Synthesis and structure-activity-relationships of 1H-imidazo[4,5-c]quinolines that induce interferon production
Synthesis and structure-activity-relationships of 1H-imidazo[4,5-c]quinolines that induce interferon production
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DOI：
10.1021/jm049211v
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发表时间：
2005-05-19
影响因子：
7.3
通讯作者：
Lupu, M
中科院分区：
文献类型：
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作者：
Gerster, JF;Lindstrom, KJ;Lupu, M
1H-咪唑并[4，5-c]喹啉类化合物是在研究新型核苷类似物作为潜在抗病毒药物时合成的。虽然这些化合物在许多细胞培养系统中测试时没有显示出直接的抗病毒活性，但在阴道内豚鼠单纯疱疹病毒-2测定中，一些化合物显示出对病毒病变发展的有效抑制。我们已经确定，在体内的抗病毒活性可以归因于这些分子的能力，以诱导细胞因子的生产，特别是干扰素（IFN），在这个模型中。随后，我们发现化合物还诱导人外周血单核细胞（hPBMC）中IFN的体外产生。本文报道的体外结果和先前报道的体内结果导致发现咪喹莫特，26，其被开发为局部药剂并已被批准用于治疗生殖器疣、光化性角化病和浅表基底细胞癌。
1H-Imidazo-[4,5-c]quinolines were prepared while investigating novel nucleoside analogues as potential antiviral agents. While these compounds showed no direct antiviral activity when tested in a number of cell culture systems, some demonstrated potent inhibition of virus lesion development in an intravaginal guinea pig herpes simplex virus-2 assay. We have determined that the in vivo antiviral activity can be attributed to the ability of these molecules to induce the production of cytokines, especially interferon (IFN), in this model. Subsequently, we found that the compounds also induce in vitro production of IFN in human peripheral blood mononuclear cells (hPBMCs). The in vitro results reported herein and the in vivo results reported previously led to the discovery of imiquimod, 26, which was developed as a topical agent and has been approved for the treatment of genital warts, actinic keratosis, and superficial basal cell carcinoma.