Meridianin derivatives as potent Dyrk1A inhibitors and neuroprotective agents

doi:10.1016/j.bmcl.2015.05.034

Bioorganic & Medicinal Chemistry Letters

Volume 25, Issue 15, 1 August 2015, Pages 2948-2952

https://doi.org/10.1016/j.bmcl.2015.05.034 Get rights and content

Abstract

Meridianins are a group of marine-derived indole alkaloids which are reported to possess kinase inhibitory activities. In the present Letter, we report synthesis of N1-substituted and C-ring modified meridianin derivatives and their evaluation as Dyrk1A inhibitors and neuroprotective agents. Among the library of 52 compounds screened, morpholinoyl linked derivative 26b and 2-nitro-4-trifluoromethyl phenyl sulfonyl derivative 29v displayed potent inhibition of Dyrk1A with IC₅₀ values of 0.5 and 0.53 μM, respectively. The derivative 26b also inhibited Dyrk2 and Dyrk3 with IC₅₀ values of 1.4 and 2.2 μM, respectively showing 2.2 and 4.4 fold selectivity for Dyrk1A with respect to Dyrk2 and Dyrk3. The compound 26b was not cytotoxic to human neuroblastoma SH-SY5Y cells (IC₅₀ >100 μM) and it displayed significant neuroprotection against glutamate-induced neurotoxicity in these cells at 10 μM. Molecular modelling studies of compound 26b led to identification of key interactions in the binding site of Dyrk1A and the possible reasons for observed Dyrk1A selectivity over Dyrk2.

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Acknowledgements

R.R.Y. thanks CSIR (India) for Senior Research Fellowship. Authors are thankful to analytical department, IIIM for analytical support. This work was supported by DST-SERB grant (no. SR/FT/CS-168/2011).

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^☆: IIIM Communication number. IIIM/1786/2015.

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Meridianin derivatives as potent Dyrk1A inhibitors and neuroprotective agents☆

Abstract

Graphical abstract

Section snippets

Acknowledgements

Cell

J. Biol. Chem.

Arch. Biochem. Biophys.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Ment. Retard. Dev. Disabil. Res. Rev.

Proc. Natl. Acad. Sci. U.S.A.

Genes Brain Behav.

Biochem. J.

FEBS J.

Biochemistry

Biochem. J.