Abl tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib are ineffective against Bcr-Abl þ leukemic stem cells. Thus, the identification of novel agents that are effective in eradicating quiescent Bcr-Abl þ stem cells is needed to cure leukemias caused by Bcr-Abl þ cells. Human Bcr-Abl þ cells engrafted in the bone marrow of immunodeficient mice survive under severe hypoxia. We generated two hypoxia-adapted (HA)-Bcr-Abl þ sublines by selection in long-term hypoxic cultures (1.0% O 2 ). Interestingly, HA-Bcr-Abl þ cells exhibited stem cell-like characteristics, including more cells in a dormant, increase of side population fraction, higher b-catenin expression, resistance to Abl TKIs, and a higher transplantation efficiency. Compared with the respective parental cells, HA-Bcr-Abl þ cells had higher levels of protein and higher enzyme activity of glyoxalase-I (Glo-I), an enzyme that detoxifies methylglyoxal, a cytotoxic by-product of glycolysis. In contrast to Abl TKIs, Glo-I inhibitors were much more effective in killing HA-Bcr-Abl þ cells both in vitro and in vivo. These findings indicate that Glo-I is a novel molecular target for treatment of Bcr-Abl þ leukemias, and, in particular, Abl TKI-resistant quiescent Bcr-Abl þ leukemic cells that have acquired stem-like characteristics in the process of adapting to a hypoxic environment.

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The first total synthesis of 14-membered macrolide sekothrixide and the originally proposed structure are reported. Seven contiguous asymmetric centers in the side chain were constructed using ring-openings of several kinds of epoxide. Assembly of the left segment and right segment was performed on the basis of the RCM reaction to generate 14-membered lactones having an E-trisubstituted olefin. These synthetic results led to a revision of C4, C6, and C8 stereochemistry in the structure of natural sekothrixide.

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