Diversity through phosphine catalysis identifies octahydro-1,6-naphthyridin-4-ones as activators of endothelium-driven immunity
Diversity through phosphine catalysis identifies octahydro-1,6-naphthyridin-4-ones as activators of endothelium-driven immunity
复制标题
DOI：
10.1073/pnas.1015254108
复制
发表时间：
2011-04-26
影响因子：
11.1
通讯作者：
Kwon, Ohyun
中科院分区：
文献类型：
--
作者：
Cruz, Daniel;Wang, Zhiming;Kwon, Ohyun
内皮在促进心血管疾病和其他慢性炎症性疾病的炎症中起着关键作用，许多小分子筛选已试图鉴定阻止内皮细胞活化的药物。相反，增强的免疫应答可以保护免受微生物病原体和癌症免疫疗法的侵害。然而，小分子筛选，以确定代理人诱导内皮细胞活化尚未报道。在这方面，开发了一种生物测定法，其通过激活内皮细胞从原代单核细胞触发巨噬细胞炎性蛋白1 β的能力来鉴定激活的内皮细胞。随后，通过基于亲核膦催化的多样性定向合成产生的39个独特支架的642化合物库筛选激活内皮的小分子。在所鉴定的活性化合物中，主要类别通过膦催化的成环、Tebbe反应、Diels-Alder反应以及在某些情况下水解的顺序合成。九十六个类似物的一个特定类别的化合物，八氢-1，6-萘啶-4-酮，有效地制备了固相分裂和池技术，并通过溶液相模拟合成。结合活性和非活性八氢-1，6-萘啶-4-酮类似物的转录谱的结构-功能分析鉴定了仅由活性化合物诱导的炎性基因网络。通过内皮细胞活化增强先天免疫的化学探针家族的鉴定为理解内皮炎症中涉及的基因网络以及开发新型内皮驱动的免疫抑制剂提供了框架。
The endothelium plays a critical role in promoting inflammation in cardiovascular disease and other chronic inflammatory conditions, and many small-molecule screens have sought to identify agents that prevent endothelial cell activation. Conversely, an augmented immune response can be protective against microbial pathogens and in cancer immunotherapy. Yet, small-molecule screens to identify agents that induce endothelial cell activation have not been reported. In this regard, a bioassay was developed that identifies activated endothelium by its capacity to trigger macrophage inflammatory protein 1 beta from primary monocytes. Subsequently, a 642-compound library of 39 distinctive scaffolds generated by a diversity-oriented synthesis based on the nucleophilic phosphine catalysis was screened for small molecules that activated the endothelium. Among the active compounds identified, the major classes were synthesized through the sequence of phosphine-catalyzed annulation, Tebbe reaction, Diels-Alder reaction, and in some cases, hydrolysis. Ninety-six analogs of one particular class of compounds, octahydro-1,6-naphthyridin-4-ones, were efficiently prepared by a solid-phase split-and-pool technique and by solution phase analog synthesis. Structure-function analysis combined with transcriptional profiling of active and inactive octahydro-1, 6-naphthyridin-4-one analogs identified inflammatory gene networks induced exclusively by the active compound. The identification of a family of chemical probes that augment innate immunity through endothelial cell activation provides a framework for understanding gene networks involved in endothelial inflammation as well as the development of novel endothelium-driven immunotherapeutic agents.