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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

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Margaret 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,^# and Giuseppe Campiani*^‡^‖

Department of Biochemistry, Trinity College, Dublin 2, Ireland, Dipartimento Farmaco Chimico Tecnologico, via Aldo Moro, and European Research Centre for Drug Discovery and Development, Università di Siena, 53100 Siena, Italy, Dipartimento di Chimica delle Sostanze Naturali and Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II, via D. Montesano 49, 80131 Napoli, Italy, and Sigma-Tau Industrie Farmaceutiche Riunite, via Pontina Km 30,400, 00040 Pomezia, Italy

J. Med. Chem., 2005, 48 (13), pp 4367–4377

DOI: 10.1021/jm049402y

Publication Date (Web): May 27, 2005

Section:

Heterocyclic Compounds (More than One Hetero Atom)

Abstract

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.

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This article has been cited by 2 ACS Journal articles (2 most recent appear below).

Non-Nucleoside Inhibitors of Human Adenosine Kinase: Synthesis, Molecular Modeling, and Biological Studies
Stefania Butini, Sandra Gemma, Margherita Brindisi, Giuseppe Borrelli, Andrea Lossani, Anna Maria Ponte, Andrea Torti, Giovanni Maga, Luciana Marinelli, Valeria La Pietra, Isabella Fiorini, Stefania Lamponi, Giuseppe Campiani, Daniela M. Zisterer, Seema-Maria Nathwani, Stefania Sartini, Concettina La Motta, Federico Da Settimo, Ettore Novellino, and Federico Focher
Journal of Medicinal Chemistry2011 54 (5), 1401-1420
- Non-Nucleoside Inhibitors of Human Adenosine Kinase: Synthesis, Molecular Modeling, and Biological Studies
  Stefania Butini, Sandra Gemma, Margherita Brindisi, Giuseppe Borrelli, Andrea Lossani, Anna Maria Ponte, Andrea Torti, Giovanni Maga, Luciana Marinelli, Valeria La Pietra, Isabella Fiorini, Stefania Lamponi, Giuseppe Campiani, Daniela M. Zisterer, Seema-Maria Nathwani, Stefania Sartini, Concettina La Motta, Federico Da Settimo, Ettore Novellino, and Federico Focher
  Journal of Medicinal Chemistry2011 54 (5), 1401-1420
  Adenosine kinase (AK) catalyzes the phosphorylation of adenosine (Ado) to AMP by means of a kinetic mechanism in which the two substrates Ado and ATP bind the enzyme in a binary and/or ternary complex, with distinct protein conformations. Most of the ...
  Abstract | Full Text HTML | Hi-Res PDF | PDF w/ Links
Palladium-Catalyzed Domino C−C/C−N Coupling Using a Norbornene Template: Synthesis of Substituted Benzomorpholines, Phenoxazines, and Dihydrodibenzoxazepines
Praew Thansandote, Eugene Chong, Kai-Oliver Feldmann and Mark Lautens
The Journal of Organic Chemistry2010 75 (10), 3495-3498
- Palladium-Catalyzed Domino C−C/C−N Coupling Using a Norbornene Template: Synthesis of Substituted Benzomorpholines, Phenoxazines, and Dihydrodibenzoxazepines
  Praew Thansandote, Eugene Chong, Kai-Oliver Feldmann and Mark Lautens
  The Journal of Organic Chemistry2010 75 (10), 3495-3498
  A rapid, four-step approach to alkyl- and aryl-substituted benzomorpholines is accomplished by a Pd-catalyzed domino C−C/C−N bond coupling using a norbornene template. Extension to phenoxazines and dihydrodibenzoxazepines is presented.
  Abstract | Full Text HTML | Hi-Res PDF | PDF w/ Links