In vitro metabolism of phenstatin: potential ...
Type de document :
Article dans une revue scientifique
PMID :
URL permanente :
Titre :
In vitro metabolism of phenstatin: potential pharmacological consequences.
Auteur(s) :
Le Broc-Ryckewaert, Delphine [Auteur]
Pommery, Nicole [Auteur]
Pommery, Jean [Auteur]
Ghinet, Alina [Auteur]
Farce, Amaury [Auteur]
Wiart, Jean-Francois [Auteur]
Gautret, Philippe [Auteur]
Rigo, Benoit [Auteur]
Henichart, Jean-Pierre [Auteur]
Pommery, Nicole [Auteur]
Pommery, Jean [Auteur]
Ghinet, Alina [Auteur]

Farce, Amaury [Auteur]

Wiart, Jean-Francois [Auteur]
Gautret, Philippe [Auteur]
Rigo, Benoit [Auteur]
Henichart, Jean-Pierre [Auteur]
Titre de la revue :
Drug metabolism letters
Nom court de la revue :
Drug Metab Lett
Numéro :
5
Pagination :
209-15
Date de publication :
2011-08-01
ISSN :
1874-0758
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
Phenstatin and its derivatives are potential anticancer drug candidates according to their inhibitory properties on tubulin polymerization, cell growth and antivascular activity. However, at the present time, neither ...
Lire la suite >Phenstatin and its derivatives are potential anticancer drug candidates according to their inhibitory properties on tubulin polymerization, cell growth and antivascular activity. However, at the present time, neither pharmacological nor metabolic studies have been conducted in order to strengthen the relevance of phenstatine as a drug discovery candidate. In the present work, the metabolic fate of phenstatin in rat and human microsomal preparations was studied to investigate the stability of this tubulin polymerization inhibitor and any effects of the metabolites on polymerization and on PC3 cancer cell proliferation. The metabolites were separated by high-performance liquid chromatography and, after their synthesis, characterized by simultaneous LC-DAD-UV and LC-ESI-MS analyses. Thus, eight metabolites were identified. The major biotransformation pathways are carbonyl reduction, O-methylation at C-3', O-methylation after aromatic hydroxylation at the position C-2' on phenyl B ring and O-demethylation on A ring. Four of the identified metabolites were as active or more active, than phenstatin in vitro. Moreover, the better stability of phenstatin versus CA-4 and the lack of quinone formation could justify the design of new analogues which could include various substituents on phenyl rings or linker group in order to modulate the metabolism of phenstatin toward even more active metabolites and so up-regulate the pharmacological activity.Lire moins >
Lire la suite >Phenstatin and its derivatives are potential anticancer drug candidates according to their inhibitory properties on tubulin polymerization, cell growth and antivascular activity. However, at the present time, neither pharmacological nor metabolic studies have been conducted in order to strengthen the relevance of phenstatine as a drug discovery candidate. In the present work, the metabolic fate of phenstatin in rat and human microsomal preparations was studied to investigate the stability of this tubulin polymerization inhibitor and any effects of the metabolites on polymerization and on PC3 cancer cell proliferation. The metabolites were separated by high-performance liquid chromatography and, after their synthesis, characterized by simultaneous LC-DAD-UV and LC-ESI-MS analyses. Thus, eight metabolites were identified. The major biotransformation pathways are carbonyl reduction, O-methylation at C-3', O-methylation after aromatic hydroxylation at the position C-2' on phenyl B ring and O-demethylation on A ring. Four of the identified metabolites were as active or more active, than phenstatin in vitro. Moreover, the better stability of phenstatin versus CA-4 and the lack of quinone formation could justify the design of new analogues which could include various substituents on phenyl rings or linker group in order to modulate the metabolism of phenstatin toward even more active metabolites and so up-regulate the pharmacological activity.Lire moins >
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
CHU Lille
Inserm
Université de Lille
Inserm
Université de Lille
Équipe(s) de recherche :
Therapeutic innovation targetting inflammation
Date de dépôt :
2019-05-17T13:14:49Z