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2‐benzoxazolyl and 2‐benzimidazolyl hydrazones derived from 2‐acetylpyridine: A novel class of antitumor agents
Author(s) -
Easmon Johnny,
Puerstinger Gerhard,
Roth Thomas,
Fiebig HeinzHerbert,
Jenny Marcel,
Jaeger Walter,
Heinisch Gottfried,
Hofmann Johann
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.1427
Subject(s) - ribonucleotide reductase , hela , cell growth , cell cycle , growth inhibition , stereochemistry , chemistry , enzyme , pharmacology , microbiology and biotechnology , biochemistry , biology , cell , protein subunit , gene
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. © 2001 Wiley‐Liss, Inc.