Synthesis and biological activities of isogranulatimide analogues.
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.
Hugon
Bernadette
B
Laboratoire SEESIB, Université Blaise Pascal, UMR 6504 du CNRS, Aubière, France.
Anizon
Fabrice
F
Bailly
Christian
C
Golsteyn
Roy M
RM
Pierré
Alain
A
Léonce
Stéphane
S
Hickman
John
J
Pfeiffer
Bruno
B
Prudhomme
Michelle
M
D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000633:toxicity; D011494:Protein Kinases / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D001372:Aza Compounds; D002227:Carbazoles; D007093:Imidazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D059004:Topoisomerase I Inhibitors; C116644:isogranulatimide; C029899:imidazole; D004247:DNA; C053339:rebeccamycin; D011494:Protein Kinases; D019061:src-Family Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D004264:DNA Topoisomerases, Type I