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The addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid to a culture of the filamentous fungus Beauveria felina significantly changed its secondary metabolite profile and led to the isolation of eight compounds, including three new cyclodepsipeptides, desmethylisaridin E (1), desmethylisaridin C2 (2), and isaridin F (3), along with five known cyclodepsipeptide compounds. Isaridin F (3) possesses a cyclodepsipeptide ring with N-methylbutyric acid, which is rare in natural peptides. Absolute configurations of the new cyclodepsipeptides were achieved by Marfey's method. The anti-inflammatory activity of the isolated compounds was investigated through evaluating their effect on superoxide anion production and elastase release by FMLP-induced human neutrophils. Among the tested compounds, desmethylisaridin E (1) inhibited superoxide anion production and desmethylisaridin C2 (2) inhibited elastase release, with IC50 values of 10.00 ± 0.80 and 10.01 ± 0.46 μM, respectively.

DNA damage caused during cancer treatment can rapidly activate the ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR)-dependent phosphorylation of Chk2 and Chk1 kinases, which are hallmarks of the DNA damage response (DDR). Pharmacologic inhibition of ATR causes a synthetic lethal effect on ATMor p53-defective cancers, suggesting that such inhibition is an effective way to improve the sensitivity of cancers to DNA-damaging agents. Here, both the natural compound protoapigenone (WYC02) and its synthetic derivative WYC0209 exhibited cytotoxic effects on various cancer cell lines. WYC02 causes chromosomal aberration in the mitotic spreads of Chinese hamster ovary cells. Interestingly, cancer cells did not exhibit typical DDR markers upon exposure to WYC02 and WYC0209 (WYCs). Further investigation into the molecular mechanisms of WYCs function revealed that they have a potential ability to inhibit DDR, particularly on activation of Chk1 and Fanconi anemia group D2 protein (FANCD2), but not Chk2. In this way, WYCs inhibited ATR-mediated DNA damage checkpoint and repair. Furthermore, when combined with the DNA cross-linking agent cisplatin, treatment with WYCs resulted in increased tumor sensitivity to interstrand crosslink-generating agents both in vitro and in vivo. Our results therefore especially implicate WYCs in enhancing tumor chemosensitivity when the ATR checkpoint is constitutively active in states of oncogene-driven replicative stress or tolerance to DNA-interfering agents.