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. © 2001 Wiley-Liss, Inc. Key words: benzoxazolyl hydrazones; benzimidazolyl hydrazones; antitumor agents; colon cancerTheoretically, approximately 50% of the patients diagnosed with cancer can be cured by surgery and radiation therapy since their tumors have not spread. Of the remaining 50%, about 10% are curable with systemic chemotherapy, including children with leukemia and sarcomas and adults with testicular cancer and choriocarcinoma. However, most metastatic cancers are currently not curable by chemotherapy. Half of all cancer patients fail to respond to chemotherapy or relapse from the initial response and ultimately die from their metastatic disease. 1 Colorectal cancer affects about 1 person in 20 in Western populations, representing 15% of all cancers. 2 Because the survival rate is low, new drugs for this type of cancer are desired. 2 The hope for improvement in treatment outcome resides in continued research designed to optimize the administration of currently available agents and to discover novel therapeutic products. 1 Taxanes and camptothecins, for example, are new classes of compounds showing promising results in ovarian, breast and colon cancers. 1 To obtain additional com...

Bis(2‐methylbenzimidazolyl)amine‐Derived Copper Complexes and Their Antineoplastic Activity

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Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition

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Vibrational spectroscopic studies and computational study of quinoline-2-carbaldehyde benzoyl hydrazone

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