Biologically Active Cyclic Peptides

描述（由申请方提供）：详细描述了糖肽类抗生素（包括万古霉素、替考拉宁和利托那）的关键类似物和部分结构的合成和评价研究。这包括努力重新设计万古霉素以结合D-Ala-D-Lac，以解决源自D-Ala-D-Ala的肽聚糖重塑的新出现的细菌耐药性，努力定义和优化芳基氯化物的作用，以及充分探索在上一个授权期发现的一类新的糖肽衍生物，其对VanB和VanA耐药细菌具有活性。这些研究应该建立重新设计万古霉素结合D-Ala-D-Lac的可行性，可以提供几种独特的方法来对抗新出现的万古霉素耐药性，并将提供对糖肽类抗生素的结构-功能关系的基本理解。这些研究的一个令人兴奋的补充是雷莫拉宁的详细探索，其同样旨在完善其作用机制的理解，定义其与脂质II结合的结构细节，并建立有助于转糖基化酶抑制和抗菌活性的关键结构特征。这些研究的扩展详细介绍了氯肽的全合成（抗HIV活性）和结构类似物，氯氟定（显示抗肿瘤活性的p53-MDM 2结合抑制剂）和广泛系列的类似物，这些类似物也将限定其发色团绝对立体化学，匈奴-7293（鉴定其抑制VCAM-1表达的生物学靶标及其抗炎活性），以及RP-66453的全合成，定义其相对和绝对立体化学。

DESCRIPTION (provided by applicant): Studies on the synthesis and evaluation of key analogs and partial structures of the glycopeptide antibiotics including vancomycin, teicoplanin, and ristocetin are detailed. This includes efforts to re-engineer vancomycin to bind D-Ala-D-Lac to address the emerging bacterial resistance derived from peptidoglycan remodeling of D-Ala-D-Ala, efforts to define and optimize the role of aryl chlorides, and the full exploration of a new class of glycopeptide derivatives discovered in the last grant period that are active against VanB and VanA resistant bacteria. These studies should establish the feasibility of re-engineering vancomycin to bind D-Ala-D-Lac, may provide several unique approaches to countering the emerging vancomycin resistance, and will provide a fundamental understanding of the structure-function relationships of the glycopeptide antibiotics. An exciting complement to these studies is the detailed exploration of ramoplanin which is similarly designed to refine the understanding of its mechanism of action, define the structural details of its binding to lipid II, and to establish key structural features contributing to tranglycosylase inhibition and antimicrobial activity. Extensions of these studies are detailed for the total synthesis of the chloropeptins (anti HIV activity) and structural analogs, chlorofusin (inhibitor of p53-MDM2 binding displaying antitumor activity) and an extensive series of analogs in efforts that will also define its chromophore absolute stereochemistry, HUN-7293 (identification of its biological target for inhibition of VCAM-1 expression and its anti-inflammatory activity), and for the total synthesis of RP-66453 defining its relative and absolute stereochemistry.