Department of Chemistry and Pharmacy, Friedrich Alexander University, Erlangen 91052, Germany.
J Med Chem. 2013 Jun 27;56(12):5019-32. doi: 10.1021/jm4003457. Epub 2013 Jun 14.
A series of 31 chalcone- and flavonoid-based derivatives were synthesized in good overall yields and screened for their inverse agonist activity on the US28 receptor of human cytomegalovirus (HCMV). With one exception (e.g., 2-(5-bromo-2-methoxyphenyl)-3-hydroxy-4H-chromen-4-one), halogen-substituted flavonoids were typically more potent inverse agonists than their related hydro derivatives. While toxicity could be used to partially explain the inverse agonist activity of some members of the series, 5-(benzyloxy)-2-(5-bromo-2-methoxyphenyl)-4H-chromen-4-one (11b) acted on the US28 receptor as a nontoxic, inverse agonist. The full inverse agonism (efficacy, -89%) and potency (EC50 = 3.5 μM) observed with flavonoid 11b is especially important as it provides both a new tool to study US28 signaling and a potential platform for the future development of HCMV-targeting drugs.
合成了一系列 31 种查尔酮和类黄酮衍生物，总收率高，并对其作为人巨细胞病毒（HCMV）US28 受体的反向激动剂活性进行了筛选。除一个例外（例如，2-（5-溴-2-甲氧基苯基）-3-羟基-4H-色烯-4-酮）外，卤代黄酮通常比其相关的氢衍生物具有更强的反向激动剂活性。虽然毒性可以部分解释该系列部分成员的反向激动剂活性，但 5-（苯氧基）-2-（5-溴-2-甲氧基苯基）-4H-色烯-4-酮（11b）作为非毒性反向激动剂作用于 US28 受体。黄酮 11b 表现出的完全反向激动作用（效力，-89%）和效力（EC50=3.5μM）特别重要，因为它不仅为研究 US28 信号提供了新工具，而且为未来开发针对 HCMV 的药物提供了潜在平台。
