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这一领域进展的主要障碍。通过我们的经验和努力，我们已经达到了初步的预期目标：氨基糖/脱氧糖库的合成，含有实际应用的氨基糖/脱氧糖分子的制备，以及这些含有氨基糖/脱氧糖分子的生物学意义的研究。我们是少数几个能够创建如此多样化的不同寻常的糖和氨基糖苷类文库的团队之一。在成功地实现了生成氨基糖/脱氧糖库的最初目标后，我们进入了不同寻常糖的可预见的应用之一：合成新型氨基糖苷类抗生素吡喃霉素的文库。与以前的工作相比，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)抗菌活性的例子，并且酸稳定性有了很大改善。后者可能潜在地降低已知的与氨基糖苷类抗生素相关的细胞毒性。利用合成方法，我们打算合成另外两个结构实体，并结合固相平行合成寡肽，以开发针对各种耐药细菌的通用氨基糖苷类设计，并具有较低的细胞毒性。这些都是非常具有挑战性但有趣和重要的任务。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合作来评估我们的吡喃霉素构建体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学到了扎实的知识。我们希望更多地了解调节相互作用、电荷-电荷和范德华的影响，并将这一发现应用于未来的药物设计。我们相信，我们拟议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，范围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，例如开发临床上重要的特殊含糖抗菌药物(针对炭疽病、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.