2-benzoxazolyl and 2-benzimidazolyl hydrazones derived from 2-acetylpyridine: A novel class of antitumor agents

Here we describe the effects of novel benzoxazol-2-yl and benzimidazol-2-yl hydrazones derived from 2-pyridinecarbaldehyde and 2-acetylpyridine. The I C., values for inhibition of cell proliferation in KB-3-1, CCRF-CEM, Burkit t's lymphoma, HT-29, HeLa, ZR-75 and MEXF276L by most of the novel compound s are in the nanomolar range. In colony-forming assays with human tumor xen ografts the compounds 2-acetylpyridine benzoxazol-2-ylhydrazone (EPH52), 2- acetylpyridine benzolmidazol-2-ylhydrazone (EPH61) and 2-acetylpyridine I - methylbenzoimidazol-2-ylhydrazone (EPH116) exhibited above-average inhibiti on 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 micr osomes, EPH116 is only moderately metabolized. The compound inhibited the g rowth of human colon cancer xenografts in nude mice in a dose-dependent man ner. Thiosemicarbazones derived from 2-formylpyridines have been shown to b e inhibitors of ribonucleotide reductase (RR). The following results show t hat RR is not the target of the novel compounds: cells overexpressing the M 2 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 hyd roxyurea is not observed after treatment with the novel compounds; and a CO MPARE analysis with the related compounds 2-acetylpyrazine benzothiazol-2-y lhydrazone (EPH95) and 3-acetylisoquinoline benzoxazol-2-ylhydrazone (EPH13 6) 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. (C) 2001 Wiley-Li ss, Inc.