Doctoral thesis (Dissertations and theses)
Conception, synthèse et évaluation biologique de dérivés coumariniques en tant qu'agents anticancéreux potentiels


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Keywords :
Medicinal Chemistry Angiogenesis; Cancer Coumarins; Tumor invasion; Metastasis
Abstract :
[en] IK9 was recently reported to be a potent inhibitor of cancer cell invasion and angiogenesis. It markedly reduced in vitro invasion of human HT1080 fibrosarcoma cells through collagen-coated porous membranes (Boyden chamber assay) and in vivo tumour growth in athymic nude mice. It was furthermore able to decrease angiogenesis ex vivo in a rat aortic ring assay and in vivo in a choroidal neovascularisation mice model. It nevertheless presents some water solubility and stability problems, which should be taken into account for further investigations. In the first part of the project, we synthesized original IK9 derivatives, modulated at the 3- and 6-positions, by introducing functional groups able to improve water solubility and metabolic stability. Their in vitro anti-invasive potency was screened and the generated results highlighted some structure-activity relationships. A second part of the project was devoted to the elucidation of the actually unknown mechanism of action of IK9. Anti-invasive or anti-proliferative effects against endothelial cells, main actors of the angiogenic process, were not emphasised. We showed that IK9 acts likely not as an inhibitor of receptor tyrosine kinases (EGFR, PDGFR and VEGFR). The compound generates a weak decrease of mRNA coding for MMP 2 and 9, and on the other hand a substantial diminution of MMP 2 and 9 secretions by HT1080 fibrosarcoma cells. In conclusion, the consideration of anti-invasive properties together with the worked out solubility and stability profiles highlights several series, notably 6-hydroxycoumarins, 6-hydroxymethylcoumarins and coumarin-3-sulfonamides, whose interest as potential successors to IK9 is undeniable.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
HEMMER, Marc ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Language :
Title :
Conception, synthèse et évaluation biologique de dérivés coumariniques en tant qu'agents anticancéreux potentiels
Defense date :
17 November 2010
Institution :
Unilu - University of Luxembourg, Luxembourg, Luxembourg
ULiège - Université de Liège, Belgium
Degree :
Docteur en Biologie
Promotor :
Pirotte, Bernard
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since 11 February 2014


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