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Article Dans Une Revue European Journal of Pharmacology Année : 2007

Bis-imide granulatimide analogues as potent Checkpoint 1 kinase inhibitors.

Résumé

Granulatimide and isogranulatimide, natural products isolated from an ascidian, were found to be abrogators of the cell cycle G2-M phase checkpoint by inhibition of Checkpoint 1 kinase (Chk1). In the course of structure–activity relationship studies on granulatimide analogues, we have synthesized a series of bis-imides, in which the imidazole moiety was replaced by an imide heterocycle. Various modifications have been introduced on one or both imide heterocycles, on the benzene ring, and on the indole nitrogen. Moreover, aza bis-imide analogues were synthesized in which the indole moiety was replaced by a 7-azaindole. Compared to those of granulatimide and isogranulatimide, the Chk1 inhibitory activities of some of the bis-imide carbazoles were stronger. In particular, 1,3,4,6-tetrahydro-10-hydroxy-7H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone 11 exhibited an IC50 value on purified full length Chk1 of 2 nM, which makes it a more potent Chk1 inhibitor than granulatimide and isogranulatimide. To get an insight into the selectivity of this new family of compounds, the inhibitory activities of 1,3,4,6-tetrahydro-7H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone A have been evaluated on a panel of 15 kinases, the strongest inhibitory potency was found for Chk1. The inhibitory activities of compounds A, 5 and 11 toward Src tyrosine kinase and the cytotoxicity of various tumor cell lines were also evaluated

Domaines

Chimie organique
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Dates et versions

hal-00119581 , version 1 (02-03-2007)

Identifiants

Citer

Hélène Henon, Samir Messaoudi, Fabrice Anizon, Bettina Aboab, N. Kucharczyk, et al.. Bis-imide granulatimide analogues as potent Checkpoint 1 kinase inhibitors.. European Journal of Pharmacology, 2007, 554, pp.106-112. ⟨10.1016/j.ejphar.2006.10.022⟩. ⟨hal-00119581⟩
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