Relationship between the structure and cytotoxic activity of asterriquinone, an antitumor metabolite of Aspergillus terreus, and its alkyl ether derivatives.

Asterriquinone (ARQ) is an antitumor metabolite of Aspergillus terreus IFO 6123. In this study we synthesized several ARQ alkyl ethers and studied their cytotoxic activity against mouse leukemia P388 cells. The dissociation constant was also similar among the ARQ monoalkyl ethers. There was a good correlation between the hydrophobicity of ARQ monoalkyl ethers estimated by high performance liquid chromatography and the intracellular content accumulated for 60 min. ARQ monoalkyl ethers were cytotoxic, but ARQ dimethyl ether was not, as previously reported. The cytotoxicity of the ARQ monoalkyl ether derivatives was increased with extension of the alkyl chain length. The cytotoxicity was closely correlated with the intracellular content. The strongest ARQ derivative, ARQ monohexyl ether (ARQHex), formed more DNA-interstrand cross-links in the cells than ARQ. After treatment of P388 cells with ARQ and ARQHex for 6 h, a nucleosomal ladder pattern, as well as the appearance of degraded DNA, observed by flow cytometry, indicated that these compounds caused cellular apoptosis. Moreover, ARQ and ARQHex accumulated in the cells at the G1 phase of the cell cycle. These results indicated that ARQ monoalkyl ethers increased cytotoxicity, according to their membrane permeability based on the hydrophobicity, and they caused apoptotic cell death, as did ARQ.