Abstract
A series of 4-(2-fluorophenoxy)-2-(1H-tetrazol-1-yl)pyridines bearing semicarbazone moieties were synthesized and evaluated for their in vitro antitumor potency. Some of the compounds (10b, 10c, 10e-10h, 10m-10p, 10r, and 11b) exhibited moderate to excellent antitumor activity as compared to sorafenib and PAC-1, as well as low levels of toxicity toward the human fetal lung fibroblast cell line WI-38. The most promising compound 10p (IC50 = 0.08, 0.36, 0.97 µM) was 45.1-, 6.1-, and 2.4-fold more active than sorafenib (IC50 = 3.61, 2.19, 2.32 µM), and 17, 3.2, and 2.9 times better than PAC-1 (IC50 = 1.36, 1.17, 2.83 µM) against three cancer cell lines (HT-29, H460, and MKN-45), respectively. In addition, further studies examining enzymatic activity suggested that the marked pharmacological activity observed might be ascribed to an inhibitory action against CRAf kinase.
Keywords:
Antitumor activity; SARs; Semicarbazone moiety; Sorafenib analogs.
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / toxicity
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Apoptosis / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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HT29 Cells
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Humans
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Hydrazones / pharmacology
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Inhibitory Concentration 50
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Molecular Structure
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Niacinamide / analogs & derivatives
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Niacinamide / pharmacology
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Phenylurea Compounds / pharmacology
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Piperazines / pharmacology
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / toxicity
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Proto-Oncogene Proteins c-raf / antagonists & inhibitors
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Proto-Oncogene Proteins c-raf / metabolism
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Pyridines / chemical synthesis*
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Pyridines / pharmacology*
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Pyridines / toxicity
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Semicarbazones / chemical synthesis*
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Semicarbazones / pharmacology*
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Semicarbazones / toxicity
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Sorafenib
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Structure-Activity Relationship
Substances
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(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine
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Antineoplastic Agents
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Hydrazones
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Phenylurea Compounds
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Piperazines
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Protein Kinase Inhibitors
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Pyridines
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Semicarbazones
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Niacinamide
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Sorafenib
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Proto-Oncogene Proteins c-raf