Executive Summary : | Marine-derived fungi are rich sources of structurally novel and biologically active secondary metabolites, which are emerging as a significant resource in drug discovery. These metabolites contain a [2.2.2]-diazaoctane ring system of densely functionalized secondary metabolite alkaloids derived from proline, tryptophan, and isoprene, with a diverse array of biological profiles. Bristol-Myers Squibb (BMS) reported the isolation of biologically active metabolites, stephacidins A (5) and B (3), from a fermentation broth of Aspergillius ochraceus in 2002. These metabolites were identified as potent inhibitors of several human tumor cell lines, with stephacidin A (5) being cytotoxic towards LNCaP cells with a half-maximum inhibitory concentration (IC50) of 1.0 μM. The dimeric alkaloid (-)-stephacidin B (3) exhibits high cytotoxic potency against testosterone-dependent prostate LNCaP lymphoma, potentially resulting in a new target for treating cancer. The structure of (-)-stephacidin B (3), which contains two [2.2.2]-diazaoctane bridged bicycles with nine stereogenic centers and five of which are quaternary, was isolated and determined by X-ray crystallographic analysis. These diketopiperazine alkaloids show a wide range of biological activities, such as antiviral, anticancer, antioxidant, and insecticidal activities. In 2011, two complex reverse-prenylated indole alkaloids, waikialoids A (1) and B (2), were isolated from metabolically talented Hawaiian Aspergillus sp., which inhibited biofilm formation and C. albicans hyphal morphogenesis. Waikialoid A (1) was not cytotoxic to fungi or human cells, making it an intriguing model compound for studying the adjunctive use of biofilm inhibitors in combination with standard antifungal antibiotics. |