Benzopyridooxathiazepine derivatives as novel potent antimitotic agents.

Abstract

Herein, we describe the structure-activity relationship study of a new 1-(arylalkyl)-11H-benzo[f]-1,2-dihydropyrido[3,2,c][1,2,5]oxathiazepine 5,5-dioxide series of antimitotic agents. The pharmacological results obtained from previous works allowed us to identify compound 1 as a new cytotoxic agent inhibiting tubulin polymerization. We have undertaken the synthesis of its non-methylated analogue 7 and have extended our investigations to a novel, structurally related benzopyridooxathiazepine dioxide series. Among all analogues synthesized in this study, compound 10b was the most promising, being 12-fold more potent than compound 1. Its activity over a panel of five tumoral cell lines was in the nanomolar range for all of the histological types tested and flow cytometric studies performed on L1210 cells showed an accumulation of the cells in the G2/M phases of the cell cycle with a significant percentage of tetraploid cells (8N DNA content). This interesting pharmacological profile, resulting from inhibition of tubulin polymerization, encouraged us to perform preliminary in vivo studies.

• Authors: Sebastien Gallet, Nathalie Flouquet, Pascal Carato, Bruno Pfeiffer, Pierre Renard, Stéphane Léonce, Alain Pierré, Pascal Berthelot, Nicolas Lebegue
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 17 Issue 3 Pg. 1132-8 (Feb 01 2009) ISSN: 1464-3391 [Electronic] England
• PMID: 19162484 (Publication Type: Journal Article)

Chemical References

• Antimitotic Agents
• Antineoplastic Agents
• Thiazepines
• Tubulin Modulators

Topics

• Animals
• Antimitotic Agents (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Cycle
• Cell Line, Tumor
• Humans
• Mice
• Structure-Activity Relationship
• Thiazepines (chemical synthesis, chemistry, pharmacology)
• Tubulin Modulators (chemical synthesis, chemistry, pharmacology)