Multimethod-guided discovery of novel α-pyrone dimers with cardiomyocyte-protective activity against cold ischemia injury from the coral-derived Talaromyces sp. TJ403-AL05

Abstract

Guided by molecular networking, HSQC-based DeepSAT, and SMART analyses, a chemical investigation of the coral-derived fungus Talaromyces sp. TJ403-AL05 led to the isolation and identification of taladipyrones A−I (1−9), a series of new α-pyrone dimers with four distinct skeletons. Among these, compounds 1 and 9 represented two unprecedented classes of rearranged α-pyrone dimers, and compounds 5−7 were the first talarolactone-type dimers obtained as racemates. Extensive spectroscopic analysis, quantum chemical calculations, and X-ray diffraction analysis were used to determine their structures, including each enantiomer of racemic compounds 5−8 after chiral HPLC resolution. In human cardiomyocytes (AC16), compounds 1−6 and 8−9 attenuated injury caused by 24 h cold ischemia (CI) at 40 µmol·L⁻¹. Moreover, compound 2 could improve CI-induced disruption of redox homeostasis via activation of the PI3K/AKT signaling pathway, representing the first fungal polyketide with such cardioprotective activity.

Keywords

Talaromyces sp / α-Pyrone dimers / GNPS molecular networking / HSQC-based SMART and DeepSAT / Cardioprotective activity

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 82274510, 82474454, 82405070, 82360918), the Natural Science Foundation of Guangdong Province, China (No. 2024A1515012173), and the Jiangxi Provincial Administration of Traditional Chinese Medicine Science and Technology Plan (No. 2023B0597).

Acknowledgments

We thank the Analytical and Testing Center at Huazhong University of Science and Technology (HUST) for measuring ECD, IR, and single-crystal X-ray diffraction data. Thanks also for the technical support by the Medical Subcenter of HUST Analytical & Testing Center.

Declaration of competing interest

These authors have no conflict of interest to declare.

4 Supporting information

Chiral HPLC separation of racemic compounds 5−8; 1D and 2D NMR, HR-ESI-MS, UV data of 1−9, and experimental ECD curves of compounds 1−3; ECD and NMR calculation details, including conformational analysis and atomic coordinates of the calculated compounds were provided. Supplementary material related to this article can be requested by sending E-mail to the corresponding authors.

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