库。与之前的工作相比，我们的吡喃霉素设计提供了唯一具有接近新霉素（低微摩尔）抗菌活性且具有显着改善的酸稳定性的例子。后者可能会降低已知与氨基糖苷类抗生素相关的细胞毒性。使用合成方法，我们打算合成另外两种结构实体，并与寡肽的固相平行合成相结合，以开发针对各种耐药细菌菌株的通用氨基糖苷设计，并具有较低的细胞毒性。这些都是非常具有挑战性但有趣且重要的任务。为了实现我们的目标，我们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合作来评估我们的吡喃霉素构建体的体内和全细胞抗菌活性。通过我们的研究，我们掌握了碳水化合物合成和氨基糖苷类抗生素设计方面的扎实知识。我们希望了解更多关于调节相互作用、电荷-电荷和范德华力的影响，并将这一发现应用于未来的药物设计。我们相信，我们提出的研究将为碳水化合物相关领域带来突破，并为更广泛的研究铺平道路，从碳水化合物和受体相互作用等基础科学研究到公共卫生和国家安全问题的实际应用，例如临床上重要的不寻常含糖抗菌药物（针对炭疽、耐多药结核病）、抗病毒药物（针对艾滋病毒）、抗真菌和抗癌药物的开发。

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.