Studies on the Cytotoxicity of Asterriquinone Derivatives.

Abstract

The antitumor agent, asterriquinone (ARQ) is a known metabolite isolated from the mycelium of Aspergillus terreus IFO 61231). YAMAMOTO et al. reported that ARQ analogues having a 2, 5-dimethoxy-p-benzoquinone moiety (ARQ dimethyl ether: ARQDMe)2,3) and the 2, 5-diamino-p-benzoquinone moiety (diamino ARQ: ARQDA)4) did not show any Cytotoxicity. As reported in our previous communication5), a new metabolite, asterridinone, which has a furo [3, 2-b] furan moiety instead of the p-benzoquinone moiety of ARQ, did not show cytotoxic activity towards P388 mouse leukemia cells, while isoasterriquinone and neoasterriquinone which have the tert-or iso-pentenyl groups at the different position of the indole ring, were active as was ARQ. These results indicate that the 2, 5-dihydroxy-p-benzoquinone structure is more important for cytotoxic activity than the kind of prenyl groups and its position. In this study, to assess the contribution of the hydroxy group in the p-benzoquinone moiety to the cytotoxic activity of ARQ, we synthesized several ARQ derivatives, of which the one or two hydroxy group(s) were substituted with the acetyl, methoxy, and/or amino groups, and examined their cytotoxicity towards P388 cells. Materials and Methods Test CompoundsARQ and ARQ monoacetate (ARQAc) were isolated as the metabolic products from mycelium of Aspergillus terreus IFO 61235). ARQ diacetate (ARQDAc)6) and ARQDMe1) were prepared from ARQ by the usual method. ARQ monomethyl ether acetate (ARQMeAc)6) was prepared by methylation of ARQAc and ARQ monomethyl ether (ARQMe)6) was prepared from (v/v) aq NH3 (5ml) in EtOH (50ml) and allowed to stand overnight at room temperature. The resulting precipitate was collected, dissolved in diethyl ether and washed with 5% (w/v) aq NaHCO3. The organic layer was washed with water, dried over anhydrous Na2SO4, evaporated under reduced pressure and the residue was purified by column chromatography (SiO2, CH2Cl2). ARQA (23mg, 0.045mmol) was obtained in 78% yield.

Electrochemical synthesis of new coumarin derivatives of potential biological significance

“…For example, asterriquinone A1 ( Fig. 1), has been shown to arrest the cell cycle in G 1 and promote apoptotic cell death [13][14].…”

Discovery of a Small Molecule Insulin Receptor Activator

“…(De Guzman et al, 1994;Fredenhagen et al, 1997;Mocek et al, 1996;Ooike et al, 1997;Sekita, 1983). The asterriquinones and related bis-indolyl-quinones have been studied as potential antitumor agents because of their DNA-intercalating properties (Kaji et al, 1998;Yamamoto et al, 1976). Some of them are also HIV-l protease inhibitors (Fredenhagen et al, 1997), antibacterial, and toxic to insects (De Guzman et al, 1994).…”

Protein Kinase Inhibitors from Microorganisms

“…Since then several benzoquinones, such as asterriquinones [81][82][83][84] (76)(77)(78)(79)(80)(81)(82)(83)(84), isocochliodinol (85), semicochliodinols (86, 87) [89], and terphenylquinones (88)(89)(90)(91)(92), were isolated [90][91][92]. Although asterriquinones were well recognized for their antibiotic and antitumour activity [87], it took around 25 years to realize their kinase inhibitory potential [85,86,88]. The bioactivity profiling of these derivatives clearly showed that the presence of the 2,5 dihydroxy groups and which of either an indol or a phenol on 3 and 6 positions, in the benzoquinone, is necessary for bioactivity.…”