Pyrrolo[1,5]benzoxa(thia)zepines as a New Class of Potent Apoptotic Agents. Biological Studies and Identification of an Intracellular Location of Their Drug Target
Autor: | Carla Cucco, C. Pisano, D. Clive Williams, Vito Nacci, Daniela M. Zisterer, Ettore Novellino, Margaret M. Mc Gee, Stefania Butini, Caterina Fattorusso, Sandra Gemma, Giuseppe Campiani, Bruno Catalanotti, Gagan Kukreja, Isabella Fiorini, Anna Ramunno |
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Přispěvatelé: | Mcgee, M., Gemma, S., Butini, S., Ramunno, A., Zisterer, D. M., Fattorusso, Caterina, Catalanotti, Bruno, Kukreja, G., Fiorini, I., Pisano, C., Cucco, C., Novellino, Ettore, Nacci, V., Williams, D. C., Campiani, G. |
Rok vydání: | 2005 |
Předmět: |
Models
Molecular Thiazepines Antineoplastic Agents Apoptosis HL-60 Cells In vivo Cell Line Tumor Drug Discovery medicine Humans Cytotoxic T cell Cytotoxicity Molecular Structure Chemistry Biological Transport In vitro Benzoxazines Mechanism of action Biochemistry Cell culture Drug Design Cancer research Molecular Medicine medicine.symptom K562 Cells Intracellular |
Zdroj: | Journal of Medicinal Chemistry. 48:4367-4377 |
ISSN: | 1520-4804 0022-2623 |
Popis: | We have recently developed five novel pyrrolo-1,5-benzoxazepines as proapoptotic agents. Their JNK-dependent induction of apoptosis in tumor cells suggested their potential as novel anticancer agents. The core structure of the apoptotic agent 6 was investigated, and the SARs were expanded with the design and synthesis of several analogues. To define the apoptotic mechanism of the new compounds and the localization of their drug target, two analogues of 6 were designed and synthesized to delineate events leading to JNK activation. The cell-penetrating compound 16 induced apoptosis in tumor cells, while its nonpenetrating analogue, 17, was incapable of inducing apoptosis or activating JNK. Plasma membrane permeabilization of tumor cells resulted in 17-induced JNK activation, suggesting that the pyrrolo-1,5-benzoxazepine molecular target is intracellular. Interestingly, compound 6 displayed cytotoxic activity against a panel of human tumor cell lines but demonstrated negligible toxicity in vivo with no effect on the animals' hematology parameters. |
Databáze: | OpenAIRE |
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