title: 2-benzoxazolyl and 2-benzimidazolyl hydrazones derived from 2-acetylpyridine: a novel class of antitumor agents.
abstract: Here we describe the effects of novel benzoxazol-2-yl and benzimidazol-2-yl hydrazones derived from 2-pyridinecarbaldehyde and 2-acetylpyridine. The IC(50) 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 (IC(50) = 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.
authors.affiliation: Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Easmon
authors.forename: G
authors.initials: G
authors.lastname: Puerstinger
authors.forename: T
authors.initials: T
authors.lastname: Roth
authors.forename: H H
authors.initials: HH
authors.lastname: Fiebig
authors.forename: M
authors.initials: M
authors.lastname: Jenny
authors.forename: W
authors.initials: W
authors.lastname: Jaeger
authors.forename: G
authors.initials: G
authors.lastname: Heinisch
authors.forename: J
authors.initials: J
authors.lastname: Hofmann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D007624:KB Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones