Bis-imide granulatimide analogues as potent Checkpoint 1 kinase inhibitors

Abstract

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 IC(50) 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.

Characterization of novel Checkpoint kinase 1 inhibitors by in vitro assays and in human cancer cells treated with topoisomerase inhibitors

“…Chk1 was predicted to be a target of granulatimides chemical family (Roberge et al, 1998); which we and others have confirmed (Henon et al, 2008;Henon et al, 2007;Jiang et al, 2004). Isogranulatimide is a natural compound from the ascidian Didemnum granulatum (Roberge et al, 1998).…”

“…S29285 is a bisimide derivative of isogranulatimide and the S29859 is a chlorinated derivative containing a pyrrole ring. S29285 was neither cytotoxic (Henon et al, 2007) or active in the checkpoint bypass assay. We subsequently found that this compound was unstable in aqueous solutions.…”

“…The chemical structures that inhibited Chk1 include hymenialdisine derivatives (S41842) (Parmentier et al, 2008), granulatimides (S29285, S29859) (Henon et al, 2007;Hugon et al, 2007) (Moreau et al, 2001), indolocarbazoles derivatives (S27888) (Moreau et al, 2001), benzodioxino carbazole (S74259) and a four ring heterocyclic molecule (S39614). Because the S39614, S41842, and S74259 structures were novel, we determined their crystal structure at high resolution (1.6-1.7 Å) in complex with Chk1-cat (see Supplemental data).…”

Palladium-Catalyzed One-Step Synthesis of Isoindole-1,3-diones by Carbonylative Cyclization of o-Halobenzoates and Primary Amines

“…10 Some isoindole-1,3-dione derivatives are active in reducing the growth of colon adenocarcinoma, osteosarcoma, and KB nasopharynx. 11 Isoindole-1,3-diones are also known for their antiviral, 12 antiinflammatory, 13 Chk1 inhibitory, 14 sedative, 15 bactericidal, and fungicidal 16 properties. They also find important applications as synthetic intermediates in the dye, 17 pesticide, 18 and polymer 19 industries.…”

An expeditious, highly efficient, catalyst and solvent-free synthesis of 9,10-dihydro-anthracene-9,10-α,β-succiniimide derivatives

“…Along with the photophysical and chemical properties, organic imides and diimides also play significant role in pharmacology. Imides possess wide range of biological activities such as antiinflammatory (21Á24), anticancer (25,26), antimicrobial (27), DNA binding, and apoptotic-inducing activities (28), etc. They also act as selective a1d-adrenergic receptor antagonists which modulate intercellular biochemical processes in response to changes in extracellular concentrations of the neurotransmitter norepinephrine and the circulating hormone epinephrine, leading to widespread physiological actions that make them attractive targets for *Corresponding author.…”