Novel Ribostamycins and SAR Study of Ring III Aminosugar

描述（由申请人提供）：碳水化合物的研究可以对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：合成了氨基糖/脱氧糖文库，制备了具有实际应用价值的氨基糖/脱氧糖分子，并研究了这些氨基糖/脱氧糖分子的生物学意义。我们是少数几个有能力创造如此多样的不寻常的糖和氨基糖苷库的团队之一。在成功地实现了我们产生氨基糖/脱氧糖文库的最初目标之后，我们已经进入了不寻常糖的预期应用之一：合成pyranmycin文库，一种新型氨基糖苷类抗生素。与以前的工作相比，我们的pyranmycin设计提供了唯一的抗菌活性接近新霉素（低微摩尔）的例子，并且酸稳定性大大提高。后者可能潜在地导致已知与氨基糖苷类抗生素相关的细胞毒性的降低。利用合成方法，我们打算合成另外两种结构实体，结合固相平行合成寡肽，用于开发针对各种耐药细菌菌株的通用氨基糖苷设计，并且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综合方法。我们已经建立了自己的设施或合作来评估我们的pyranmycin构建物在体内和全细胞中的抗菌活性。通过我们的研究，我们在碳水化合物合成和氨基糖苷类抗生素设计方面有了扎实的知识。我们希望了解更多关于调节相互作用、电荷-电荷和范德华效应的影响，并将这一发现应用于未来的药物设计。我们相信，我们提出的研究将在碳水化合物相关领域取得突破，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有关公共卫生和国家安全问题的实际应用，例如开发临床重要的不寻常的含糖抗菌药物（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。

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.