Novel benzopyridothiadiazepines as potential active antitumor agents.

Abstract

The synthesis of novel thiadiazepine derivatives, that could be considered as constraint analogues of E-7010, are reported. These molecules were evaluated for their antiproliferative activity toward the murine L1210 leukemia cell line. Flow cytometric studies performed on L1210 cells with the most cytotoxic compounds 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). Submicromolar cytotoxicities were observed with compounds 2b, 4b, 4e, 4g, and 4i. Two of them, compounds 2b and 4b, were found to be potent inhibitors of tubulin polymerization with IC50 of respectively 3.8 and 2.4 microM compared to 2.4 microM for desoxypodophyllotoxin. A 4-methoxyphenylethyl substitution on the pyridinyl nitrogen of the benzopyridothiadiazepine was found to be essential for the antiproliferative activity. The in vitro activities of compounds 2b and 4b make benzopyridothiadiazepine dioxides a promising new class of tubulin binders which warrant further in vivo evaluation.

• Authors: Nicolas Lebegue, Sebastien Gallet, Nathalie Flouquet, Pascal Carato, Bruno Pfeiffer, Pierre Renard, Stéphane Léonce, Alain Pierré, Philippe Chavatte, Pascal Berthelot
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 23 Pg. 7363-73 (Nov 17 2005) ISSN: 0022-2623 [Print] United States
• PMID: 16279796 (Publication Type: Journal Article)

Chemical References

• 1-(4-methoxyphenylethyl)-6-methylbenzo(c)-1,2-dihydropyrido(2,3-f)(1,2,5)thiadiazepine 5,5-dioxide
• Aminophenols
• Antimitotic Agents
• Antineoplastic Agents
• Cyclic S-Oxides
• Heterocyclic Compounds, 3-Ring
• Sulfonamides
• Thiazepines
• Tubulin Modulators
• E 7010

Topics

• Aminophenols (chemistry)
• Animals
• Antimitotic Agents (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cyclic S-Oxides (chemical synthesis, chemistry, pharmacology)
• Drug Screening Assays, Antitumor
• Heterocyclic Compounds, 3-Ring (chemical synthesis, chemistry, pharmacology)
• Mice
• Structure-Activity Relationship
• Sulfonamides (chemical synthesis, chemistry, pharmacology)
• Thiazepines (chemical synthesis, chemistry, pharmacology)
• Tubulin Modulators (chemical synthesis, chemistry, pharmacology)