Martin-Benlloch Xavier, Haid Sibylle, Novodomska Alexandra, Rominger Frank, Pietschmann Thomas, Davioud-Charvet Elisabeth, Elhabiri Mourad
Université de Strasbourg, Université de Haute-Alsace, CNRS, LIMA, UMR 7042, Equipe Chimie Bioorganique et Médicinale, ECPM, 25 Rue Becquerel, 67000 Strasbourg, France.
Institute of Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research; A Joint Venture of the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
ACS Omega. 2019 Mar 5;4(3):4871-4887. doi: 10.1021/acsomega.8b03332. eCollection 2019 Mar 31.
Ladanein (i.e., 5,6,7-trihydroxylated flavone) was demonstrated to act as a powerful virucidal agent toward a broad range of enveloped virus particles. Fe(III) coordination and pH are indeed among the key parameters that might favor both bioactivation of the flavone and consequent host cell entry inhibition. In this present work, the impact of fluorinated groups on the physicochemical and antiviral properties of the flavone was investigated, thus allowing a deeper understanding of the antiviral mode of action. The improved synthesis of ladanein allowed accessing a broad range of analogues, some of them being significantly more active than the former ladanein lead compound. We first determined the acido-basic properties of this homogenous series of compounds and then investigated their electrochemical behavior. Fe(III) coordination properties (stability, spectral behavior, and kinetics) of ladanein and its analogues were then examined (quasiphysiological conditions) and provided key information of their stability and reactivity. Using the determined physicochemical parameters, the critical impact of the iron complexation and medium acidity was confirmed on hepatitis C virus (HCV) particles (pre)treated with ladanein. Finally, a preliminary structure-HCV entry inhibition relationship study evidenced the superior antiviral activity of the ladanein analogues bearing an electron-withdrawing group in para position ( > > > > ) on the B cycle in comparison with the parent ladanein itself.
拉丹宁（即5,6,7-三羟基黄酮）被证明是一种对多种包膜病毒颗粒具有强大杀病毒作用的药剂。铁（III）配位和pH确实是可能有利于黄酮生物活化以及随后抑制宿主细胞进入的关键参数。在本研究中，研究了氟代基团对黄酮物理化学性质和抗病毒特性的影响，从而能更深入地了解其抗病毒作用模式。拉丹宁的改进合成方法使得能够获得多种类似物，其中一些比原来的拉丹宁先导化合物活性显著更高。我们首先测定了这一系列同类化合物的酸碱性质，然后研究了它们的电化学行为。接着研究了拉丹宁及其类似物的铁（III）配位性质（稳定性、光谱行为和动力学）（准生理条件下），并提供了它们稳定性和反应性的关键信息。利用所测定的物理化学参数，证实了铁络合作用和介质酸度对用拉丹宁（预先）处理的丙型肝炎病毒（HCV）颗粒有至关重要的影响。最后，一项初步的结构-丙型肝炎病毒进入抑制关系研究证明，与母体拉丹宁本身相比，在B环对位带有吸电子基团的拉丹宁类似物具有更强的抗病毒活性。
