Novel Benzopyridothiadiazepines as Potential Active Antitumor Agents

• Published in: Journal of medicinal chemistry 2005-11, Vol.48 (23), p.7363-7373
• Main Authors: Lebegue, Nicolas, Gallet, Sebastien, Flouquet, Nathalie, Carato, Pascal, Pfeiffer, Bruno, Renard, Pierre, Léonce, Stéphane, Pierré, Alain, Chavatte, Philippe, Berthelot, Pascal
• Format: Article
• Language: English
• Subjects: Aminophenols - chemistry; Animals; Antimitotic Agents - chemical synthesis; Antimitotic Agents - chemistry; Antimitotic Agents - pharmacology; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Chemical Sciences; Cyclic S-Oxides - chemical synthesis; Cyclic S-Oxides - chemistry; Cyclic S-Oxides - pharmacology; Drug Screening Assays, Antitumor; General aspects; Heterocyclic Compounds, 3-Ring - chemical synthesis; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacology; Medical sciences; Mice; Pharmacology. Drug treatments; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Thiazepines - chemical synthesis; Thiazepines - chemistry; Thiazepines - pharmacology; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0503897

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, 4 g, 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 μM compared to 2.4 μM 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.