Synthesis and biological activities of isogranulatimide analogues.

Abstract	The synthesis of new isogranulatimide analogues, their inhibitory activities toward the Checkpoint 1 kinase (Chk1), and their in vitro cytotoxicities toward four tumor cell lines (one murine L1210 leukemia, and three human cell lines: DU145 prostate carcinoma, A549 non-small cell lung carcinoma, and HT29 colon carcinoma) are described. The affinity for DNA of some representative compounds and their ability to induce DNA cleavage mediated by topoisomerase I have been examined. In some of the newly synthesized compounds, the imidazole heterocycle of isogranulatimide is replaced by a pyrrole and/or the indole unit is replaced by a 7-azaindole. Compounds in which a sugar part is attached to the 7-azaindole moiety have also been prepared. Some of the newly synthesized compounds are more potent Chk1 inhibitors than granulatimide. The selectivity of two potent Chk1 inhibitors 24 and 26 has been evaluated using various kinases. The strongest inhibitory properties are found toward Chk1.
Authors	Bernadette Hugon, Fabrice Anizon, Christian Bailly, Roy M Golsteyn, Alain Pierré, Stéphane Léonce, John Hickman, Bruno Pfeiffer, Michelle Prudhomme
Journal	Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 15 Issue 17 Pg. 5965-80 (Sep 01 2007) ISSN: 0968-0896 [Print] England
PMID	17582773 (Publication Type: Journal Article)
Chemical References	Aza Compounds Carbazoles Imidazoles Indoles Protein Kinase Inhibitors Pyrroles Topoisomerase I Inhibitors isogranulatimide imidazole DNA rebeccamycin Protein Kinases src-Family Kinases CHEK1 protein, human Checkpoint Kinase 1 DNA Topoisomerases, Type I
Topics	Aza Compounds (chemical synthesis, chemistry) Carbazoles (chemistry, pharmacology) Cell Line, Tumor Cell Proliferation (drug effects) Checkpoint Kinase 1 DNA (metabolism) DNA Topoisomerases, Type I (metabolism) Humans Imidazoles (chemical synthesis, chemistry, toxicity) Indoles (chemical synthesis, chemistry, pharmacology, toxicity) Magnetic Resonance Spectroscopy Molecular Structure Protein Kinase Inhibitors (chemistry, toxicity) Protein Kinases (metabolism) Pyrroles (chemistry) Structure-Activity Relationship Topoisomerase I Inhibitors src-Family Kinases (antagonists & inhibitors, metabolism)

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