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Planta Med 2012; 78(10): 951-956
DOI: 10.1055/s-0031-1298625
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Library-based Discovery of DYRK1A/CLK1 Inhibitors from Natural Product Extracts

Patrick Grabher
1   Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland
,
Emilie Durieu
2   Protein Phosphorylation & Human Disease Group, Station Biologique de Roscoff, CNRS, Roscoff, France
,
Eirini Kouloura
3   Laboratory of Pharmacognosy and Natural Products Chemistry, School of Pharmacy, University of Athens, Athens, Greece
,
Maria Halabalaki
3   Laboratory of Pharmacognosy and Natural Products Chemistry, School of Pharmacy, University of Athens, Athens, Greece
,
Leandros A. Skaltsounis
3   Laboratory of Pharmacognosy and Natural Products Chemistry, School of Pharmacy, University of Athens, Athens, Greece
,
Laurent Meijer
2   Protein Phosphorylation & Human Disease Group, Station Biologique de Roscoff, CNRS, Roscoff, France
4   ManRos Therapeutics, Centre de Perharidy, Roscoff, France
,
Matthias Hamburger
1   Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland
,
Olivier Potterat
1   Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland
› Author Affiliations
Further Information

Publication History

received 02 March 2012
revised 07 May 2012

accepted 08 May 2012

Publication Date:
06 June 2012 (online)

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Abstract

The dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A possesses diverse roles in neuronal development and adult brain physiology, and increased activity has been linked to neurodegenerative diseases. Very few inhibitors of this kinase have been reported up to now. Screening of a library of > 900 plant and fungal extracts afforded 25 extracts with IC50s < 10 µg/mL against DYRK1A. To identify the active constituents, the extracts were submitted to a process integrating physicochemical data with biological information, referred to as HPLC-based activity profiling. Follow-up investigation of four extracts led to the targeted isolation of harmine (1, IC50 0.022 µM) from Peganum harmala, emodin (3, IC50 4.2 µM) from Cassia nigricans, kaempferol (4, IC50 0.91 µM) from Cuscuta chinensis, and 3,8-di-O-methylherbacetin (11, IC50 8.6 µM), 3,3′,4′-tri-O-methylmyricetin (12, IC50 7.1 µM) and ombuin (15, IC50 1.7 µM) from Larrea tridentata as the active constituents. Active extracts and compounds were also tested on the closely related cdc2-like kinase CLK1. Finally, the selectivity profile of compounds was evaluated by including other members of the DYRKs and CLKs families. While the flavonoids and emodin did not show significant differences in the potency of their activities, harmine (1) was most active against DYRK1A, CLK1, and CLK4, and less potent against the other kinases, with selectivity ranging from 2- to 20-fold.

Key words

library-based natural product screening - DYRK1A - CLK1 - HPLC-based activity profiling - harmine - emodin - flavonoids - Peganum harmala - Zygophyllaceae - Cuscuta chinensis - Convolvulaceae - Larrea tridentate - Zygophyllaceae - Cassia nigricans - Caesalpiniaceae

Supporting Information

 

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