New (RS)-benzoxazepin-purines with antitumour activity: The chiral switch from (RS)-2,6-dichloro-9-[1-(p-nitrobenzenesulfonyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-9H-purine

• DOI: 10.1016/j.ejmech.2010.11.011
• Publication Date: 2010-11-15T09:10:47Z
• Authors: Luisa C. López-Cara; Ana Conejo-García; Juan A. Marchal; Giuseppe Macchione; Olga Cruz-López; Houria Boulaiz; María A. García; Fernando Rodrígue...; Alberto Ramírez; Carlos Cativiela; Ana I. Jiménez; Juan M. García-Ruiz; Duane Choquesillo...; Antonia Aránega; Joaquín M. Campos
• Keywords: Mice, Inbred BALB C; 0303 health sciences; Cell Cycle; Antineoplastic Agents; Apoptosis; Stereoisomerism; 3. Good health; Inhibitory Concentration 50; Mice; Oxazepines; 03 medical and health sciences; Purines; Cell Line, Tumor; Animals; Humans; Female; Cell Proliferation

Completing an SAR study, a series of (RS)-6-substituted-7- or 9-(1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl)-7H or 9H-purines has been prepared under microwave-assisted conditions. Their antiproliferative activities on MCF-7 and MDA-MB-231 cancerous cell lines are presented, being the majority of the IC(50) values below 1μM. The most active compound (RS)-2,6-dichloro-9-[1-(p-nitrobenzenesulfonyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-9H-purine (14) presents an IC(50) of 0.166μM against the human cancerous cell line MDA-MB-231. Compound 14 was the most selective against the human breast adenocarcinoma MCF-7 and MDA-MB-231 cancer cell lines (Therapeutic Indexes, TIs=5.1 and 11.0, respectively) in relation to the normal one MCF-10A. (RS)-14 was resolved into its enantiomers. Both enantiomers are equally potent, but more potent than the corresponding racemic mixture. (R)-14 induces apoptosis against MCF-7 up to 52.50% of cell population after 48h, being more potent than the clinical-used drug paclitaxel (43%). (RS)-14 induces no acute toxicity in mice after two weeks of treatment.