Optimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity
Optimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity
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DOI：
10.1016/j.bmcl.2020.126984
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发表时间：
2020-03-15
影响因子：
2.7
通讯作者：
Evans, Jay T.
中科院分区：
文献类型：
--
作者：
Bazin, Helene G.;Bess, Laura S.;Evans, Jay T.
Toll样受体7和8（TLR 7/8）激动剂是作为疫苗佐剂引起相当大兴趣的有效免疫刺激剂。我们最近报道了一系列新的2-O-丁基-8-氧代腺嘌呤的合成，在9-位被各种连接基和N-杂环取代，并表明TLR 7/8的选择性，效力和细胞因子诱导可以通过改变烷基连接基长度和N-杂环来调节。在本研究中，我们通过研究在氧代腺嘌呤的2-位上的不同取代基对人PBMC中的TLR 7/8效力/选择性、细胞因子诱导和DC成熟的影响来进一步优化氧代腺嘌呤支架。结果显示，在氧代腺嘌呤的2-位引入1-（S）-甲基丁氧基显著增加了TLR 7/8活性、细胞因子诱导和DC成熟的效力。
Toll-like receptors 7 and 8 (TLR7/8) agonists are potent immunostimulants that are attracting considerable interest as vaccine adjuvants. We recently reported the synthesis of a new series of 2-O-butyl-8-oxoadenines substituted at the 9-position with various linkers and N-heterocycles, and showed that TLR7/8 selectivity, potency and cytokine induction could be modulated by varying the alkyl linker length and the N-heterocyclic ring. In the present study, we further optimized the oxoadenine scaffold by investigating the effect of different substituents at the 2-position of the oxoadenine on TLR7/8 potency/selectivity, cytokine induction and DC maturation in human PBMCs. The results show that introducing a 1-(S)-methylbutoxy group at the 2-position of the oxoadenine significantly increased potency for TLR7/8 activity, cytokine induction and DC maturation.