Total synthesis and semi synthetic derivatization of [13]cytochalasans

[13]细胞松弛聚糖的全合成和半合成衍生化

• 批准号: 454870350
• 负责人: Professor Dr. Philipp Klahn
• 金额: --
• 依托单位: Institutionen för Kemi och Molekylärbiologi
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/454870350?language=en
• 关键词: Total; synthesis; semi; synthetic; derivatization

Cytochalasans comprise a diverse group of fungal polyketide-amino acid hybrid metabolites with a wide range of biological functions. A hallmark of the cytochalasans is their tricyclic core structure in which a size-variable macrocycle is fused to a bicyclic isoindolone system derived from an amino acid. The eleven known subclasses of the cytochalasan natural product family differ in the size of the fused macrocycle and its oxidation pattern as well as the oxidation pattern in the 6-membered ring of the isoindolone core. In some representatives of the respected subclasses additional structural diversity is achieved by fusion of the macrocycle into polycyclic frameworks and even non-macrocyclic Cytochalasans are known. Despite all available biological data on cytochalasans, a comprehensive picture of the structure-activity relationships (SAR) for specific activities or of the correlation between the structural motives (ring sizes, oxidation pattern, substituents) of the respected cytochalasan subclasses and the different biological targets addressed by them is still missing. Although, several total syntheses for specific representatives of known cytochalasan subclasses have been published, none of them has been targeting the subclass of [13]cytochalasans. As access to natural cytochalasans is limited, only very few semi-synthetic derivatization studies have been made, only limited to [11]cytochalasans. Thus, there are no comprehensive synthetic studies on [13]cytochalasans enabling the elucidation of SAR of incorporated amino acid, oxidation pattern or macrocycle size on the biological activities and target selectivity.Furthermore, considering the biosynthetic pathways leading to cytochalasans already elucidated, we can expect that there are formally missing cytochalasan subclasses existing in nature, which could be formed from a biosynthetically perspective, but have not been isolated from natural sources yet. Thus, there might be even more hidden biological activity to discover from the cytochalasan natural product family.Within the present project, on the one hand, we plan to derivatize natural [13]cytochalasans obtained by fermentation and on the other hand develop an efficient, convergent and variable synthetic access to the subclass of [13]cytochalasans via a late-stage derivatization strategy and generate several [13]cytochalasan derivatives. Furthermore, we aim to synthetically access the formally missing subclass of 23-oxa-[13]cytochalasans based on the developed synthesis. Thus, we will provide appropriate [13]cytochalasan derivatives for biological evaluation, target identification and imaging purposes and enable systematic comprehensive SAR studies for specific biological activities by different collaboration partners within the envisaged DFG Researcher Group CytoLabs.

细胞松果体包括一组不同的真菌聚酮-氨基酸杂化代谢产物，具有广泛的生物学功能。细胞松驰剂的一个特点是它们的三环核心结构，其中一个可变大环与一个从氨基酸衍生的双环异吲哚系统融合在一起。细胞松弛素天然产物家族的11个已知亚类在融合大环的大小及其氧化模式以及异吲哚酮核的6元环上的氧化模式方面存在差异。在一些受人尊敬的亚类的代表中，通过将大环融合到多环框架中实现了额外的结构多样性，甚至已知了非大环胞松质。尽管有关于细胞松弛素的所有现有生物学数据，但具体活动的结构-活性关系(SAR)或受人尊敬的细胞松弛素亚类的结构动机(环大小、氧化模式、取代基)与它们所涉及的不同生物靶标之间的相关性仍然缺乏全面的图景。虽然已经发表了几个针对已知细胞松弛亚类的特定代表的全合成，但没有一个是针对[13]细胞松弛亚类的。由于获得天然细胞松驰剂的途径有限，仅有很少的半合成衍生化研究，仅限于[11]细胞松弛素。因此，还没有关于[13]细胞松弛素的全面的合成研究，能够阐明所结合的氨基酸、氧化模式或大环大小对生物活性和靶标选择性的影响。此外，考虑到导致细胞松弛素的生物合成途径已经被阐明，我们可以预期自然界中存在形式上缺失的细胞松弛素亚类，从生物合成的角度来看，这些亚类可以形成，但还没有从自然来源中分离出来。因此，从细胞松弛素天然产物家族中可能会发现更多隐藏的生物活性。在本项目中，我们计划一方面对发酵获得的天然细胞松弛素进行衍生化，另一方面通过后期衍生化策略开发一种高效、收敛和可变的合成途径来获得[13]细胞松弛素亚类，并产生几个[13]细胞松弛素衍生物。此外，我们的目标是在已开发的合成的基础上，合成形式上缺失的23-氧杂-[13]细胞松弛素亚类。因此，我们将为生物评估、目标识别和成像目的提供适当的[13]细胞松弛素衍生物，并使设想的DFG研究小组CytoLabs内的不同合作伙伴能够对特定生物活动进行系统全面的SAR研究。