Preparação de um novo agente anti-proliferativo de células leucémicas

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Preparação de um novo agente anti-proliferativo de células leucémicas

Quinta, 29.05.2014

Um novo agente anti-proliferativo do tipo bis-4-hidroxicumarina foi desenhado e preparado por dois métodos de síntese alternativos. Com este processo de síntese efetuou-se a racionalização do conceito de construção de uma molécula biologicamente ativa a partir de fragmentos que não apresentaram qualquer tipo de atividade. Demonstrou-se que o novo composto inibe a proliferação de linhas celulares leucémicas K-562 and JUKAT associadas a uma acumulação de células na fase G0/G1 do ciclo celular, sem afectar a viabilidade das células mononucleares periféricas do dadores saudáveis. Além disso, este composto bloqueia a ativação da via de sinalização de processos inflamatória NF-kB.

 

Autores e Afiliações:

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.

 

Revista:

Bioorganic & Medicinal Chemistry

 

Link:

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