A novel approach towards studying non-genotoxic enediynes as potential anticancer therapeutics

Gholam Hossein Hakimelahi, Gassan Sh Gassanov, Ming Hua Hsu, Jih Ru Hwu, Shahram Hakimelahi

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Abstract

A novel uracil-containing enediyne 7 was synthesized by the fusion at N1 and N3 of uracil with an 11-membered cyclic enediyne. Compound 7 was found to be stable against cycloaromatization at 80°C. Thus, it did not cause DNA-damage. Unlike other alkylated uracil derivatives 2-6, highly strained uracil-containing enediyne 7 was reacted with methyl thioglycolate at 25°C to produce uracil (1) and linear enediyne 8. This reactivity toward a sulfhydryl group may play a significant role in the mechanism by which compound 7 directed its cytotoxicity toward tumor cell lines. Tumor cells were found to be more susceptible to enediyne 7 than normal human embryonic lung cells. A combination of 7 with adriamycin or 1-(β-D-arabinofuranosyl)cytosine resulted in synergistic anticancer activity against murine L1210 and P388 leukemias, Sarcoma 180, and human CCRF-CEM lymphoblastic leukemia. After treatment of Molt-4 cells with uracil-containing enediyne 7, light microscope examination demonstrated the presence of cell shrinkage and nuclear segmentation. Treatment of cultured Molt-4 human leukemia cells with enediyne 7 resulted in a time-dependent depletion of glutathione (GSH) whereas the exposure of the cells to the GSH precursor N-acetylcysteine (NAC) resulted in a substantial suppression of this effect. As such, involvement of GSH depletion in the process of apoptosis may explain the mechanism of action of non-genotoxic enediyne 7 against malignant tumor cell lines.

Original languageEnglish
Pages (from-to)1321-1328
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume10
Issue number5
DOIs
Publication statusPublished - 2002 Mar 21

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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