A novel approach towards studying non-genotoxic enediynes as potential anticancer therapeutics.
A novel uracil-containing enediyne was synthesized by the fusion at N(1) and N(3) of uracil with an 11-membered cyclic enediyne. Compound was found to be stable against cycloaromatization at 80 degreesC. Thus, it did not cause DNA-damage. Unlike other alkylated uracil derivatives 2--6, highly strained uracil-containing enediyne was reacted with methyl thioglycolate at 25 degreesC to produce uracil () and linear enediyne. This reactivity toward a sulfhydryl group may play a significant role in the mechanism by which compound directed its cytotoxicity toward tumor cell lines. Tumor cells were found to be more susceptible to enediyne than normal human embryonic lung cells. A combination of with adriamycin or 1-(beta-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, light microscope examination demonstrated the presence of cell shrinkage and nuclear segmentation. Treatment of cultured Molt-4 human leukemia cells with enediyne 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 against malignant tumor cell lines.
Hakimelahi
Gholam Hossein
GH
Institute of Chemistry, Academia Sinica, Taipei, 115, ROC, Taiwan. hosein@chem.sinica.edu.tw
Gassanov
Gassan Sh
GSh
Hsu
Ming Hua
MH
Hwu
Jih Ru
JR
Hakimelahi
Shahram
S
D000475:Alkenes / Q000138:chemical synthesis* / Q000494:pharmacology; D000480:Alkynes / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009152:Mutagenicity Tests; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D000475:Alkenes; D000480:Alkynes; D000970:Antineoplastic Agents; D014498:Uracil; D004317:Doxorubicin; D005978:Glutathione