Amino acids derived benzoxazepines: Design, synthesis and antitumor activity
| Autor: | Bandana Chakravarti, Gautam Panda, Manisha Yadav, Abhishek Singh, Sankalan Mondal, Sabyasachi Sanyal, Rituraj Konwar, Krishnananda Samanta, Shailendra Kumar Dhar Dwivedi, Naibedya Chattopadhyay, Amit Kumar Jana, Arun Kumar Trivedi |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Clinical Biochemistry
Mice Nude Pharmaceutical Science Antineoplastic Agents Apoptosis Breast Neoplasms Lithium aluminium hydride Biochemistry Mice chemistry.chemical_compound Cell Line Tumor Drug Discovery Animals Humans Amino Acids Tyrosine Molecular Biology Cell Proliferation chemistry.chemical_classification Cell growth Chemistry Organic Chemistry G1 Phase Cell Cycle Checkpoints Xenograft Model Antitumor Assays Amino acid Oxazepines Drug Design Cancer cell MCF-7 Cells Molecular Medicine SN2 reaction DNA fragmentation Female |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 23:6816-6821 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2013.10.013 |
| Popis: | Two series of new benzoxazepines substituted with different alkyl amino ethyl chains were synthesized comprising synthetic steps of inter and intramolecular Mitsunobu reaction, lithium aluminium hydride (LAH) reduction, debenzylation, bimolecular nucleophilic substitution (SN2) reaction. The present study investigates the effect of a tyrosine-based benzoxazepine derivative in human breast cancer cells MCF-7 and MDA-MB-231 and in breast cancer animal model. The anti-proliferative effect of 15a on MCF-7 cells was associated with G1 cell-cycle arrest. This G1 growth arrest was followed by apoptosis as 15a dose dependently increased phosphatidylserine exposure, PARP cleavage and DNA fragmentation that are hallmarks of apoptotic cell death. Interestingly, 15a activated components of both intrinsic and extrinsic pathways of apoptosis characterized by activation of caspase-8 and -9, mitochondrial membrane depolarization and increase in Bax/Bcl2 ratio. However, use of selective caspase inhibitors revealed that the caspase-8-dependent pathway is the major contributor to 15a-induced apoptosis. Compound 15a also significantly reduced the growth of MCF-7 xenograft tumors in athymic nude mice. Together, 15a could serve as a base for the development of a new group of effective breast cancer therapeutics. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect