Synthesis and biological evaluation of thiobenzanilides as anticancer agents.
A series of novel thiobenzanilides is described. These compounds have been previously found to show strong biological activity such as antimycotic and antifungal actions. This is the first demonstration on the mechanism of the anticancer effect of thiobenzanilide agents (4a-c) on human melanoma A375 cells. The cytotoxic studies of compounds 4a-c on human melanoma A375 cells indicate thiobenzanilides induced higher cytotoxicity than nitrobenzanilides (3a-c). In addition, DNA flow cytometric analysis shows that 4a-c displays a significant G2/M phase arrest, which progresses to early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide (PI). Because cellular apoptosis is often preceded by the disruption of mitochondrial function, the assessment of mitochondrial function in 4a-c-treated cells is worthy of investigation. Our data revealed that treatment of A375 cells with 4a-c resulted in the loss of mitochondrial membrane potential (DeltaPsi(mt)), a reduction of ATP synthesis, increased reactive oxygen species (ROS) generation, and activation of caspase-3. Thus, we suggest that 4a-c agents are potent inducers of cell apoptosis in A375 cells.
Hu
Wan-Ping
WP
Faculty of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
Yu
Hsin-Su
HS
Chen
Yan-Ren
YR
Tsai
Yi-Min
YM
Chen
Yin-Kai
YK
Liao
Chao-Cheng
CC
Chang
Long-Sen
LS
Wang
Jeh-Jeng
JJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry / Q000379:methods; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D017382:Reactive Oxygen Species / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000813:Anilides; D000970:Antineoplastic Agents; D001549:Benzamides; D004272:DNA, Mitochondrial; C530906:N-(4-bromo-phenyl)-4-nitrothiobenzamide; C530907:N-(4-nitrophenyl)-4-nitrothiobenzamide; C530908:N-(4-trifluoromethyl-phenyl)-4-nitrothiobenzamide; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; C034595:benzanilide; D053148:Caspase 3