Design and synthesis of novel archazolids: Development of simplified analogues

聚酮化合物天然产物archazolid A和B构成了新型的特别有效（IC 50在低纳摩尔和亚纳摩尔范围内）且特异性的V-ATP酶体外和体内抑制剂。在该研究组的第一个资助期内，它们已被证明在小鼠中具有强效抗肿瘤活性，这使它们成为具有高度吸引力的化合物，可用于进一步的临床前研究。然而，由于其天然来源的低可用性和结构复杂性阻碍了通过全合成进行大规模获取，这一点受到了严重阻碍。 在该研究小组的跨学科方法中，该项目提出了简化的archazolids作为改进的抗肿瘤剂的设计和合成。该项目的第一部分将开发创新的archazolid衍生物作为化学工具，以更详细地分析这些有效的大环内酯类药物在分子水平上的体内相互作用。基于这些研究，设计和合成精心挑选的archazolid类似物，然后将追求。将特别强调开发等效但更容易获得的类似物。结构简化将依赖于基于靶标抑制剂相互作用的详细计算机模拟分析的合理方法。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获得。然后，将在本研究组中全面评价所有类似物的抗肿瘤潜力。

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.