*3.2. Fungus Material*

The fungus *Penicillium* sp. KFD28 (GenBank accession No. MK934323) was isolated from a bivalve mollusk, *Meretrix lusoria*, collected from Haikou Bay, Hainan province, in China. A reference culture of *Penicillium* sp. KFD28 is deposited in our laboratory and maintained at −80 ◦C.

## *3.3. Culture Conditions*

The fungus *Penicillium* sp. KFD28 was cultured in 200 × 1000 mL Erlenmeyer flasks containing 100 g rice and 100 mL of water (33 g sea salt, 5 g L-tryptophan per liter pure water). The fungus was cultured in the medium and incubated at room temperature for thirty days.

#### *3.4. Extraction and Isolation*

The fermented material was extracted three times with EtOAc to obtain 300 g crude extract. The extract was extracted between petroleum ether and 90% methanol (1:1) to remove the oil. The secondary metabolites extract (46 g) was subjected to a silica gel VLC column, eluting with a stepwise gradient of petroleum ether-EtOAc (10:1, 8:1, 6:1, 4:1, 2:1, 1:1, 1:2, *v/v*) to yield ten subfractions (Fr. 1–Fr. 10).

Fr. 3 (4.2 g) was applied to ODS silica gel with gradient elution of MeOH-H2O (1:4, 3:7, 2:3, 1:1, 3:2, 7:3, 4:1, 9:1, 0:1, *v/v*) and afforded nine subfractions (Fr. 3-1–Fr. 3- 9). Fr. 3-9 (182 mg) was applied to semipreparative HPLC (YMC-pack ODS-A, 5 μm; 10 × 250 mm; 85% MeOH/H2O; 4 mL/min) to obtain compounds **16** (*<sup>t</sup>*R 20.0 min, 1.0 mg), **11** (*<sup>t</sup>*R 23.0 min, 9.7 mg), and **8** (*<sup>t</sup>*R 32.0 min, 20.8 mg). Fr. 5 (3.8 g) was applied to ODS silica gel with gradient elution of MeOH-H2O (1:9, 1:4, 3:7, 2:3, 1:1, 3:2, 7:3, 4:1, 9:1, 0:1, *v/v*) to ge<sup>t</sup> ten subfractions. Fr. 5-10 (323 mg) was purified by semipreparative HPLC (YMCpack ODS-A, 5 μm; 10 × 250 mm; 80% MeOH/H2O; 4 mL/min) to give compound **15** (*<sup>t</sup>*R 28.5 min, 53.4 mg). Fr. 6 (5.1 g) was separated by ODS silica gel with gradient elution of MeOH-H2O (1:9, 1:4, 3:7, 2:3, 1:1, 3:2, 7:3, 4:1, 9:1, 0:1, *v/v*) to yield ten subfractions (Fr. 6-1– Fr. 6-10). Fr. 6-10 (1.1 g) was subjected to semipreparative HPLC (YMC-pack ODS-A, 5 μm;

10 × 250 mm; 65% MeCN/H2O; 4 mL/min) to give compounds **5** (*<sup>t</sup>*R 11.5 min, 182.6 mg) and **6** (*<sup>t</sup>*R 18.0 min, 25.8 mg). Fr. 7 (4.7 g) was applied to ODS silica gel with gradient elution of MeOH-H2O (1:9, 1:4, 3:7, 2:3, 1:1, 3:2, 7:3, 4:1, 9:1, 0:1, *v/v*), ten subfractions (Fr. 7-1–7-10) were obtained. Fr. 7-7 (587 mg) was eluted with MeCN-H2O through ODS silica gel (3:7, 2:3, 1:1, 3:2, 7:3, *v/v*) to afford five subfractions (Fr. 7-7-1–7-7-5). Fr. 7-7-4 (117 mg) was separated by semipreparative HPLC (YMC-pack ODS-A, 5 μm; 10 × 250 mm; 70% MeCN/H2O; 4 mL/min) to give compounds **2** (*<sup>t</sup>*R 8.6 min, 0.6 mg), **3** (*<sup>t</sup>*R 9.4 min, 1.8 mg), **1** (*<sup>t</sup>*R 10.4 min, 2.0 mg), **13** (*<sup>t</sup>*R 11.6 min, 0.6 mg), **14** (*<sup>t</sup>*R 13.5 min, 9.9 mg), and **7** (*<sup>t</sup>*R 22.0 min, 8.1 mg). Fr. 7-7-5 (137 mg) was applied to semipreparative HPLC (YMC-pack ODS-A, 5 μm; 10 × 250 mm; 70% MeOH/H2O; 4 mL/min) to ge<sup>t</sup> compounds **9** (*<sup>t</sup>*R 14.0 min, 2.0 mg) and **10** (*<sup>t</sup>*R 18.4min, 3.4 mg). Fr. 8 (5.8 g) was subjected to ODS silica gel with gradient elution of MeOH-H2O (1:4, 3:7, 2:3, 1:1, 3:2, 7:3, 4:1, 9:1, 0:1, *v/v*) to ge<sup>t</sup> nine subfractions. Then, Fr. 8-7 (925 mg) was eluted through ODS silica gel column of MeCN-H2O (1:4, 3:7, 2:3, 1:1, 3:2, *v/v*) to ge<sup>t</sup> five subfractions (Fr. 8-7-1–8-7-5). Fr. 8-7-5 (29 mg) was separated by a semipreparative HPLC (YMC-pack ODS-A, 5 μm; 10 × 250 mm; 60% MeCN/H2O; 4 mL/min) to yield compound **4** (*<sup>t</sup>*R 13.0 min, 2.2 mg). Fr. 8-9 (812 mg) was eluted by a semipreparative HPLC (YMC-pack ODS-A, 5 μm; 10 × 250 mm; 80% MeOH/H2O; 4 mL/min) to afford compound **12** (*<sup>t</sup>*R 30.0 min, 157.9 mg).

Penerpene K (**1**): Yellow oil; [α]<sup>25</sup> D −23.0 (*c* 0.01, MeOH); UV (MeOH) *λ*max (log*ε*): 231 (3.41), 280 (2.77) nm; ECD (0.38 mM, MeOH) *λ*max (Δ*ε*): 204 (2.46), 223 ( −6.08), 255 (2.89); 294 ( −0.62) nm; IR (KBr) *ν*max: 3412, 2933, 1640, 1606, 1458, 1382, 1307, 1257, 1212, 1160, and 1088 cm<sup>−</sup>1; 1H and 13C NMR spectral data, Tables 1 and 2; HRESIMS *m/z* 476.2565 ([M+K]+ calcd 476.2562).

Penerpene L (**2**): Yellow oil; [α]<sup>25</sup> D −22.0 (*c* 0.01, MeOH); UV (MeOH) *λ*max (log*ε*): 231 (3.15), 282 (2.41) nm; ECD (1.10 mM, MeOH) *λ*max (Δ*ε*): 203 (0.14), 224 ( −1.63), 260 (0.58), 292 ( −0.08), 330 (0.24) nm; IR (KBr) *ν*max: 3411, 2935, 1645, 1604, 1452, 1381, 1307, 1256, 1158, 1074, and 1018 cm<sup>−</sup>1; 1H and 13C NMR spectral data, Tables 1 and 2; HRESIMS *m/z* 476.2210 ([M+K]+ calcd 476.2198).

Penerpene M (**3**): White powder; [α]<sup>25</sup> D +15.0 (*c* 0.01, MeOH); UV (MeOH) λmax (log*ε*): 226 (2.84), 261 (2.32) nm; ECD (1.15 mM, MeOH) λmax (Δ*ε*): 198 (1.32), 202 ( −1.27), 221 (−0.92), 263 (0.94) nm; IR (KBr) *ν*max: 3383, 2931, 1648, 1609, 1575, 1357, 1316, 1257, 1208, 1160, 1118, and 1044 cm<sup>−</sup>1; 1H and 13C NMR spectral data, Tables 1 and 2; HRESIMS *m/z* 446.3020 ([M+Na]+ calcd 446.3030).

Penerpene N (**4**): Yellow oil; [α]<sup>25</sup> D +21.0 (*c* 0.01, MeOH); UV (MeOH) λmax (log*ε*): 231 (3.05), 277 (2.44) nm; ECD (0.77mM, MeOH) λmax (Δ*ε*): 197 ( −3.23), 219 (4.27), 238 ( −6.39), 257 (3.21) nm; IR (KBr) *ν*max: 3415, 2937, 1641, 1408, 1110, 1408, 1110, 1042, 922, 852, 688, and 565 cm<sup>−</sup>1; 1H and 13C NMR spectral data, Tables 1 and 2; HRESIMS *m/z* 434.2338 ([M-H]- calcd 434.2331).
