The chemical structure of mumbaistatin, a novel glucose-6-phosphate translocase inhibitor produced by Streptomyces sp DSM 11641

The characterization of the structure of mumbaistatin (1), an effective inh ibitor of the glucose-6-phosphatase system (EC 3.1.3.9), is reported. Isola tion of mumbaistatin from cultures of Streptomyces sp. DSM 11641 was achiev ed by anion-exchange and reversed-phase chromatography. The acid-labile inh ibitor was methylated for the structure determination. Single-crystal X-ray structure analysis of a triply methylated dehydration product, C31H24O11, revealed the structure of an aromatic dispirodiketal (2), a compound contai ning a previously undescribed ring system. Extensive 2D-NMR experiments wit h mumbaistatin and with the methylation products showed that mumbaistatin i tself possesses the hydroxydiketodicarboxylic acid structure 1, C28H20O12, which, in the presence of acid or upon activation through methyl eater form ation, undergoes self-condensation with loss of water to the dispirodiketal form (2). Mumbaistatin is an anthraquinone derivative, whose open-chain di keto form acts as a specific and powerful inhibitor of glucose-6-phosphate translocase: IC50=5 nM. The activity towards same enzyme of the cyclized di spirodiketal derivatives is roughly one thousand times lower.