Cancer Diagnosis and Prevention
2-benzoxazolyl and 2-benzimidazolyl hydrazones derived from 2-acetylpyridine: A novel class of antitumor agents
Article first published online: 16 JUL 2001
Copyright © 2001 Wiley-Liss, Inc.
International Journal of Cancer
Volume 94, Issue 1, pages 89–96, 1 October 2001
How to Cite
Easmon, J., Puerstinger, G., Roth, T., Fiebig, H.-H., Jenny, M., Jaeger, W., Heinisch, G. and Hofmann, J. (2001), 2-benzoxazolyl and 2-benzimidazolyl hydrazones derived from 2-acetylpyridine: A novel class of antitumor agents. Int. J. Cancer, 94: 89–96. doi: 10.1002/ijc.1427
- Issue published online: 23 AUG 2001
- Article first published online: 16 JUL 2001
- Manuscript Accepted: 3 MAY 2001
- Manuscript Revised: 16 MAR 2001
- Manuscript Received: 15 DEC 2000
- Austrian Science Fund. Grant Number: P09879-MED.
- benzoxazolyl hydrazones;
- benzimidazolyl hydrazones;
- antitumor agents;
- colon cancer.
Here we describe the effects of novel benzoxazol-2-yl and benzimidazol-2-yl hydrazones derived from 2-pyridinecarbaldehyde and 2-acetylpyridine. The IC50 values for inhibition of cell proliferation in KB-3-1, CCRF-CEM, Burkitt's lymphoma, HT-29, HeLa, ZR-75 and MEXF276L by most of the novel compounds are in the nanomolar range. In colony-forming assays with human tumor xenografts the compounds 2-actylpyridine benzoxazol-2-ylhydrazone (EPH52), 2-acetylpyridine benzoimidazol-2-ylhydrazone (EPH61) and 2-acetylpyridine 1-methylbenzoimidazol-2-ylhydrazone (EPH116) exhibited above-average inhibition of colon carcinoma (IC50 = 1.3–4.56 nM); EPH52 and EPH116 also exhibited above-average inhibition of melanoma cells. As shown with human liver microsomes, EPH116 is only moderately metabolized. The compound inhibited the growth of human colon cancer xenografts in nude mice in a dose-dependent manner. Thiosemicarbazones derived from 2-formylpyridines have been shown to be inhibitors of ribonucleotide reductase (RR). The following results show that RR is not the target of the novel compounds: cells overexpressing the M2 subunit of RR and resistant to the RR inhibitor hydroxyurea are not cross-resistant to the novel compounds; inhibition of RR occurs at 6- to 73-fold higher drug concentrations than that of inhibition of cell proliferation; the pattern of cell cycle arrest in S phase induced by the RR inhibitor hydroxyurea is not observed after treatment with the novel compounds; and a COMPARE analysis with the related compounds 2-acetylpyrazine benzothiazol-2-ylhydrazone (EPH95) and 3-acetylisoquinoline benzoxazol-2-ylhydrazone (EPH136) showed that the pattern of these compounds is not related to any of the standard antitumor drugs. Therefore, these novel compounds show inhibition of colon cancers and exhibit a novel mechanism of action. © 2001 Wiley-Liss, Inc.