*Article* **Exploring Verrucosidin Derivatives with Glucose-Uptake-Stimulatory Activity from** *Penicillium cellarum* **Using MS/MS-Based Molecular Networking**

**Junjie Han 1,†, Baosong Chen 1,†, Rui Zhang <sup>2</sup> , Jinjin Zhang <sup>1</sup> , Huanqin Dai <sup>1</sup> , Tao Wang <sup>1</sup> , Jingzu Sun <sup>1</sup> , Guoliang Zhu <sup>3</sup> , Wei Li <sup>1</sup> , Erwei Li <sup>4</sup> , Xueting Liu <sup>3</sup> , Wenbing Yin <sup>1</sup> and Hongwei Liu 1,2,\***


**Abstract:** Under the guidance of LC-MS/MS-based molecular networking, seven new verrucosidin derivatives, penicicellarusins A-G (**3**–**9**), were isolated together with three known analogues from the fungus *Penicillium cellarum*. The structures of the new compounds were determined by a combination of NMR, mass and electronic circular dichroism spectral data analysis. The absolute configuration of penicyrone A (**10**) was corrected based on X-ray diffraction analyses. Bioactivity screening indicated that compounds **1**, **2**, and **4** showed much stronger promising hypoglycemic activity than the positive drug (rosiglitazone) in the range of 25–100 µM, which represents a potential new class of hypoglycemic agents. Preliminary structure-activity relationship analysis indicates that the formation of epoxy ring on C<sup>6</sup> -C<sup>7</sup> in the structures is important for the glucose uptake-stimulating activity. The gene cluster for the biosynthesis of **1–12** is identified by sequencing the genome of *P. cellarum* and similarity analysis with the gene cluster of verrucosidins in *P. polonicum*.

**Keywords:** verrucosidins; *Penicillium cellarum*; glucose uptake-stimulating activity; molecular networking
