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This communication describes the first total synthesis of asterriquinone B1, a representative member of a group of anti-tumor metabolites of Aspergillus terreus. The synthesis described herein is potentially applicable to other members of the asterriquinone family.

Bis(indolyl)dihydroxyquinone 2, the tetrahydro analogue of naturally occurring 1a, was synthesized by a novel, expeditious route. The short synthesis was accomplished by treating p-bromanil (3) with 2 equiv of indole 4 in the presence of cesium carbonate in acetonitrile at ambient temperature to provide a 1:1 mixture of the dibromo regioisomers 7 and 8, followed by hydrolysis of the mixture to afford 2. The synthetic compound 2 was found to inhibit the binding of the Grb2 adapter protein to tyrosine-phosphorylated EGF receptor (IC50 = 1.2 μM).

Asterriquinone D was easily synthesized in three steps from 2,5-dichloro-1,4-benzoquinone. The reaction of benzoquinone with indole in the presence of Pd(OAc)2, followed by oxidation with cerium (IV) ammonium nitrate (CAN) produced 3,6-dichloro-2,5-bis (3-indolyl)-1,4-benzoquinone. The methoxylation of the dichloride with NaOH in CH3OH afforded asterriquinone D.

The 3-indolylbenzoquinone nucleus is present in various biologically active natural products such as asterriquinones. 1 The asterriquinones and demethylasterriquinones (Figure 1) have recently been isolated from a wide range of fungi, including Aspergillus terreus, Chaetomium sp. and Pseudomassaria sp. 2 They exhibit a wide spectrum of biological activities including antitumor properties and are inhibitors of HIV reverse transcriptase. 3 Asterriquinone A1 has been shown to arrest the cell cycle in G1 and promote apoptotic cell death. 4 Recently, asterriquinone has also been reported

A new typw of indoloditerpene, petromindole (1), and a new asterriquinone derivative, PM-53 (2), were isolated from the ascostromata of Petromyces muricatus, along with bisindolylbenzenoids, petromurins A (3)-D (6). The structure of 1 was suggested by spectroscopic data and confirmed by an X-ray crystallographic analysis, while that of 2 was determined by analyses of the various NMR spectra.

This communication describes the first total synthesis of asterriquinone B1, a representative member of a group of anti-tumor metabolites of Aspergillus terreus. The synthesis described herein is potentially applicable to other members of the asterriquinone family.

A new typw of indoloditerpene, petromindole (1), and a new asterriquinone derivative, PM-53 (2), were isolated from the ascostromata of Petromyces muricatus, along with bisindolylbenzenoids, petromurins A (3)-D (6). The structure of 1 was suggested by spectroscopic data and confirmed by an X-ray crystallographic analysis, while that of 2 was determined by analyses of the various NMR spectra.

Four new metabolites (1-4) were isolated from mycelium of Aspergillus terreus IFO 6123 producing asterriquinone (ARQ). The structures of 1 and 2 were shown to be 3, 6-bis[1-(1, 1-dimethyl-2-propenyl)-1H-indol-3-yl]-furo[3, 2-b]furan-2, 5-dione (asterridinone) and 2, 5-bis[1-(1, 1-dimethyl-2-propenyl)-1H-indol-3-yl]-3-acetoxy-6-hydroxy-2, 5-cyclohexadiene-1, 4-dione (ARQ monoacetate), respectively, by the chemical and spectral data. Compounds 3 and 4 were identified with known asterriquinone isomers, 2-[(1, 1-dimethyl-2-propenyl)-1H-indol-3-yl]-5-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]-3, 6-dihydroxy-2, 5-cyclohexadiene-1, 4-dione (isoARQ) and 2, 5-bis[2-(3-methyl-2-butenyl)-1H-indol-3-yl]-3, 6-dihydroxy-2, 5-cyclohexadiene-1, 4-dione (neoARQ), respectively.

The interaction of asterriquinone (ARQ), a novel antitumor agent isolated from Aspergillus fungi, with deoxyribonucleic acid (DNA), has been studied. The binding of ARQ in vitro with DNA (calf thymus) was ascertained by its behavior in gel filtration using a Sephadex G-25 column at pH 5.4. Some ARQ analogs having no, or less, antitumor activity did not exhibit any evidence of interaction with DNA under the same condition. From the results obtained in this work, the pK_a value of ARQs seemed to be critical between 6 and 7 for their binding to DNA and for exhibition of antitumor activity. Also, ARQ showed serious membrane deformations and an inhibitory effect on the membranous adenosine triphosphatase of Ehrlich carcinoma cells.

Asterriquinone (ARQ; 2,5-bis-[1'-(1", 1"-dimethyl-2"-propenyl)- indol-3'-yl]-3,6-dihydroxy-1,4-benzoquinone) and its three analogues [i.e., 3,6-dihydroxy-2-[2'-(1", 1"-dimethyl-2"-propenyl)-indol-3'-yl]-5-[1', 7'- (1",1"-dimethylpropano)-indol-3'-yl]-1,4-benzoquinone (B1-4), 3,6-dihydroxy-2-[2'-(1", 1"-dimethyl-2"-propenyl)-indol-3'-yl]-5-indol-3'-yl-1,4-benzoquinone (C1-1) and 3,6-dihydroxy-2,5-diindol-3'-yl-1,4-benzoquinone (D-1)] were found to be strong inhibitors of the activity of reverse transcriptase from human immunodeficiency virus type-1. Under the reaction conditions employed, the enzyme activity was inhibited by more than 70% in the presence of 10 microM each of these compounds. The mode of inhibition by these compounds was competitive with respect to the template.primer, (rA)n.(dT)12-18, and noncompetitive with respect to the triphosphate substrate, dTTP. The Ki values of HIV-1 reverse transcriptase were determined to be 2.3, 1.5, 0.1 and 0.3 microM for ARQ, B1-4, C1-1 and D-1, respectively.

Asterriquinone (ARQ) diacetate : 2, 5-bis[1-(1, 1-dimethyl-2-propenyl)-1H-indol-3-yl]-3, 6-diacetoxy-2, 5-cyclohexadiene-1, 4-dione (3), was converted into ARQ monoalkyl ether (6) by treatment with a mixture of alcohol and K2CO3 under heating, followed by acidification. The reaction was shown to proceed via ARQ monoacetate monoalkyl ether (4) and ARQ monoacetal monoalkyl ether (5).

Eleven kinds of bisindolyl-dimethoxyl-p-benzoquinones, "asterriquinones A-1, A-2, A-3, A-4, B-1, B-2, B-3, B-4, C-1, C-2, and D"were isolated from Aspergillus terreus IFO 8835, and their structures were determined. Asterriquinone D had the basic structure, and the others were substituted with dimethylallyl group (s) in the indole ring.

The metabolites of Aspergillus terreus IFO 6123 were studied. 3-Methylorsellinic acid, 4-O-demethylbarbatic acid and a new metabolite named asterriquinone were isolated. The chemical structure of asterriquinone was established as 2, 5-bis-[N-(1", 1"-dimethyl-2"-propenyl)-indoyl-3']-3, 6-dihydroxy-1, 4-benzoquinone by chemical and physical experimental data. The incorporation experiments using 14C-labeled compounds showed that asterriquinone is biosynthesized from tryptophan and isopentenyl unit derived from mevalonate.

An attempt was made to obtain more potent antitumor compounds by chemically modifying asterriquinones. Amino-and aziridinyl-asterriquinone were newly synthesized, but showed no activity. However, dimethylallylation of asterriquinone Cl, which had no effect in vivo, yielded an active compound, with a change in pKa value from 5.0 to 7.2. This suggests that other active compounds may be obtained by the chemical modification of asterriquinones with various other functional groups.