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
posted on 2005-06-30, 00:00authored byMargaret M. Mc Gee, Sandra Gemma, Stefania Butini, Anna Ramunno, Daniela M. Zisterer, Caterina Fattorusso, Bruno Catalanotti, Gagan Kukreja, Isabella Fiorini, Claudio Pisano, Carla Cucco, Ettore Novellino, Vito Nacci, D. Clive Williams, Giuseppe Campiani
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.