Structurally diverse tetrahydroxanthone analogues from Paraconiothyrium sp. AC31 with pyroptosis induction through targeted inhibition of PARP1 in hepatocellular carcinoma cells

Article

Author: He, Li-Ming ; Zeng, Xiao-Bin ; Yuan, Rui-Ying ; Zhu, Kong-Kai ; Hu, Qiao-Qiao ; Wu, Xiao-Yan ; Chen, Wei-Chen ; Cai, You-Sheng ; Gao, Ping ; Zhang, Meng-Ke ; Li, Mu

This study reports the isolation and characterization of six novel tetrahydroxanthone derivatives, paraconixanthones A - F (1-6), a new diphenyl ether (7), and thirteen known compounds (8-20) from the endophytic fungus Paraconiothyrium sp. AC31. The chemical structures were elucidated using NMR, MS, X-ray diffraction, and ECD analyses. Paraconixanthones A and B (1 and 2) represent the first examples of tetrahydroxanthone-benzoate dimers, suggesting a unique biosynthetic pathway. Compound 12 exhibited potent anti-proliferative activity against HepG2 hepatocellular carcinoma cells (IC₅₀ = 1.19 μM), outperforming the standard therapy lenvatinib. Mechanistic studies revealed that compound 12 inhibits PARP1, leading to DNA damage, ROS accumulation, and caspase-3/GSDME-mediated pyroptosis. Additionally, it induces intrinsic apoptosis through BAX/BCL-2 modulation and caspase-7 activation. Meanwhile, GSDME deficiency treated with 12 exhibited the increased levels of PARP1 and caspase-3, supporting the cell death induced by 12 shifted from pyroptosis to apoptosis. These findings highlight the therapeutic potential of tetrahydroxanthones as selective agents targeting multiple cell death pathways in hepatocellular carcinoma, expanding the scope of natural product-based anti-cancer strategies.

01 Apr 2025·Bioorganic & Medicinal Chemistry

Rational design and synthesis of pyrazole derivatives as potential SARS-CoV-2 Mpro inhibitors: An integrated approach merging combinatorial chemistry, molecular docking, and deep learning

Article

Author: Maigret, Bernard ; Moura, Sidnei ; de Oliveira, Arildo José Braz ; de Souza, João Vítor Perez ; Ferrarezi, Arthur Antunes ; Kioshima, Érika Seki ; Gonçalves, Regina Aparecida Correia ; Rosa, Fernanda Andreia

The global impact of SARS-CoV-2 has highlighted the urgent need for novel antiviral therapies. This study integrates combinatorial chemistry, molecular docking, and deep learning to design, evaluate and synthesize new pyrazole derivatives as potential inhibitors of the SARS-CoV-2 main protease (M^pro). A library of over 60,000 pyrazole-based structures was generated through scaffold decoration to enhance chemical diversity. Virtual screening employed molecular docking (ChemPLP scoring) and deep learning (DeepPurpose), with consensus ranking to identify top candidates. Binding free energy calculations refined the selection, revealing critical structural features such as tryptamine and N-phenyl fragments for M^pro binding. High-temperature solvent-free amidation allowed the synthesis of a selected derivative. Final compounds demonstrated favorable drug-likeness properties based on Lipinski's and Veber's rules. This work highlights the integration of computational and synthetic strategies to accelerate the discovery of M^pro inhibitors and provides a framework for future antiviral development.

01 Dec 2024·Bioorganic Chemistry

Nigenolides A–H, 13 new microperfuranones with ferroptosis inhibitory activity from the deep-sea-derived Aspergillus niger

Article

Author: Zhang, Meng ; Zou, Zheng-Biao ; Yang, Xian-Wen ; Li, Li-Sheng ; Xie, Chun-Lan ; Li, You ; Dong, Hao-Yu ; Li, Jing-Yi ; Wang, Yuan

Thirteen new microperfuranones, including five pairs of enantiomers, (±)-nigenolides A-E (1a/1b-5a/5b), and three racemate nigenolides F-H (6-8), together with four known analogues (9-12) were isolated from a deep-sea-derived Aspergillus niger 3A00562. The absolute configurations of the five pairs of enantiomers were determined by the comparison of the calculated and experimental ECD spectra. Compounds 3a, 4a, 4b, and 12 were able to inhibit RSL3-induced ferroptosis. Compound 12 inhibited ferroptosis of A375 cells and 786-O cells with EC₅₀ values of 0.76 μM and 0.67 μM, respectively. Compound 12 was a potential iron chelator and radical trapping antioxidant. Furthermore, compound 12 inhibited ferroptosis through down-regulating the expression of TXNIP gene.

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Indication	Highest Phase	Country/Location	Organization	Date
COVID-19	Preclinical	Switzerland	Idorsia Pharmaceuticals Ltd.	29 Apr 2024

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