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Brossard D.,University of Caen Lower Normandy | Brossard D.,Center Detudes Et Of Recherche Sur Le Medicament Of Normandie Cermn | Lechevrel M.,University of Caen Lower Normandy | Lechevrel M.,Laboratoire Microenvironnement Cellulaire et Pathologies MILPAT | And 9 more authors.
European Journal of Medicinal Chemistry | Year: 2014

We previously reported that the cinnamylpiperazinyl group in the side chain of the chenodeoxycholic acid showed apoptosis-inducing activity on multiple myeloma cancer cell line KMS-11. In the present study, we synthesized and tested the pro-apoptotic potency of fifteen new piperazinyl bile carboxamide derived from cholic, ursodeoxycholic, chenodeoxycholic, deoxycholic and lithocholic acids on human colon adenocarcinoma cell lines DLD-1, HCT-116, and HT-29. Cell viability was first measured using XTT assay. The most of the synthetic bile carboxamide derivatives decreased significantly cell viability in a dose-dependent manner. HCT-116 and DLD-1 cell lines were more sensitive than HT-29 to tested compounds. 9c, 9d showed the best in vitro results in term of solubility and dose-response effect on the three colon adenocarcinoma cell lines. Additionally, flow cytometric and Western-blotting analysis showed that 9c induced pro-apoptosis in DLD-1 and HCT-116 whereas 9d did not. We conclude that the benzyl group improved anti-proliferative activity and that the α-hydroxyl group was found to be more beneficial at the 7-position in steroid skeleton. © 2014 Published by Elsevier Masson SAS.

Marassio G.,ERTi 1083 | Marassio G.,University of Caen Lower Normandy | Prange T.,University of Paris Descartes | David H.N.,ERTi 1083 | And 9 more authors.
FASEB Journal | Year: 2011

The remarkably safe anesthetics xenon (Xe) and, to lesser extent, nitrous oxide (N 2O) possess neuroprotective properties in preclinical studies. To investigate the mechanisms of pharmacological action of these gases, which are still poorly known, we performed both crystallography under a large range of gas pressure and biochemical studies on urate oxidase, a prototype of globular gas-binding proteins whose activity is modulated by inert gases. We show that Xe and N 2O bind to, compete for, and expand the volume of a hydrophobic cavity located just behind the active site of urate oxidase and further inhibit urate oxidase enzymatic activity. By demonstrating a significant relationship between the binding and biochemical effects of Xe and N 2O, given alone or in combination, these data from structure to function highlight the mechanisms by which chemically and metabolically inert gases can alter protein function and produce their pharmacological effects. Interestingly, the effects of a Xe:N 2O equimolar mixture were found to be equivalent to those of Xe alone, thereby suggesting that gas mixtures containing Xe and N 2O could be an alternative and efficient neuroprotective strategy to Xe alone, whose widespread clinical use is limited due to the cost of production and availability of this gas. © FASEB.

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