Microwave-Assisted Syntheses of Benzimidazole-Containing Selenadiazole Derivatives That Induce Cell-Cycle Arrest and Apoptosis in Human Breast Cancer Cells by Activation of the ROS/AKT Pathway.
The use of selenium-containing heterocyclic compounds as potent cancer chemopreventive and chemotherapeutic agents has been well documented by a large number of clinical studies. In this study we developed a new approach to synthesize four benzimidazole-containing selenadiazole derivatives (BSeDs). The method uses a combination of peptide coupling reagents and microwave irradiation. This strategy features milder reaction conditions, higher yields, and shorter reaction times. The synthetic BSeDs were identified as potent antiproliferative agents against the human MCF-7 and MDA-MB-231 breast cancer cell lines. Compounds 1 b (5-(6-methyl-1H-benzo[d]imidazol-2-yl)benzo[c][1,2,5]selenadiazole), 1 c (5-(6-chloro-1H-benzo[d]imidazol-2-yl)benzo[c][1,2,5]selenadiazole), and 1 d (5-(6-bromo-1H-benzo[d]imidazol-2-yl)benzo[c][1,2,5]selenadiazole) were found to show greater cytotoxicity against the triple-negative breast cancer cell line MDA-MB-231 than MCF-7, and to exhibit dose-dependent inhibition of cell migration, in which a significant decrease in the zone of cell monolayer wound closure was observed relative to untreated controls. Our results demonstrate that BSeDs can cause cell-cycle arrest and apoptosis in MDA-MB-231 cells by inducing DNA damage, inhibiting protein kinase B (AKT), and activating mitogen-activated protein kinase (MAPK) family members through the overproduction of reactive oxygen species (ROS). Taken together, the results of this study provide a facile microwave-assisted strategy for the synthesis of selenium-containing organic compounds that exhibit a high level of anticancer efficacy.
Department of Chemistry, Jinan University, Guangzhou, 510632, P.R. China.
Yuanwei
Y
Liang
Department of Chemistry, Jinan University, Guangzhou, 510632, P.R. China.
Yangliang
Y
Zhou
Department of Chemistry, Jinan University, Guangzhou, 510632, P.R. China.
Shulin
S
Deng
Department of Chemistry, Jinan University, Guangzhou, 510632, P.R. China. tchentf@jnu.edu.cn.
Tianfeng
T
Chen
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008872:Microwaves; D015394:Molecular Structure; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001393:Azoles; D001562:Benzimidazoles; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; C031000:benzimidazole; D051057:Proto-Oncogene Proteins c-akt
apoptosis; benzimidazoles; microwave irradiation; reactive oxygen species; selenadiazoles