RELATIONSHIP BETWEEN THE STRUCTURE AND CYTOTOXIC ACTIVITY OF ASTERRIQUINONE, AN ANTITUMOR METABOLITE OF ASPERGILLUS-TERREUS, AND ITS ALKYL ETHER DERIVATIVES
A. Kaji et al., RELATIONSHIP BETWEEN THE STRUCTURE AND CYTOTOXIC ACTIVITY OF ASTERRIQUINONE, AN ANTITUMOR METABOLITE OF ASPERGILLUS-TERREUS, AND ITS ALKYL ETHER DERIVATIVES, Biological & pharmaceutical bulletin, 21(9), 1998, pp. 945-949
Asterriquinone (ARQ) is an antitumor metabolite of Aspergillus terreus
IFO 6123. In this study we synthesized several ARQ alkyl ethers and s
tudied 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 monoa
lkyl ethers estimated by high performance liquid chromatography and th
e intracellular content accumulated for 60 min. ARQ monoalkyl ethers w
ere 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 closel
y correlated with the intracellular content. The strongest ARQ derivat
ive, ARQ monohexyl ether (ARQHex), formed more DNA-interstrand cross-l
inks 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 appearan
ce of degraded DNA, observed by flow cytometry indicated that these co
mpounds caused cellular apoptosis. Moreover, ARQ and ARQHex accumulate
d in the cells at the G(1), phase of the cell cycle. These results ind
icated that ARQ monoalkyl ethers increased cytotoxicity according to t
heir membrane permeability based on the hydrophobicity: and they cause
d apoptotic cell death, as did ARQ.