Design and synthesis of novel archazolids: Development of simplified analogues

聚酮类天然产物阿古唑啉A和B在体外和体内都是特别有效的新型v - atp酶抑制剂（IC50在低纳摩尔和亚纳摩尔范围内）和特异性抑制剂。在Forschergruppe的第一个资助期内，它们已在小鼠身上显示出强大的抗肿瘤活性，这使它们成为进一步临床前研究的极具吸引力的化合物。然而，由于天然来源的低可得性和结构复杂性阻碍了全合成的大规模获取，这严重阻碍了这一进程。在这个Forschergruppe的跨学科方法中，该项目提出了设计和合成简化的古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烷衍生物作为化学工具，以更详细地分析这些强效大环内酯在分子水平上的体内相互作用。在这些研究的基础上，精心挑选的仿古唑烷类似物的设计和合成将继续进行。将特别强调发展同等效力但更容易获得的类似物。结构简化将依赖于基于目标抑制剂相互作用的详细硅分析的合理方法。这些化合物可以通过模合成、全合成或基于母体天然产物本身的衍生化得到。所有类似物都将在这个Forschergruppe中被彻底评估其抗肿瘤潜力。

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.