Department of Clinical Veterinary Medicine, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
J Nat Med. 2013 Oct;67(4):773-81. doi: 10.1007/s11418-013-0743-6. Epub 2013 Jan 24.
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-γ 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.
我们之前表明，（5S）-5-羟基-7-（4-羟基苯基）-1-苯基庚-3-酮（AO-0011）和（5S）-5-甲氧基-1,7-二苯基庚-3-酮（AO-0016）从益智中分离出来，其抗流感病毒活性和抗呼吸道合胞病毒（RSV）活性分别强于其他分离的二芳基庚烷。在这项研究中，我们合成了 AO-0011 的对映异构体（AO-0503）和外消旋体（AO-0504）以及 AO-0016 的对映异构体（AO-0514）。在体外和体内研究了这三种立体异构体（AO-0503、AO-0504 和 AO-0514）和 AO-0011 对 RSV 的抗活性，以评估立体异构效应对抗 RSV 活性的影响。在用人表皮癌细胞进行的蚀斑减少测定中，所有四种二芳基庚烷均显著表现出抗 RSV 活性，并且 AO-0514 和 AO-0016 比 AO-0503、AO-0504 和 AO-0011 表现出更强的抗 RSV 活性。在鼠 RSV 感染模型中，在体外具有抗 RSV 活性的所有四种二芳基庚烷在 RSV 感染小鼠肺部的病毒滴度降低方面也具有显著作用。在 RSV 感染肺部的组织病理学分析中，即使给予肺部病毒滴度降低最低的 AO-0514 进行口服给药，也能有效减少 RSV 感染小鼠支气管肺泡灌洗液中淋巴细胞浸润，并降低干扰素-γ 水平，这是 RSV 感染性肺炎严重程度的标志物。虽然二芳基庚烷对抗 RSV 活性的立体异构体效应略有不同，但所检查的所有四种二芳基庚烷均被认为可改善肺炎并具有体内抗 RSV 活性。它们可能是未来抗 RSV 药物开发的母体化合物。
