title: Amino acids derived benzoxazepines: design, synthesis and antitumor activity.
abstract: 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.
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, 10 Janakipuram Extension, Sitapur Road, Lucknow 226031, UP, India.
authors.forename: Shailendra Kumar Dhar
authors.initials: SK
authors.lastname: Dwivedi
authors.forename: Krishnananda
authors.initials: K
authors.lastname: Samanta
authors.forename: Manisha
authors.initials: M
authors.lastname: Yadav
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Jana
authors.forename: Abhishek Kumar
authors.initials: AK
authors.lastname: Singh
authors.forename: Bandana
authors.initials: B
authors.lastname: Chakravarti
authors.forename: Sankalan
authors.initials: S
authors.lastname: Mondal
authors.forename: Rituraj
authors.initials: R
authors.lastname: Konwar
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Trivedi
authors.forename: Naibedya
authors.initials: N
authors.lastname: Chattopadhyay
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Sanyal
authors.forename: Gautam
authors.initials: G
authors.lastname: Panda
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D010077:Oxazepines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D010077:Oxazepines
keywords: Amino acids; Anticancer activity; Benzoxazepine; Capasase; Mitsunobu reaction