Bis(4-hydroxy-2H-chromen-2-one): synthesis and effects on leukemic cell lines proliferation and NF-κB regulation.
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 μM) and JURKAT (IC50 19.0 μM) cell lines, after 8h 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 μM from 24h of treatment. Importantly, it did not affect the viability of peripheral blood mononuclear cells (PBMCs) from healthy donors, even at concentrations above 100 μM.
QOPNA, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.
Oualid
O
Talhi
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, L-2540 Luxembourg, Luxembourg.
Michael
M
Schnekenburger
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, L-2540 Luxembourg, Luxembourg; School of Pharmacy, Building B 2.1., Room 1.13, University of Saarland, Campus, 66123 Saarbrucken, Germany.
Jana
J
Panning
QOPNA, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.
Diana G C
DG
Pinto
CICECO, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.
José A
JA
Fernandes
CICECO, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.
Filipe A
FA
Almeida Paz
School of Pharmacy, Building B 2.1., Room 1.13, University of Saarland, Campus, 66123 Saarbrucken, Germany.
Claus
C
Jacob
College of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea. Electronic address: marcdiederich@snu.ac.kr.
Marc
M
Diederich
QOPNA, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. Electronic address: artur.silva@ua.pt.
Artur M S
AM
Silva
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020014:K562 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002867:Chromones; D016328:NF-kappa B; C000593704:bis(4-hydroxy-2H-chromen-2-one)
2D-NMR; Biscoumarins; Leukaemia cell lines; NF-κB inhibition; X-ray crystallography