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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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

Fingerprint

Enediynes
Uracil
Tumors
Cells
Therapeutics
Tumor Cell Line
Leukemia P388
Sarcoma 180
Leukemia L1210
Cytosine
Acetylcysteine
Cytotoxicity
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Doxorubicin
DNA Damage
Glutathione
Leukemia
Microscopes
Fusion reactions
Apoptosis

All Science Journal Classification (ASJC) codes

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

Cite this

Hakimelahi, Gholam Hossein ; Gassanov, Gassan Sh ; Hsu, Ming-Hua ; Hwu, Jih Ru ; Hakimelahi, Shahram. / A novel approach towards studying non-genotoxic enediynes as potential anticancer therapeutics. In: Bioorganic and Medicinal Chemistry. 2002 ; Vol. 10, No. 5. pp. 1321-1328.
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A novel approach towards studying non-genotoxic enediynes as potential anticancer therapeutics. / Hakimelahi, Gholam Hossein; Gassanov, Gassan Sh; Hsu, Ming-Hua; Hwu, Jih Ru; Hakimelahi, Shahram.

In: Bioorganic and Medicinal Chemistry, Vol. 10, No. 5, 21.03.2002, p. 1321-1328.

Research output: Contribution to journalArticle

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AU - Hakimelahi, Gholam Hossein

AU - Gassanov, Gassan Sh

AU - Hsu, Ming-Hua

AU - Hwu, Jih Ru

AU - Hakimelahi, Shahram

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