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Design and synthesis of antiviral pseudo-natural products via effective one-step acylmethylation macrocyclization

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    Sarker A, Gu Z, Mao L, et al. Influenza-existing drugs and treatment prospects [J]. Eur J Med Chem, 2022, 232: 114189. doi: 10.1016/j.ejmech.2022.114189
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    Song B, Guo X, Yang L, et al. Rhodium(III)-Catalyzed C-H/O(2) Dual Activation and Macrocyclization: Synthesis and Evaluation of Pyrido[2, 1-a]isoindole Grafted Macrocyclic Inhibitors for Influenza H1N1 [J]. Angew Chem Int Ed Engl, 2023: e202218886.
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Design and synthesis of antiviral pseudo-natural products via effective one-step acylmethylation macrocyclization

    Corresponding author: E-mail: xbwang@cpu.edu.cn
  • 1. Jiangsu Key Laboratory of Bioactive Natural Product Research, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China

Abstract: 

  • The influenza virus is a greatly concerned threat to the world public health system, seriously affecting human life and health. Kinds of antiviral drugs engaged with virus itself or its host were identified in the past decades. However, a severe drug resistance problem caused by the influenza virus mutations still put these existing anti-influenza drugs into dilemma[1, 2], and it is urgently needed to develop novel molecules with new skeletons. Macrocyclic natural products are important resources for target verification and lead compound discovery[3, 4]. However, due to the limitations of natural biosynthetic pathways, macrocyclic natural products provided by nature are still very limited, which restricts the development of macrocyclic drugs. By comparison, pseudo-natural products obtained by artificial synthesis have more strong availability and diversity with similar biofunctions[5], which have attracted wide attention from medicinal chemists. Hence, it is valuable to develop effective synthetic methods to accelerate the discovery of macrocyclic lead compounds.

    Macrocyclization is favored in drug design due to its unique ring skeleton, reasonable three-dimensional conformation, and proper rigidity and flexibility [6]. Previously, Yang et al. constructed a series of bioactive macrocyclic compound libraries through the modular biomimetic strategy [7-9]. In the article entitled “Rhodium(III)-Catalyzed C-H/O2 Dual Activation and Macrocyclization: Synthesis and Evaluation of Pyrido[2,1-a]isoindole Grafted Macrocyclic Inhibitors for Influenza H1N1” recently published in Angew Chem Int Ed, Yang et al. designed a series of α-aryl acetophenones-supported macrocycle compounds through the development of a novel rhodium(III)-catalyzed C-H/O2 dual activation and macrocyclization [10]. Compared to traditional three-step reaction including C-H iodination, Heck coupling and Wacker oxidation, the one-step straightforward route greatly accelerates the synthesis of such macrocyclic compounds (Fig. 1).

    Figure 1.  The schematic diagram of pseudo-natural product synthesis and its application as potent anti-H1N1 inhibitors.

    The research team first used the intermolecular reaction as the template to explore the best reaction conditions. A combination of [Cp*Rh(CH3CN)3](SbF6)2 (10 mol%), L1 (5 mol%), NPh3 (50 mol%), and AcOH (50 mol%) in fluorobenzene/2-methoxyethyl acetate at 60 °C showed the best isolated yield, with good functional group compatibility. The researchers next applied this approach to pseudo-natural product synthesis, which obtained good availability as well. Through the cell-based phenotype screening, the researchers found that the resultant macrocyclic compounds containing α-aryl acetone and nitrogen hybrid ring structure showed promising activity against H1N1, providing inspirations for the development of macrocyclic drugs against H1N1. Especially, the best performed compound 41 showed significant inhibitory potency without obvious cytotoxic effects (EC50 = 0.28 μM; CC50 > 100 μM). Using 18O-labled isotopic tracing study and density functional theory (DFT) calculations, the researchers figured out molecular oxygen is greatly involved in the reaction, where the O-O bond cleavage step is calculated to be rate-determining for the whole catalytic cycle.

    In conclusion, this study constructed a highly effective method for obtaining macrocyclic pseudo-natural products, breaking through the limitation that the original C-H/O2 dual activation is commonly restricted to two components. Moreover, since fragment-based drug design is involved in pseudo-natural products as well [11], this study could be further developed by replacing the linker with other natural product fragments with potential bioactivity, intended for treating complex human diseases.

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