Human Health Therapeutics, National Research Council of Canada, 100 Sussex Drive, Ottawa K1N 5A2, Canada.
J Org Chem. 2021 Feb 5;86(3):2184-2199. doi: 10.1021/acs.joc.0c02333. Epub 2021 Jan 15.
Pathogen-associated molecular patterns activate the immune system via pattern recognition receptors. Recently, newly discovered pathogen-associated molecular patterns, d--β-d-heptose phosphate and d--β-d-heptose 1,7-biphosphate, were shown to induce a TRAF-interacting protein with a forkhead-associated domain-dependent immune response in human embryonic kidney cells and colonic epithelial cells. Concurrently, ADP-heptose was shown to bind α-kinase 1 and activate TIFA via phosphorylation leading to an immune cascade to ultimately activate NF-κB. These pathogen-associated molecular patterns have raised interest in the pharmaceutical industry for their potential use as immunomodulators. However, little is understood about the host cell uptake of d--β-d-heptose phosphate, d--β-d-heptose 1,7-biphosphate, and ADP-heptose in vivo and derivatives of these molecules are needed to interrogate this. In this regard, herein we describe 7--modifications of d--β-d-heptose phosphate to produce molecular probes toward the development of a useful toolbox for biologists. A convergent strategy that involves introduction of a substituent at -7 before alkene oxidation was investigated and proved successful in the generation of a range of molecular probes.
病原体相关分子模式通过模式识别受体激活免疫系统。最近，新发现的病原体相关分子模式 d-β-d-庚糖磷酸和 d-β-d-庚糖 1,7-双磷酸被证明能够在人胚肾细胞和结肠上皮细胞中诱导一种具有叉头相关结构域的 TRAF 相互作用蛋白，从而引发免疫反应。同时，ADP-庚糖被证明能够与α-激酶 1 结合，并通过磷酸化激活 TIFA，从而引发免疫级联反应，最终激活 NF-κB。这些病原体相关分子模式因其作为免疫调节剂的潜在用途而引起了制药行业的兴趣。然而，对于这些分子在体内被宿主细胞摄取的情况，人们知之甚少，并且需要这些分子的衍生物来进行研究。在这方面，本文描述了对 d-β-d-庚糖磷酸进行 7-修饰，以生成分子探针，为生物学家开发有用的工具包。我们研究了一种在烯烃氧化前在-7 位引入取代基的会聚策略，并成功地生成了一系列分子探针。
