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.
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.
Department of Biochemistry, Trinity College, Dublin 2, Ireland.
Margaret M
MM
Mc Gee
Sandra
S
Gemma
Stefania
S
Butini
Anna
A
Ramunno
Daniela M
DM
Zisterer
Caterina
C
Fattorusso
Bruno
B
Catalanotti
Gagan
G
Kukreja
Isabella
I
Fiorini
Claudio
C
Pisano
Carla
C
Cucco
Ettore
E
Novellino
Vito
V
Nacci
D Clive
DC
Williams
Giuseppe
G
Campiani
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001692:Biological Transport; D045744:Cell Line, Tumor; D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D013841:Thiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D048588:Benzoxazines; D013841:Thiazepines