Synthesis of a new antiproliferative agent of leukaemia cell lines

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Synthesis of a new antiproliferative agent of leukaemia cell lines

Quinta, 29.05.2014

A novel antiproliferative agent bis-4-hydroxycoumarin-type compound have been designed and prepared by two alternative synthetic methods. We have rationalized the concept of a biologically active molecule built from inactive constructive fragments. We demonstrated that the new compound inhibits proliferation of K-562 and JUKAT leukaemia cell lines associated to an accumulation of cells in G0/G1 phase of cell cycle without affecting the viability of healthy peripheral blood mononuclear cells (PBMCs). In addition, this compound blocks the activation of the pro40 inflammatory NF-κB pathway.

 

Authors and Affiliations:

Oualid Talhi,a Michael Schnekenburger,b Jana Panning,b,c Diana G. C. Pinto,a José A. Fernandes,d Filipe A. Almeida Paz,d Claus Jacob,c Marc Diederiche,e,* and Artur M. S. Silvaa,*

a QOPNA, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.

b Laboratoire de Biologie Moleculaire et Cellulaire du Cancer, Hopital 55 Kirchberg, L-2540 Luxembourg, Luxembourg.

c School of Pharmacy Building B 2.1., Room 1.13 Campus 66123 Saarbrucken, Germany.

d CICECO, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.

e College of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea.

 

Abstract:

Synthesis of the bis-4-hydroxycoumarin-type compound, 3,3'-[3-(2-hydroxyphenyl)-3-oxopropane-1,1-diyl]bis(4-hydroxy-2H-chromen-2-one, was performed by two alternative pathways, either involving a basic organocatalyzed 1,4-conjugate addition tandem reaction of 4-hydroxycoumarin on chromone-3-carboxylic acid, or a double condensation of 4-hydroxycoumarin on ω-formyl-2’-hydroxyacetophenone. The anti-proliferative effects of the bis-4-hydroxycoumarin-type compound on human K-562 (chronic myeloid leukaemia) and JURKAT (acute T-cell leukaemia) cell lines using trypan blue staining, as well as its involvement in nuclear factor-kappa B (NF-κB) regulation analyzed by luciferase reporter gene assay, gene expression analysis and western blots were analysed. This compound inhibited TNFα- induced NF-κB activation in K-562 (IC50 17.5 CM) and JURKAT (IC50 19.0 CM) cell lines, after 8 h of incubation. Interestingly, it exerted mainly cytostatic effects at low doses on both cell lines tested, whereas it decreased JURKAT cell viability starting at 50 CM from 24 h of treatment. Importantly, it did not affect the viability of peripheral blood mononuclear cells (PBMCs) from healthy donors, even at concentrations above 100 CM.

 

Journal:

Bioorganic & Medicinal Chemistry

 

Link:

http://www.sciencedirect.com/science/article/pii/S0968089614002429