Synthesis and biological activities of isogranulatimide analogues

• Published in: Bioorganic & medicinal chemistry 2007-09, Vol.15 (17), p.5965-5980
• Main Authors: Hugon, Bernadette, Anizon, Fabrice, Bailly, Christian, Golsteyn, Roy M., Pierré, Alain, Léonce, Stéphane, Hickman, John, Pfeiffer, Bruno, Prudhomme, Michelle
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antitumor drugs; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Biological and medical sciences; Carbazoles - chemistry; Carbazoles - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Checkpoint Kinase 1; Chk1 inhibitors; DNA - metabolism; DNA Topoisomerases, Type I - metabolism; General aspects; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - toxicity; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Indoles - toxicity; Isogranulatimide; Magnetic Resonance Spectroscopy; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - toxicity; Protein Kinases - metabolism; Pyrroles - chemistry; Pyrrolo[3,4- c]carbazole; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Structure-Activity Relationship; Topoisomerase I Inhibitors
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.05.073

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.