Antiviral activity of diarylheptanoid stereoisomers against respiratory syncytial virus in vitro and in vivo
Antiviral activity of diarylheptanoid stereoisomers against respiratory syncytial virus in vitro and in vivo
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DOI：
10.1007/s11418-013-0743-6
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发表时间：
2013-10-01
影响因子：
3.3
通讯作者：
Kurokawa, Masahiko
中科院分区：
文献类型：
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作者：
Konno, Katsuhiko;Miura, Motofumi;Kurokawa, Masahiko
我们先前从高良姜中分离得到的(5S)-5-hydroxy-7-(4-hydroxyphenyl)-1-phenylhept-3-one(AO-0011)和(5S)-5-甲氧基-1，7-二苯基-3-酮(AO-0016)分别比其他分离的二芳基庚烷类化合物具有更强的抗流感病毒活性和抗呼吸道合胞病毒活性。在本研究中，我们合成了AO-0011的对映体(AO-0503)、外消旋体(AO-0504)和对映体(AO-0514)。为了评价立体异构体对呼吸道合胞病毒的抑制作用，我们检测了三种立体异构体(AO-0503、AO-0504和AO-0514)和AO-0011的体内外抗呼吸道合胞病毒活性。在人表皮样癌细胞空斑减少实验中，四种二芳基庚烷化合物均表现出显著的抗呼吸道合胞病毒活性，其中，AO-0514和AO-0016的抗RSV活性强于AO-0503、AO-0504和AO-0011。在小鼠呼吸道合胞病毒感染模型中，四个体外具有抗呼吸道合胞病毒活性的二芳基庚烷化合物也显著地降低了呼吸道合胞病毒感染小鼠肺中的病毒滴度。在呼吸道合胞病毒感染肺的组织病理学分析中，口服病毒滴度最低的A0-0514可显著减少呼吸道合胞病毒感染小鼠支气管肺泡灌洗液中淋巴细胞的渗入和降低反映呼吸道合胞病毒感染所致肺炎严重程度的干扰素-γ水平。尽管二芳基庚烷类化合物在抗呼吸道合胞病毒活性上的立体异构体作用有适度的差异，但所有四个二芳基庚烷类化合物都被认为可以改善肺炎，并在体内具有潜在的抗呼吸道合胞病毒活性。它们可能是未来开发抗呼吸道合胞病毒药物的母体化合物。
We previously showed that (5S)-5-hydroxy-7-(4-hydroxyphenyl)-1-phenylhept-3-one (AO-0011) and (5S)-5-methoxy-1,7-diphenylhept-3-one (AO-0016) isolated from Alpinia officinarum exhibited stronger anti-influenza virus activity and anti-respiratory syncytial virus (RSV) activity, respectively, than the other isolated diarylheptanoids. In this study, we synthesized an enantiomer (AO-0503) and racemate (AO-0504) of AO-0011 and an enantiomer (AO-0514) of AO-0016. The anti-RSV activities of the three stereoisomers (AO-0503, AO-0504, and AO-0514) and AO-0011 were examined in vitro and in vivo to evaluate the stereoisomeric effect on anti-RSV activity. In a plaque reduction assay using human epidermoid carcinoma cells, all four diarylheptanoids significantly exhibited anti-RSV activity, and AO-0514 and AO-0016 exhibited stronger anti-RSV activity than AO-0503, AO-0504, and AO-0011. In a murine RSV infection model, all four diarylheptanoids with anti-RSV activity in vitro were also significantly effective in reducing virus titers in the lungs of RSV-infected mice. In the histopathological analysis of RSV-infected lungs, the oral administration of even AO-0514, which showed the lowest reduction of virus titers in the lungs, was significantly effective in reducing the infiltration of lymphocytes and in reducing the interferon-gamma level, which is a marker of severity of pneumonia due to RSV infection, in bronchoalveolar lavage fluids prepared from RSV-infected mice. Although the stereoisomeric effects of diarylheptanoids on anti-RSV activity varied moderately, all four diarylheptanoids examined were suggested to ameliorate pneumonia and have a potential anti-RSV activity in vivo. They are possibly mother compounds for the development of an anti-RSV drug in the future.