Synthesis of new imidazole-triazole-glycoside hybrids as anti-breast cancer candidates

Abstract

One of the leading causes of death worldwide among women is breast cancer. Thus, discovering new multi-target anti-breast cancer drugs is mandatory to stimulate nitric oxide (NO) and cyclooxygenase-2 (COX-2) as a cross-talking strategy for killing breast cancerous cells. 1-(3-(4-bromophenyl)-5-methyl-2-thioxo-2,3-dihydro-1H -imidazol-4-yl)ethan-1-one 1 was prepared and allowed to react with various alkyl halide propargyl bromide; 1,2-dibromoethane; and 1,3-dichloropropane to afford the corresponding alkyl imidazolo derivatives 2, and 14a,b respectively; Compound 2 allowed to react undergoes click reaction condition afforded the corresponding 1,2,3-triazole-N-acetylated glycosides 4 and 5 which reacted with methanolic ammonia solution to obtain free hydroxyl 1,2,3-triazole N-glycosides 6 and 7; respectively. Also, Compounds 14a,b reacted with sodium azide to give the azido derivatives 15,16; which reacted under click reaction condition to produce 1,2,3-triazole-C-glycosides compounds 18-21, respectively. Meanwhile, the previous compounds can be deacetylated to afford the free hydroxyl thioglycosides 22-25. Moreover, the thioglycoside derivatives of compound 1 were synthesized and underwent glycosylation conditions utilizing acetylated glycosyl bromides to give S-glycoside analogs 8-10 which proceeded to undergo deacetylated condition to obtain free hydroxyl imidazolo- S-glycosides 11-13; respectively. All newly synthesized compounds were tested against human breast MCF-7 and MDA-MB-231 cancerous cell lines. Cytotoxicity using MTT assay was performed as well as IC50 was measured for all candidates. Then, nitric oxide (NO) levels and cyclooxygenase-2 (COX-2) enzyme activity were investigated in the proposed cancerous cells. We resulted that the prepared compounds were more cytotoxic against MDA-MB-231 cells than MCF-7 cells. MCF-7 breast cancerous cells were resistant to doxorubicin in addition to the applied compounds, while MDA-MB-231 cells were sensitive. It was reported that compounds 22, 12, and 6 recorded the highest cytotoxic effects against both cancer cell lines. The signaling crosstalk between NO and COX-2 in cancer cells achieved that compounds 12 and 22 induced the significant elevation of NO levels in MCF-7 cells which in turn inhibited the COX-2 enzyme activity. In conclusion, the newly prepared compounds containing an imidazole nucleus have anti-breast cancer potential through modulation of NO and COX-2 signaling track.