Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine

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Abstract

The marine sponge metabolite hymenialdisine is a potent inhibitor of a variety of kinases including MEK-1, GSK-3β, and CK1. In addition, hymenialdisine and debromohymenialdisine exhibit inhibition of the G2 cell cycle checkpoint at micromolar concentrations. We report herein the potent inhibition of cell cycle kinase Chk2 by the indolic-hymenialdisine indoloazepine 1 (IC50=8 nM).

The inhibition of kinase activity by a hymenialdisine-derived indoloazepine is reported. Compound 1 was found to be a potent inhibitor of Chk2 (IC50=8 nM).

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Introduction

DNA replication is a process that requires great accuracy and relies on surveillance mechanisms, which monitor DNA damage and initiate DNA repair.1 The inability to carry out DNA repair often leads to the transformation of normal cells into malignancies.2 Upon DNA damage, cell cycle checkpoints get activated, which delay the cell cycle progression and allow for DNA repair. A multi-faceted involvement of these checkpoint pathways regulate DNA repair,[1], [2], [3] telomere length,4 and the induction of apoptotic cell death.[1], [5]

Protein kinases regulate a host of cellular processes such as growth and differentiation, cell proliferation, and apoptosis.6 DNA damage caused by radiation or chemotherapy triggers the DNA damage-responsive protein kinases ATM and ATR, which activate Chk1 and Chk2. Chk1 and Chk2 in turn phosphorylate Cdc25 and prevent Cdc2 activation, resulting in cell cycle arrest.7 Hence, small molecules that can inhibit the checkpoints may enhance the efficacy of DNA damaging chemotherapeutics or radiation therapy.8

The marine sponge metabolite hymenialdisine (Fig. 1) was originally isolated from the sponges Axinella verrucosa and Acantella aurantiaca and its structure was established on the basis of X-ray crystallography.9 Hymenialdisine and other oroidin compounds have been established to be potent anti-proliferative, anti-neurodegenerative, and anti-inflammatory agents in various cell lines and animal models.[10], [11], [12], [13], [14] Hymenialdisine was found to be a potent kinase inhibitor of several related CDKs.10 In addition, hymenialdisine was found to be a potent inhibitor of the nuclear transcription factor NF-κB11 and acts as a competitive nanomolar inhibitor of the cyclin-dependent kinases, GSK-3β and CK1 with IC50 values of 10 and 35 nM, respectively.12 Crystallographic data portrayed the binding of the kinase inhibitor in the ATP binding pocket of the kinases.12 In addition, Ireland and co-workers have identified hymenialdisine as a very potent mitogen-activated protein kinase kinase-1 (MEK-1) inhibitor with low nanomolar IC50 values (IC50=6 nM).13 In these studies we describe the synthesis and kinase activity of the indole-derivative of hymenialdisine, 1.

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Chemistry and biology

Roberge and co-workers have shown the inhibition of the G2 DNA damage checkpoint by debromohymenialdisine as well as hymenialdisine in cells.7 Inhibition of Chk1 and Chk2 by debromohymenialdisine was reported to correspond with IC50 values of 3 and 3.5 μM, respectively. Both debromohymenialdisine and hymenialdisine showed comparable IC50 values for inhibition of the G2 checkpoint at 8 and 6 μM, respectively. This indicates that the bromide at the C2 position of hymenialdisine did not

Supplementary data

Acknowledgements

The authors gratefully acknowledge the financial support by Research Scholar Grant RSG-04-018-01-CDD from the American Cancer Society and Michigan State University.

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  • Fused-azepinones: Emerging scaffolds of medicinal importance

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    Citation Excerpt :

    Oroidin alkaloids and paullones belong to medicinally important fused-azepinone class of compounds. Hymenialdisine (HMD), a marine natural product, is reported to possess a wide range of pharmacological activities including potent kinase inhibitory properties, anti-cancer [32–36], anti-inflammatory [38–44], anti-viral [46], neuroprotective [54] and anti-fouling properties [55]. However, its closely related debromohymenialdesine (DBH) did not exhibit significant inhibitory properties against various protein kinases other than MEK1 [33] and Chk [34].

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Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.bmcl.2004.05.079

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