*2.3. Cyclopeptides*

Cyclopeptides are cyclic compounds mainly formed by the amide bonds of proteinogenic or non-proteinogenic amino acids bound together. Several fungal cyclic peptides have been developed as pharmaceuticals, such as the echinocandins, pneumocandins and cyclosporin A [58]. Six cyclopeptides were produced by the co-cultures of marine fungi–fungi (four isolates, 67%) and fungi–bacteria (two isolates, 33%) from di fferent marine sources. However, marine bacteria–bacteria did not yield these structures in this period of investigation.

#### 2.3.1. Cyclopeptides Derived from the Co-Cultures of Di fferent Marine Fungi

Three new cyclic tetrapeptides, named cyclo-(L-leucyl-*trans*-4-hydroxy-L-prolyl-D-leucyl-*trans*-4- hydroxy-L-proline) (**94**) [59] cyclo (D-Pro-L-Tyr-L-Pro-L-Tyr) (**95**) and cyclo (Gly-L-Phe-L-Pro-L-Tyr)

(**96**) (Figure 15) [60] were identified from the co-culture of two mangrove fungi *Phomopsis* sp. K38 and *Alternaria* sp. E33 isolated from the South China Sea. Meanwhile, the co-cultivation of two marine alga-derived fungi *Aspergillus* sp. BM-05 and BM-05ML isolated from a brown algal species collected off Helgoland, North Sea, Germany, yielded a new cyclotripeptide, psychrophilin E (**97**) (Figure 15) [30].

**Figure 15.** Chemical structures of **94**–**97**.

Compound **94** exhibited in vitro moderate to high inhibitory activity towards four crop-threatening fungi, *Helminthosporium sativum*, *Gaeumannomyces graminis*, *F. graminearum* and *Rhizoctonia cereals* with MIC values of 130, 220, 250 and 160 μg/mL, respectively [59]. **95** and **96** showed high in vitro antifungal activity against human fungus (*Candida albicans*) with MIC values of 35 μg/mL and 25 μg/mL, respectively [60]. **97** exhibited anti-proliferative activities against four human cancer cells, human cisplatin-resistant ovarian cancer A2780CisR, colon carcinoma HCT116, ovarian cancer A2780 and chronic myelogenous leukemia K562 with IC50 values of 49.4, 28.5, 27.3 and 67.8 μM, respectively. The inhibition of HCT116 cells by **97** was more potent than that of the positive control, cisplatin (IC50 33.4 μM) [30].

#### 2.3.2. Cyclopeptides Derived from the Co-Cultures of Marine Fungi and Bacteria

Recently, the chemical investigation of the mixed-fermentation of a marine fungus *Aspergillus versicolor* isolated from the sponge *Agelas oroides* and *B. subtilis* yielded two cyclic pentapeptides, one new cotteslosin C (**98**) and a known cotteslosin A (**99**) (Figure 16) [38]. Both of them did not show significant cytotoxic activity towards mouse lymphoma cell line L5178Y, or even antibacterial activity against five Gram-positive microbes, including one *S. aureus*, two *E. faecalis* and two *E. faecium* [38]. **99** displayed weak cytotoxicity against another three human cancer cell lines, prostate DU145, melanoma MM418c5 and breast T47D, with EC50 values of 90, 66 and 94 μg/mL, respectively [61].

**Figure 16.** Chemical structures of **98**–**99**.
