Aminoparthenolides as novel anti-leukemic agents: Discovery of the NF-κB inhibitor, DMAPT (LC-1)

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Abstract

A series of aminoparthenolide analogs (637) were synthesized and evaluated for their anti-leukemic activity. Eight compounds exhibited good anti-leukemic activity with LD50’s in the low μM range (1.5–3.0 μM). Compounds 16, 24 and 30 were the most potent compounds in the series, causing greater than 90% cell death at 10 μM concentration against primary AML cells in culture, with LD50 values of 1.7, 1.8 and 1.6 μM.

Graphical abstract

A series of water-soluble parthenolide (1) analogs (6–37) were synthesized and evaluated for anti-leukemic activity against primary acute myelogenous (AML) cells in culture. Analogs 16 (R1 = R2 = CH3), 24 (R1 = CH3, R2 = CH2CH2OH) and 30 (R1, R2 = (CH2)2CH(CH3)(CH2)2 had LD50 values in the range 1.6–1.8 μM.

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Acknowledgement

This work was supported by a grant from the Kentucky Lung Cancer Research Program.

References and notes (33)

  • I.H. Hall et al.

    J. Pharm. Sci.

    (1979)
  • P.M. Bork et al.

    FEBS Lett.

    (1997)
  • J. Wen et al.

    J. Biol. Chem.

    (2002)
  • M. Mendonca et al.

    Int. J. Radiat. Oncol. Biol. Phys.

    (2003)
  • S.P. Hehner et al.

    J. Biol. Chem.

    (1998)
  • M.L. Guzman et al.

    Blood

    (2005)
  • D.R. Hwang et al.

    Bioorg. Med. Chem.

    (2006)
  • S. Nasim et al.

    Bioorg. Med. Chem. Lett.

    (2008)
  • N.J. Lawrence et al.

    Bioorg. Med. Chem. Lett.

    (2001)
  • H. Matsuda et al.

    Life Sci.

    (2000)
  • M.L. Guzman et al.

    Blood

    (2001)
  • H. Matsuda et al.

    Bioorg. Med. Chem.

    (2003)
  • M.L. Guzman et al.

    Blood

    (2007)
  • S. Hewamana et al.

    Blood

    (2008)
  • S. Heptinstall et al.

    Folia Haematol. Int. Mag. Klin. Morphol. Blutforsch.

    (1988)
  • V. Pfaffenrath et al.

    Cephalalgia

    (2002)
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