This review summarizes the structural diversity, bioactivities, and biomimetic synthesis of [2 + 2]-type cyclobutane natural products, along with discussion of their biosynthesis, stereochemical analysis, racemic occurrence, and biomimetic synthesis.

Since the discovery of penicillin, Penicillium has become one of the most attractive fungal genera for the production of bioactive molecules. Marine-derived Penicillium has provided numerous excellent pharmaceutical leads over the past decades. In this review, we focused on the cytotoxic metabolites * (* Cytotoxic potency was referred to five different levels in this review, extraordinary (IC₅₀/LD₅₀: <1 μM or 0.5 μg/mL); significant (IC₅₀/LD₅₀: 1~10 μM or 0.5~5 μg/mL); moderate (IC₅₀/LD₅₀: 10~30 μM or 5~15 μg/mL); mild (IC₅₀/LD₅₀: 30~50 μM or 15~25 μg/mL); weak (IC₅₀/LD₅₀: 50~100 μM or 25~50 μg/mL). The comparative potencies of positive controls were referred when they were available). produced by marine-derived Penicillium species, and on their cytotoxicity mechanisms, biosyntheses, and chemical syntheses.