Trichodimerol

Excessive inflammation causes chronic diseases and tissue damage. Although there has been drug treatment, its side effects are relatively large. Searching for effective anti-inflammatory drugs from natural products has become the focus of attention. First isolated from Trichoderma longibraciatum, trichodimerol is a natural product with TNF inhibition. In this study, lipopolysaccharide (LPS)-induced RAW264.7 macrophages were used as a model to investigate the anti-inflammatory activity of trichodimerol. The results of nitric oxide (NO) detection, enzyme-linked immunosorbent assay (ELISA), and reactive oxygen species (ROS) showed that trichodimerol could reduce the production of NO, ROS, and the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α. Western blotting results showed that trichodimerol could inhibit the production of inflammatory mediators such as cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) and the protein expression of nuclear transcription factor-kappaB (NF-κB), p-IKK, p-IκB, Toll-like receptor 4 (TLR4), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), cysteinyl aspartate specific proteinase (Caspase)-1, and ASC, which indicated that trichodimerol may inhibit inflammation through the NF-κB and NLRP3 pathways. At the same time, molecular docking showed that trichodimerol can directly combine with the TLR4-MD2 complex. Hence, trichodimerol inhibits inflammation by obstructing the interaction between LPS and the TLR4-MD2 heterodimer and suppressing the downstream NF-κB and NLRP3 pathways.

Six new sorbicillinoids, trichoreeseione A (1) and B (2), trichodermolide B (3), 13-hydroxy-trichodermolide (4), 24-hydroxy-trichodimerol (5), 15-hydroxy-bisvertinol (7), together with three known analogs, trichodimerol (6), 24-hydroxy-bisvertinol (8), and bisvertinol (9), were isolated from the sponge-derived fungus Trichoderma reesei (HN-2016-018). Their structures including absolute configurations were elucidated by analysis of NMR, MS data, and calculated ECD spectra. Compounds 1 and 2 with a characteristic naphthalene-trione ring were firstly reported in sorbicillinoid family. Compounds 3 and 4 were two rare sorbicillinoids containing a unique bicycle [3.2.1] lactone skeleton, while 3 with a propan-2-one moiety was also recorded first time in this family. Compound 5 displayed cytotoxic activity against A549, MCF-7, and HCT116 cell lines with the IC50 values of 5.1, 9.5, and 13.7 μM, respectively.

Sorbicillinoids are a class of structurally diverse hexaketide metabolites with good biological activities. To explore new structural sorbicillinoids and their bioactivities, the marine-derived fungus Acremonium chrysogenum C10 was studied. Three new sorbicillinoid derivatives, acresorbicillinols A-C (1-3), along with five known ones, trichotetronine (4), trichodimerol (5), demethyltrichodimerol (6), trichopyrone (7) and oxosorbicillinol (8), were isolated. The structures of new sorbicillinoids were elucidated by analysis of nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectroscopy (HRESIMS). The absolute configurations of compounds 1-3 were determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Compound 3 exhibited a strong 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, with the IC50 value ranging from 11.53 ± 1.53 to 60.29 ± 6.28 μM in 24 h. Additionally, compounds 2 and 3 showed moderate activities against Staphylococcus aureus and Cryptococcus neoformans, with IC50 values of 86.93 ± 1.72 and 69.06 ± 10.50 μM, respectively. The boundary of sorbicillinoid biosynthetic gene cluster in A. chrysogenum was confirmed by transcriptional analysis, and the biosynthetic pathway of compounds 1-8 was also proposed. In summary, our results indicated that A. chrysogenum is an important reservoir of sorbicillinoid derivatives, and compound 3 has the potential for new natural agents in DPPH radical scavenging.