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A new class of insulin receptor activator with a hydroxyfuroic acid in place of a hydroxyquinone moiety is reported. The synthesis of 3-(1H-indol-3-yl)-5-(1H-indole-3-carbonyl)-4-hydroxyfuroic acids (26–30) requires seven major steps. Key elements in the syntheses include (1) sequential preparation of two 4-(N-protected indole)-3-methoxy-furoic 2,5-dicarboxylic esters (4 and 6); (2) regioselective conversion of the furoic diacid 8 into its C-5 methyl ester 10 with methyl chloroformate; and (3) acylation of 10 by a 7-substituted indole under a mild condition. This study demonstrates a feasible route of synthesizing insulin receptor activators with a hydroxyfuroic acid scaffold. Among those hydroxyfuroic acid compounds, compound 28 demonstrates insulin receptor activation potential comparable to Merck's compound 2 with a dihydroxybenzoquinone scaffold. Drug Dev Res 72: 247–258, 2011. © 2010 Wiley-Liss, Inc. |
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