Co-cultivation With 5-Azacytidine Induced New Metabolites From the Zoanthid-Derived Fungus Cochliobolus lunatus

Jing-Shuai Wu; Xiao-Hui Shi; Ya-Hui Zhang; Jia-Yin Yu; Xiu-Mei Fu; Xin Li; Kai-Xian Chen; Yue-Wei Guo; Chang-Lun Shao; Chang-Yun Wang

doi:10.3389/fchem.2019.00763

Co-cultivation With 5-Azacytidine Induced New Metabolites From the Zoanthid-Derived Fungus Cochliobolus lunatus

Front Chem. 2019 Nov 8:7:763. doi: 10.3389/fchem.2019.00763. eCollection 2019.

Authors

Jing-Shuai Wu^{1

2}, Xiao-Hui Shi^{1

2}, Ya-Hui Zhang^{1

2}, Jia-Yin Yu^{1

2}, Xiu-Mei Fu^{1

2}, Xin Li^{1

2}, Kai-Xian Chen³, Yue-Wei Guo³, Chang-Lun Shao^{1

2}, Chang-Yun Wang^{1

2

4}

Affiliations

¹ Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
² Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
³ Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China.
⁴ Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao, China.

Abstract

The zoanthid-derived fungus Cochliobolus lunatus (TA26-46) has been proven to be a source of bioactive 14-membered resorcylic acid lactones (RALs). In the present study, chemical epigenetic manipulation was applied to this fungal strain with a DNA methyltransferase inhibitor resulting in the significant changes of the secondary metabolites. Cultivation of C. lunatus (TA26-46) with 10 μM 5-azacytidine in Czapek-Dox liquid medium led to the isolation of new types of metabolites, including two α-pyrones, cochliobopyrones A (1) and B (2), along with three isocoumarins (3-5) and one chromone (6). The planar structures of the new compounds (1-2) were elucidated by comprehensive analyses of NMR and HRESIMS data. Their challenging relative configurations were established by a combination of acetonide reaction, coupling constants and NOESY correlations analysis, and DP4+ probability calculation. Their absolute configurations were determined by comparing with the ECD calculation data of the fragment molecules, 6-(1,2-dihydroxypropyl)-4-methoxy-2H-pyran-2-ones. It is the first time to obtain α-pyrone compounds with the epoxy ring or bromine atom on the seven-numbered side chain. It could be concluded that chemical epigenetic agents could induce C. lunatus to produce new types of secondary metabolites differing from its original products (RALs).

Keywords: Cochliobolus lunatus; DNA methyltransferase inhibitor; DP4+ probability calculation; chemical epigenetic manipulation; the fragment molecules; α-pyrones.