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Purine-rich foods have long been suspected as a major cause of hyperuricemia. We hypothesized that inhibition of human concentrative nucleoside transporter 2 (hCNT2) would suppress increases in serum urate levels derived from dietary purines. To test this hypothesis, the development of potent hCNT2 inhibitors was required. By modifying adenosine, an hCNT2 substrate, we successfully identified 8-aminoadenosine derivatives as a new class of hCNT2 inhibitors. Compound 12 moderately inhibited hCNT2 (IC50 = 52 ± 3.8 μM), and subsequent structure-activity relationship studies led to the discovery of compound 48 (IC50 = 0.64 ± 0.19 μM). Here we describe significant findings about structural requirements of 8-aminoadenosine derivatives for exhibiting potent hCNT2 inhibitory activity.

The reverse aromatic Cope rearrangement of 2-allyl-3-alkylideneindolines obtained by Horner-Wadsworth-Emmons olefination of 2-allylindolin-3-ones was performed. When 2-allylindolin-3-ones were treated with phosphonium ylides in refluxing toluene, domino Wittig reaction and reverse aromatic Cope rearrangement took place to give alpha-allyl-3-indole acetate derivatives in good yields. The aromatization as a new driving force in the Cope rearrangement is preferable to the conjugation with the carbonyl and cyano groups and also to the alkyl substitution pattern, which are well-known driving forces.

2-Alkyl-1,2-dihydroindol-3-ones are prepared from readily available 1-acetyl-2-methoxy-1,2-dihydroindol-3-one by alkylation reduction with sodium borohydride, and demethoxylation of the resulting 3-hydroxy-2-methoxy-4,3-dihydroindoles with Lewis acids. The stereochemistry of the reduction is also described.

3-Alkylindoles can be conveniently prepared by the Wittig reaction of 1-acetyl-indol-3(2H)-ones with the stabilized phosphonium ylides

3-Oxygenated carbazoles are prepared in 4 steps from 1 -acetyl-2-methoxy-1,2-dihydroindol-3-one 6 by Wittig reaction with phosphonium ylides 10 to afford the 3-alkylindoles 11, followed by silylation to the silyl enol ethers 12. Electrocyclic reaction of the enol ethers 12 followed by desilylation give the 3-hydroxycarbazoles 15. The carbazoles 15a, b were converted into the carbazole alkaloid hyellazole 1 and 4-deoxycarbazomycin B 2c, respectively.

3-Alkylindoles can be conveniently prepared by the Wittig reaction of 1-acetyl-indol-3(2H)-ones with the stabilized phosphonium ylides

3-Oxygenated carbazoles are prepared in 4 steps from 1 -acetyl-2-methoxy-1,2-dihydroindol-3-one 6 by Wittig reaction with phosphonium ylides 10 to afford the 3-alkylindoles 11, followed by silylation to the silyl enol ethers 12. Electrocyclic reaction of the enol ethers 12 followed by desilylation give the 3-hydroxycarbazoles 15. The carbazoles 15a, b were converted into the carbazole alkaloid hyellazole 1 and 4-deoxycarbazomycin B 2c, respectively.

2-Alkyl-1,2-dihydroindol-3-ones are prepared from readily available 1-acetyl-2-methoxy-1,2-dihydroindol-3-one by alkylation reduction with sodium borohydride, and demethoxylation of the resulting 3-hydroxy-2-methoxy-4,3-dihydroindoles with Lewis acids. The stereochemistry of the reduction is also described.

The Wittig reaction of 1-acetyl-2-methoxy-(1) and 1 -acetyl-2-hydroxyindol-3(2H)-one (2) with stabilized and semistabilized ylides gave predominantly 3-alkylidenedihydroindoles (4), (7), and (13) with (Z)-stereochemistry. When the Wittig reaction was carried out under more drastic conditions, the Wittig products (4) and (7) isomerized to afford 3-alkylindoles (5) and the indol-2-one (8), respectively. These isomerizations are also described.

A short synthesis of hyellazole (1) based on a new method of benzannelation of indoles which involves cyclization of 3-buta -1,3-dienylindole (6) is described.

A short synthesis of hyellazole (1) based on a new method of benzannelation of indoles which involves cyclization of 3-buta -1,3-dienylindole (6) is described.