Abstract
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 tubulin 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.
Keywords: Phenstatin, liver microsomes, metabolites, prostate cancer, tubilin polymerization, benzophenone, Combretastatin A-4 (CA-4) analogue, cytotoxicity, antiproliferative activity, electrospray mass spectrometry
Drug Metabolism Letters
Title: In Vitro Metabolism of Phenstatin: Potential Pharmacological Consequences
Volume: 5 Issue: 3
Author(s): Delphine Le Broc-Ryckewaert, Nicole Pommery, Jean Pommery, Alina Ghinet, Amaury Farce, Jean-Francois Wiart, Philippe Gautret, Benoit Rigo and Jean-Pierre Henichart
Affiliation:
Keywords: Phenstatin, liver microsomes, metabolites, prostate cancer, tubilin polymerization, benzophenone, Combretastatin A-4 (CA-4) analogue, cytotoxicity, antiproliferative activity, electrospray mass spectrometry
Abstract: 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 tubulin 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.
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Cite this article as:
Le Broc-Ryckewaert Delphine, Pommery Nicole, Pommery Jean, Ghinet Alina, Farce Amaury, Wiart Jean-Francois, Gautret Philippe, Rigo Benoit and Henichart Jean-Pierre, In Vitro Metabolism of Phenstatin: Potential Pharmacological Consequences, Drug Metabolism Letters 2011; 5 (3) . https://dx.doi.org/10.2174/187231211796904973
DOI https://dx.doi.org/10.2174/187231211796904973 |
Print ISSN 1872-3128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1874-0758 |
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