Herrmann Lars, Yaremenko Ivan A, Çapcı Aysun, Struwe Julia, Tailor Dhanir, Dheeraj Arpit, Hodek Jan, Belyakova Yulia Yu, Radulov Peter S, Weber Jan, Malhotra Sanjay V, Terent'ev Alexander O, Ackermann Lutz, Tsogoeva Svetlana B
Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander-University Erlangen-Nürnberg, Nikolaus Fiebiger-Straße 10, 91058, Erlangen, Germany.
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991, Moscow, Russian Federation.
ChemMedChem. 2022 May 4;17(9):e202200005. doi: 10.1002/cmdc.202200005. Epub 2022 Mar 29.
The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause life-threatening diseases in millions of people worldwide, in particular, in patients with cancer, and there is an urgent need for antiviral agents against this infection. While in vitro activities of artemisinins against SARS-CoV-2 and cancer have recently been demonstrated, no study of artemisinin and/or synthetic peroxide-based hybrid compounds active against both cancer and SARS-CoV-2 has been reported yet. However, the hybrid drug's properties (e. g., activity and/or selectivity) can be improved compared to its parent compounds and effective new agents can be obtained by modification/hybridization of existing drugs or bioactive natural products. In this study, a series of new artesunic acid and synthetic peroxide based new hybrids were synthesized and analyzed in vitro for the first time for their inhibitory activity against SARS-CoV-2 and leukemia cell lines. Several artesunic acid-derived hybrids exerted a similar or stronger potency against K562 leukemia cells (81-83 % inhibition values) than the reference drug doxorubicin (78 % inhibition value) and they were also more efficient than their parent compounds artesunic acid (49.2 % inhibition value) and quinoline derivative (5.5 % inhibition value). Interestingly, the same artesunic acid-quinoline hybrids also show inhibitory activity against SARS-CoV-2 in vitro (EC 13-19 μm) and no cytotoxic effects on Vero E6 cells (CC up to 110 μM). These results provide a valuable basis for design of further artemisinin-derived hybrids to treat both cancer and SARS-CoV-2 infections.
新出现的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）在全球数百万人中引发危及生命的疾病，尤其是癌症患者，因此迫切需要针对这种感染的抗病毒药物。虽然最近已证明青蒿素对SARS-CoV-2和癌症具有体外活性，但尚未有关于对癌症和SARS-CoV-2均具有活性的青蒿素和/或基于合成过氧化物的杂合化合物的研究报道。然而，与母体化合物相比，杂合药物的性质（例如活性和/或选择性）可以得到改善，并且通过对现有药物或生物活性天然产物进行修饰/杂交可以获得有效的新药物。在本研究中，首次合成了一系列基于青蒿琥酯和合成过氧化物的新型杂合物，并对其针对SARS-CoV-2和白血病细胞系的抑制活性进行了体外分析。几种青蒿琥酯衍生的杂合物对K562白血病细胞的抑制效力（抑制值81-83%）与参考药物阿霉素（抑制值78%）相似或更强，并且它们也比其母体化合物青蒿琥酯（抑制值49.2%）和喹啉衍生物（抑制值5.5%）更有效。有趣的是，相同的青蒿琥酯-喹啉杂合物在体外也显示出对SARS-CoV-2的抑制活性（EC 13-19 μM），并且对Vero E6细胞无细胞毒性作用（CC高达110 μM）。这些结果为进一步设计用于治疗癌症和SARS-CoV-2感染的青蒿素衍生杂合物提供了有价值的基础。
