Biologically Active Cyclic Peptides

描述(申请人提供)：详细介绍了包括万古霉素、替考拉宁和瑞索西汀在内的糖肽抗生素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与D-Ala-D-Lac结合，以解决D-Ala-D-Ala肽聚糖重塑产生的新的细菌耐药性，努力确定和优化芳基氯化物的作用，以及全面探索在上一次授权期发现的一种新的糖肽衍生物，这些糖肽衍生物对VanB和Vana耐药细菌具有活性。这些研究将建立重组万古霉素与D-丙氨酸-D-乳酸结合的可行性，可能会提供几种独特的方法来对抗新出现的万古霉素耐药性，并将提供对糖肽抗生素结构与功能关系的基本理解。对这些研究的一个令人兴奋的补充是对雷莫拉宁的详细探索，该研究同样旨在完善对其作用机制的理解，定义其与脂质II结合的结构细节，并建立有助于糖基酶抑制和抗菌活性的关键结构特征。这些研究的扩展包括氯肽的全合成(抗艾滋病毒活性)和结构类似物，氯福辛(具有抗肿瘤活性的P53-MDM2结合的抑制剂)和一系列广泛的类似物，这些努力也将定义其发色团的绝对立体化学，HUN-7293(确定其抑制血管细胞黏附分子1表达的生物靶点和其抗炎活性)，以及RP-66453的全合成，确定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.