Novel lipophilic 7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid derivatives as potential antitumor agents: Improved synthesis and in vitro evaluation

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• 作者：Alex ; er Korolyov ; S ; ra Dorbes ; Joë ; lle Azé ; ma ; Brigitte Guidetti ; Mathieu Danel ; Delphine Lamoral-Theys ; Thierry Gras ; Jacques Dubois ; Robert Kiss ; Robert Martino ; Myriam Malet-Martino
• 关键词：Fluoroquinolones ; Lipophilic levofloxacin derivatives ; Microwave-assisted synthesis ; In vitro antitumor activity
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2010
• 出版时间：15 December 2010
• 年：2010
• 卷：18
• 期：24
• 页码：8537-8548
• 全文大小：473 K

文摘

A convenient route for the synthesis of some acyloxymethyl esters and carboxamides of levofloxacin (LV) with modulated lipophilicity is described. The synthesized compounds were evaluated in vitro for their growth inhibitory effect in five human cancer cell lines. The most efficient LV derivatives (ester 2e and amide 4d) displayed IC₅₀ values in the 0.2–2.2 μM range, while IC₅₀ values for parent LV ranged between 70 and 622 μM depending on the cell line. The esters displayed no in vivo toxicity up to 80 mg/kg when administered intraperitoneally. This study thus shows that LV analogs displayed antitumor efficacy, at least in vitro, a feature that appeared to be independent from the lipophilicity of the grafted substituent.