Design and synthesis of novel archazolids: Development of simplified analogues

聚酮类天然产物仿古唑A和B在体外和体内都构成了新型的特别有效的(低纳摩尔和亚纳摩尔范围的IC50)和V-ATPase的特异性抑制剂。在Forschergruppe的第一个资助期内，它们已被证明在小鼠身上显示出强大的抗肿瘤活性，这使得它们具有极具吸引力的化合物，可用于进一步的临床前研究。然而，由于天然来源的低可用性和结构的复杂性阻碍了通过全合成进行大规模的获取，这严重阻碍了这一点。在Forschergruppe的跨学科方法中，该项目建议设计和合成简化的古拉唑类化合物作为改进的抗肿瘤药物。该项目的第一部分将开发创新的古唑类化合物作为化学工具，在分子水平上更详细地分析这些有效的大环内酯类化合物在体内的相互作用。在这些研究的基础上，将继续设计和合成经过精心挑选的青蒿素类似物。将特别重视开发同等但更容易获得的类似物。结构简化将依赖于一种合理的方法，该方法基于对目标抑制剂相互作用的详细的计算机分析。这些化合物将通过模块化、全合成或基于母体天然产物本身的衍生化而获得。然后，所有类似物都将在这个Forschergruppe中进行彻底的抗肿瘤潜力评估。

The polyketide natural products archazolid A and B constitute novel types of particularly efficient (IC50 in the low nanomolar and subnanomolar range) and specific inhibitors of V-ATPases, both in vitro and in vivo. During the first funding period of this Forschergruppe, they have been shown to demonstrate potent antitumor activity in mice, which renders them highly attractive compounds for further preclinical advancement. However this has been severely hampered by the low availability from their natural source and the structural complexity that impedes a large scale access by total synthesis. Within the interdisciplinary approach of this Forschergruppe this project proposes the design and synthesis of simplified archazolids as improved antitumor agents. The first part of the project will develop innovative archazolid derivatives as chemical tools to analyse in more detail the in vivo interactions of these potent macrolides at a molecular level. Based on these studies the design and synthesis of carefully selected archazolid analogues will then be pursued. Particular emphasis will be placed on the development of equipotent but more readily available analogues. Structural simplification will rely on a rational approach based on a detailed in silico analysis of target inhibitor interactions. These compounds will be obtained either by a modular, total synthesis or based on derivatization of the parent natural products themselves. All analogues will then be thoroughly evaluated for their antitumor potential within this Forschergruppe.