Computational & experimental evaluation of the structure/activity relationship of β-carbolines as DYRK1A inhibitors

被引：36

作者：

Drung, Binia ^{[1
]}

Scholz, Christoph ^{[1
]}

Barbosa, Valeria A. ^{[2
]}

Nazari, Azadeh ^{[1
]}

Sarragiotto, Maria H. ^{[2
]}

Schmidt, Boris ^{[1
]}

机构：

[1] Tech Univ Darmstadt, Clemens Schopf Inst Organ Chem & Biochem, D-64287 Darmstadt, Germany

[2] Univ Estadual Maringa, Dept Quim, BR-87020900 Maringa, PR, Brazil

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 20期

关键词：

DYRK1A; MAO-A; Pharmacophore; Docking; Inhibitor; beta-Carboline; SAR; PROTEIN-KINASE CK2; BIOLOGICAL EVALUATION; IN-VITRO; ANTIPROLIFERATIVE ACTIVITIES; DERIVATIVES; POTENT; OPTIMIZATION; ROSCOVITINE; DISCOVERY; DISEASE;

D O I：

10.1016/j.bmcl.2014.08.054

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

DYRK1A has been associated with Down's syndrome and neurodegenerative diseases, therefore it is an important target for novel pharmacological interventions. We combined a ligand-based pharmacophore design with a structure-based protein/ligand docking using the software MOE in order to evaluate the underlying structure/activity relationship. Based on this knowledge we synthesized several novel beta-carboline derivatives to validate the theoretical model. Furthermore we identified a modified lead structure as a potent DYRK1A inhibitor (IC50 = 130 nM) with significant selectivity against MAO-A, DYRK2, DYRK3, DYRK4 & CLK2. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：4854 / 4860

页数：7

共 43 条

[1]

[Anonymous], 2015, MOL OP ENV MOE

[2] The selectivity of protein kinase inhibitors: a further update [J].

Bain, Jenny ;

Plater, Lorna ;

Elliott, Matt ;

Shpiro, Natalia ;

Hastie, C. James ;

Mclauchlan, Hilary ;

Klevernic, Iva ;

Arthur, J. Simon C. ;

Alessi, Dario R. ;

Cohen, Philip .

BIOCHEMICAL JOURNAL, 2007, 408 :297-315

[3] (1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives:: Further optimisation as highly potent and selective MSK-1-inhibitors [J].

Bamford, MJ ;

Bailey, N ;

Davies, S ;

Dean, DK ;

Francis, L ;

Panchal, TA ;

Parr, CA ;

Sehmi, S ;

Steadman, JG ;

Takle, AK ;

Townsend, JT ;

Wilson, DM .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (14) :3407-3411

[4] Activation, regulation, and inhibition of DYRK1A [J].

Becker, Walter ;

Sippl, Wolfgang .

FEBS JOURNAL, 2011, 278 (02) :246-256

[5] Novel Tetrahydropyrido[1,2-a]isoindolone Derivatives (Valmerins): Potent Cyclin-Dependent Kinase/Glycogen Synthase Kinase 3 Inhibitors with Antiproliferative Activities and Antitumor Effects in Human Tumor Xenografts [J].

Boulahjar, Rajaa ;

Ouach, Aziz ;

Matteo, Chiurato ;

Bourg, Stephane ;

Ravache, Myriam ;

le Guevel, Remy ;

Marionneau, Severine ;

Oullier, Thibauld ;

Lozach, Olivier ;

Meijer, Laurent ;

Guguen-Guillouzo, Christiane ;

Lazar, Said ;

Akssira, Mohamed ;

Troin, Yves ;

Guillaumet, Gerald ;

Routier, Sylvain .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (22) :9589-9606

[6] Synthesis and biological evaluation of 3,6-diamino-1H-pyrazolo[3,4-b]pyridine derivatives as protein kinase inhibitors [J].

Chioua, Mourad ;

Samadi, Abdelouahid ;

Soriano, Elena ;

Lozach, Olivier ;

Meijer, Laurent ;

Marco-Contelles, Jose .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (16) :4566-4569

[7] Identification of ellagic acid as potent inhibitor of protein kinase CK2: A successful example of a virtual screening application [J].

Cozza, G ;

Bonvini, P ;

Zorzi, E ;

Poletto, G ;

Pagano, MA ;

Sarno, S ;

Donella-Deana, A ;

Zagotto, G ;

Rosolen, A ;

Pinna, LA ;

Meggio, F ;

Moro, S .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (08) :2363-2366

[8]

Cuny G. D., 2015, BIOORG MED CHEM LETT, V2012, P22

[9] Potent inhibitors of CDK5 derived from roscovitine: Synthesis, biological evaluation and molecular modelling [J].

Demange, Luc ;

Abdellah, Fatma Nait ;

Lozach, Olivier ;

Ferandin, Yoan ;

Gresh, Nohad ;

Meijer, Laurent ;

Galons, Herve .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (01) :125-131

[10] Microwave irradiation for accelerating each step for the synthesis of 1,2,4-triazino[5,6-b]indole-3-thiolsand their derivatives from isatin and 5-chloroisatin [J].

El Ashry, ESH ;

Ramadan, ES ;

Hamid, HMA ;

Hagar, M .

SYNLETT, 2004, (04) :723-725

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