Aniline-Tetramic Acids from the Deep-Sea-Derived Fungus Cladosporium sphaerospermumL3P3 Cultured with the HDAC Inhibitor SAHA

Four new tetramic acids, cladosins H–K (1–4), and a related known compound, cladodionen (5), were isolated from the culture of the Mariana Trench (depth 6562 m) sediment-derived fungus Cladosporium sphaerospermumL3P3 treated with the histone deacetylase inhibitor SAHA (suberanilohydroxamic acid). Interestingly, compounds 1–5existed as equilibrium E/Zmixtures and 1–4were the first cases of tetramic acids containing aniline moieties. Their structures including absolute configurations were elucidated through a combination of NMR, MS, and Mosher’s method, together with the consideration of biogenetic origins. Incubation experiments of exogenous aniline and N-phenyloctanamide revealed that the aniline moiety in cladosins H–K (1–4) is probably derived from the degradation of SAHA, indicating that the well-known histone deacetylase inhibitor SAHA could be metabolized by L3P3 and provide aniline as a precursor for biotransformation of chemically reactive polyketides. The cytotoxicity of 1–5was evaluated against the PC-3, MGC-803, SH-SY5Y, HCT-116, K562, and HL-60 cell lines, and compound 2showed promising cytotoxicity against the HL-60 cell line with an IC50value of 2.8 μM.