Frenolicin

An efficient diastereoselective oxa-Pictet-Spengler reaction strategy was developed to construct benzoisochroman diastereomers. The utility of the reaction was demonstrated in the context of both the total synthesis of naturally occurring pyranonaphthoquinones (+)-frenolicin B and epi-(+)-frenolicin B as well as a range of frenolicin precursor analogs. The method is versatile and offers exquisite stereocontrol and, as such, offers a synthetic advance for the synthesis of pyranonaphthoquinone analogs.

In this study, the supernatant extract from fermentation broth of Streptomyces sp. NEAU-H3 showed strong antifungal activity against Fusarium graminearum strain PH-1 in vitro and in vivo. Three known pyranonaphthoquinones were isolated by means of an activity-guided method, and frenolicin B was characterized as the main active ingredient. Frenolicin B displayed strong antifungal activity against F. graminearum strain PH-1 with an EC50 value of 0.51 mg/L, which is lower than that of carbendazim (0.78 mg/L) but higher than that of phenamacril (0.18 mg/L). Frenolicin B could also strongly inhibit the mycelial growth of Fusarium species, including F. graminearum and F. asiaticum, as well as carbendazim-resistant Fusarium strains isolated from field, with EC50 values of 0.25-0.92 mg/L. Results from field experiments showed that the efficacy of frenolicin B in controlling Fusarium head blight at a treatment concentration of 75 g ai/ha was better than those of phenamacril (375 g ai/ha) and carbendazim (600 g ai/ha) or had no significant difference with that of phenamacril (375 g ai/ha) in 2 years. Scanning electron microscope and transmission electron microscope observations revealed that after treating F. graminearum mycelia with frenolicin B, the mycelia appeared aberrant and had an uneven thickness and swelling, the cytoplasm had disintegrated, and some cell contents were lost. Transcriptome analysis suggests that frenolicin B might inhibit the metabolism of nucleotides and energy by affecting genes involved in phosphorus utilization but did not affect the expression of myosin 5, which is the specific target of phenamacril. These findings indicate that frenolicin B may be a potential agrochemical fungicide for controlling Fusarium head blight.

Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis. FB structure-activity relationship studies reveal a positive correlation between inhibition of 4E-BP1 phosphorylation, ROS-mediated cancer cell cytotoxicity, and suppression of tumor growth in vivo. These findings establish FB as the most potent Prx1/Grx3 inhibitor reported to date and also notably highlight 4E-BP1 phosphorylation status as a potential predictive marker in response to ROS-based therapies in cancer.