Discovery of a new family of bis-8-hydroxyquinoline substituted benzylamines with pro-apoptotic activity in cancer cells: synthesis, structure-activity relationship, and action mechanism studies.

Abstract

Bis-8-hydroxyquinoline substituted benzylamines have been synthesized and screened for their antitumor activity on KB3 cell line model. Synthesis of this series of new analogues was accomplished using a one pot specific methodology which allows the synthesis of both bis- and mono-8-hydroxyquinoline substituted benzylamines. Among the synthesized compounds two compounds (4a and 5a), respectively, named JLK 1472 and JLK 1486, were particularly potent on KB3 cell line. Their CC(50) values being, respectively, 2.6 and 1.3 nM. Screened on a panel of cell lines showing various phenotype alterations, both compounds were found inactive on some cell lines such as PC3 (prostate cell line) and SF268 (neuroblastoma cell line) while highly active on other different cell lines. Mechanistic studies reveal that these two analogues did not affect tubulin and microtubules neither they exert a proteasomal inhibition effect. In contrast 4a and 5a activate specifically caspase 3/7 and not caspase 8 and 9, suggesting that their biological target should be located upstream from caspase 3/7. Moreover their cytotoxic effect is potentiated by the pro-apoptotic effects of TRAIL.

• Authors: Vincent Moret, Younes Laras, Thierry Cresteil, Geneviève Aubert, Dou Q Ping, Chen Di, Magali Barthélémy-Requin, Christophe Béclin, Vincent Peyrot, Diane Allegro, Amandine Rolland, Francesca De Angelis, Evelina Gatti, Philippe Pierre, Luca Pasquini, Eleonora Petrucci, Ugo Testa, Jean-Louis Kraus
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 44 Issue 2 Pg. 558-67 (Feb 2009) ISSN: 1768-3254 [Electronic] France
• PMID: 18485536 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzylamines
• Hydroxyquinolines
• TNF-Related Apoptosis-Inducing Ligand
• Caspases

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Apoptosis (drug effects)
• Benzylamines (chemical synthesis, pharmacology)
• Caspases (drug effects)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Female
• Humans
• Hydroxyquinolines
• Male
• Structure-Activity Relationship
• TNF-Related Apoptosis-Inducing Ligand