Potent Farnesyltransferase Inhibitors with 1,4-Diazepane Scaffolds as Novel Destabilizing Microtubule Agents in Hormone-Resistant Prostate Cancer

Potent Farnesyltransferase Inhibitors with 1,4-Diazepane Scaffolds as Novel Destabilizing Microtubule Agents in Hormone-Resistant Prostate Cancer

A new class of potent farnesyltransferase inhibitors based on a 1,4-diazepane scaffold was synthesized with protein farnesyltransferase inhibition potencies in the low nanomolar range. The compounds block the growth on two hormone-resistant tumor prostatic cell lines (DU145 and PC3). The advanced ce...

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Veröffentlicht in:Journal of medicinal chemistry 2011-03, Vol.54 (5), p.1178-1190
Hauptverfasser: Wlodarczyk, Nicolas, Le Broc-Ryckewaert, Delphine, Gilleron, Pauline, Lemoine, Amélie, Farce, Amaury, Chavatte, Philippe, Dubois, Joëlle, Pommery, Nicole, Hénichart, Jean-Pierre, Furman, Christophe, Millet, Régis
Format: Artikel
Sprache:eng
Schlagworte:
Androgen Antagonists - therapeutic use
Azepines - chemical synthesis
Azepines - pharmacokinetics
Azepines - pharmacology
Cell Line
Cell Line, Tumor
Chemical Sciences
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Farnesyltranstransferase - antagonists & inhibitors
Humans
Hydrophobic and Hydrophilic Interactions
Male
Models, Molecular
Organic chemistry
Prostatic Neoplasms - drug therapy
Structure-Activity Relationship
Tubulin - drug effects
Tubulin - ultrastructure
Tubulin Modulators - chemical synthesis
Tubulin Modulators - pharmacokinetics
Tubulin Modulators - pharmacology
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Zusammenfassung:A new class of potent farnesyltransferase inhibitors based on a 1,4-diazepane scaffold was synthesized with protein farnesyltransferase inhibition potencies in the low nanomolar range. The compounds block the growth on two hormone-resistant tumor prostatic cell lines (DU145 and PC3). The advanced cellular evaluation of the more potent farnesyltransferase inhibitors was explored and revealed a disorganization of tubulin in PC3 cells.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm101067y