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The asterriquinones represent a class of ascomycete metabolic products whose significance stems from remarkable and useful pharmacological activities, among those antiretroviral (e.g., against the HI-virus), antitumor, and antidiabetes properties. Recently, the first genetic locus for an asterriquinone, the clustered terrequinone genes tdiA-E, was identified during a genome-wide screen in Aspergillus nidulans for "orphan" natural product biosynthesis loci. Here, we describe overexpression and characterization of TdiB, which catalyzes the reverse prenylation event during terrequinone A biosynthesis, which is the transfer of dimethylallyl diphosphate to carbon atom 2' of the intermediate didemethylasterriquinone D, to yield asterriquinone C-1. TdiB does not depend on the presence of divalent metal cations for catalysis and lacks the canonical prenyl diphosphate binding motif (D/N)DXXD.

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.

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

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.

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.

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.