Identification of phenyl-pyridine-2-carboxylic acid derivatives as novel cell cycle inhibitors with increased selectivity for cancer cells
作者:
Steven Berthel,
Ian Marks,
Xuefeng Yin,
Steven Mischke,
Lucja Orzechowski,
Gabriella Pezzoni,
Franca Sala,
Lyubomir Vassilev,
期刊:
Anti-Cancer Drugs
(OVID Available online 2002)
卷期:
Volume 13,
issue 4
页码: 359-366
ISSN:0959-4973
年代: 2002
出版商: OVID
关键词: Antitumor;cancer cells;cell cycle;mitosis;xenografts
数据来源: OVID
摘要:
Ro 41-4439, a phenyl-pyridine-2-carboxylic acid derivative, was identified by a cell-based screening approach that exploits the differences between normal and cancer cells in their sensitivity to cytotoxic agents. This compound showed low micromolar antiproliferative activity and cytotoxicity against a broad panel of human cancer cell linesin vitro, and over 10-fold selectivity to cancer cells when tested in parallel with a panel of proliferating normal human cells. Cytotoxicity of Ro 41-4439 is due to arrest of cell cycle progression in mitosis followed by induction of apoptosis. Four-week treatment of nude mice bearing established mammary tumor xenografts (MDA-MB-435) with well-tolerated doses of the compound showed 73% inhibition of tumor growth. Limited exploration of structure–activity relationships involving side chain length, and aryl and pyridine rings allowed for the identification of more potent analogs.
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