Tumor-specific cytotoxicity and type of cell death induced by benzo[b]cyclohept[e][1,4]oxazine and 2-aminotropone derivatives.

Abstract

A total of twenty benzo[b]cyclohept[e] [1,4]oxazines and their S-analogs, and 2-aminotropone derivatives were investigated for their cytotoxicity against three human normal cells and four tumor cell lines. These compounds showed moderate tumor-specific cytotoxicity. The cytotoxicity was enhanced by bromination at the tropone ring and replacement by formylbenzene. The cytotoxicity of 2-(2-hydroxyanilino) tropone was enhanced by introduction of bromine or isopropyl group to the tropone ring. The presence of a hydroxyl group at ortho or para-position should be necessary for the appearance of cytotoxicity and tumor-specificity. The highly active derivatives, 7-bromo-2-(4-hydroxyanilino)tropone [16] and 4-isopropyl-2-(2-hydroxyanilino)tropone [20], induced internucleosomal DNA fragmentation and caspase-3, -8 and -9 activation in human promyelocytic leukemia HL-60 cells, but only at concentrations twice or four times higher than CC(50) values. These compounds induced no discernible DNA fragmentation, and activated caspases much more weakly in human oral squamous cell carcinoma HSC-2 cells. Both [16] and [20] failed to induce the production of acidic organelles, a marker of autophagy, in contrast to the nutritional starvation. These data demonstrated that 2-aminotropones showed relatively higher tumor-specificity than benzo[b]cyclohept[e] [1,4]oxazine, and that 2-aminotropones induced little or no apoptotic cell death in oral squamous cell carcinoma, in contrast to HL-60 cells.

• Authors: Taichi Narita, Akina Suga, Masaki Kobayashi, Ken Hashimoto, Hiroshi Sakagami, Noboru Motohashi, Teruo Kurihara, Hidetsugu Wakabayashi
• Journal: Anticancer research (Anticancer Res) Vol. 29 Issue 4 Pg. 1123-30 (Apr 2009) ISSN: 0250-7005 [Print] Greece
• PMID: 19414354 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-aminotropone
• 4-isopropyl-2-(2-hydroxyanilino)tropone
• 7-bromo-2-(4-hydroxyanilino)tropone
• Tropolone
• Caspases

Topics

• Carcinoma, Squamous Cell (drug therapy, metabolism, pathology)
• Caspases (metabolism)
• Cell Death (drug effects)
• Cells, Cultured
• Drug Screening Assays, Antitumor
• Enzyme Activation (drug effects)
• Fibroblasts (drug effects)
• Humans
• Mouth Neoplasms (drug therapy, metabolism, pathology)
• Tropolone (analogs & derivatives, chemical synthesis, chemistry, pharmacology)