The isolation and identification of an increasing number of secondary metabolites featuring unique skeletons and possessing diverse bioactivities sourced from marine microorganisms have garnered the interest of numerous natural product chemists. There has been a growing emphasis on how to cultivate microorganisms to enhance the chemical diversity of metabolites and avoid the rediscovery of known ones. Given the significance of secondary metabolites as a means of communication among microorganisms, microbial co-culture has been introduced. By mimicking the growth patterns of microbial communities in their natural habitats, the co-culture strategy is anticipated to stimulate biosynthetic gene clusters that remain dormant under traditional laboratory culture conditions, thereby inducing the production of novel secondary metabolites. Different from previous reviews mainly focusing on fermentation conditions or metabolite diversities from marine-derived co-paired strains, this review covers the marine-derived co-culture microorganisms from 2012 to 2022, and turns to a particular discussion highlighting the selection of co-paired strains for marine-derived microorganisms, especially the fermentation methods for their co-cultural apparatus, and the screening approaches for the convenient and rapid detection of novel metabolites, as these are important in the co-culture. Finally, the structural and bioactivity diversities of molecules are also discussed. The challenges and prospects of co-culture are discussed on behave of the views of the authors.

Based on the marine natural products piperafizine B, XR334, and our previously reported compound 4m, fourteen novel 3,6-diunsaturated 2,5-diketopiperazine (2,5-DKP) derivatives (1, 2, 4–6, 8–16), together with two known ones (3 and 7), were designed and synthesized as anticancer agents against the A549 and Hela cell lines. The MTT assay results showed that the derivatives 6, 8–12, and 14 had moderate to good anticancer capacities, with IC₅₀ values ranging from 0.7 to 8.9 μM. Among them, compound 11, with naphthalen-1-ylmethylene and 2-methoxybenzylidene functions at the 3 and 6 positions of 2,5-DKP ring, respectively, displayed good inhibitory activities toward both A549 (IC₅₀ = 1.2 μM) and Hela (IC₅₀ = 0.7 μM) cancer cells. It could also induce apoptosis and obviously block cell cycle progression in the G2/M phases in both cells at 1.0 μM. The electron-withdrawing functions might not be favorable for the derivatives with high anticancer activities. Additionally, compared to piperafizine B and XR334, these semi-N-alkylated derivatives have high liposolubilities (>1.0 mg mL⁻¹). Compound 11 can be further developed, aiming at the discovery of a novel anticancer candidate.

Based on the marine natural products piperafizine B, X334 and our previously reported compound 4m, fourteen novel 3,6-diunsaturated 2,5-diketopiperazine (2,5-DPK) derivatives (1-2, 4-6, 8-16), together with two known ones (3 and 7), were designed and synthesized as anticancer agents against cell lines A549 and Hela. The MTT assay results showed that the derivatives 6, 8-12 and 15 had moderate to good anticancer capacities with the IC50 values ranging from 0.7 to 8.9 μM. Among them, compound 11 with naphthalen-1-ylmethylene and 2-methoxybenzylidene functions at the 3- and 6-positions of 2,5-DPK ring, respectively, displayed good inhibitory activities to both cancer cells A549 (IC50 = 1.2 μM) and Hela (IC50 = 0.7 μM). It could also induce apoptosis and obviously block the cell cycle progression at G2/M phase in both cells at 1.0 μM. The electron withdrawing functions might not be favorable for the derivatives with high anticancer activities. Additionally, compared to piperafizine B and X334, these semi-N-alkylated derivatives have high liposolubilities (> 1.0 mg•mL-1). Compound 11 can be further developed aiming to the discovery of novel anticancer candidate.