Antiproliferative activity of a series of 5-(1H-1,2,3-triazolyl) methyl- and 5-acetamidomethyl-oxazolidinone derivatives

Abstract

In the face of increasing resistance to the existing antibiotics, oxazolidinones (exemplified by linezolid) have been developed as promising antibacterial agents, but may have other useful actions. In the present study, a series of 5‑(1H‑1,2,3‑triazoly) l‑methyl‑, 5‑acetamidomethyl‑morpholino and N‑substituted‑piperazino oxazolidinone derivatives were investigated to determine whether they are active against eukaryotic cells. An MTT assay, validated by cell counting, was used to assess the effect of nine oxazolidinone derivatives (concentrations 100 nM‑10 µM) on the proliferation of MCF7 human breast cancer cells. The three most active compounds were then tested on MDA231 breast cancer cells. Cytotoxicity of the selected derivatives was determined by assessing the extent of apoptosis by flow cytometry. The antimetastatic potential of these compounds was assessed on MDA231 cells using wound healing and agarose invasion assays. The 5‑triazolylmethyl piperazino‑oxazolidinone derivatives containing 4‑N‑(2‑chlorocinnamoyl), 4‑N‑(4‑nitrobenzoyl) and 4‑N‑methylsulfonyl moieties exhibited the most potent cytostatic activity against cancer, inhibiting proliferation by up to 70%, in the same order as their reported antibacterial activity against Staphylococcus aureus, but at higher concentrations. Unexpectedly, several derivatives stimulated proliferation at 100 nM, well below their antibacterial minimum inhibitory concentrations. Certain compounds also retarded the motility and invasion of MDA231 cells. Three of the tested derivatives had no effect on the eukaryotic cell lines, demonstrating their preferential activity against bacteria. Two compounds actually stimulated eukaryotic cell proliferation. The remaining three exhibited potent cytostatic activity against and cancer cells, displaying differences in response at low and high concentrations, which may suggest multiple targets on eukaryotic cells. These latter compounds may be useful as anticancer agents.

5-(Carbamoylmethylene)-oxazolidin-2-ones as a Promising Class of Heterocycles Inducing Apoptosis Triggered by Increased ROS Levels and Mitochondrial Dysfunction in Breast and Cervical Cancer

“…Very recently, dehydroabietic acid oxazolidinone hybrids have shown to exert a promising antiproliferative activity on several human cancer cell lines, and a particular compound is able to induce apoptosis by causing an arrest of the cell cycle in the G1 phase [24]. Thus, development and evaluation of new oxazolidinones as possible anticancer agents is a very interesting ongoing research topic [23,25,26].…”

Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment

“…The effects of a recent class of antibiotics, oxazolidinones, from the progenitor linezolid, have been widely reported the scientific literature. These molecules have been found to potently inhibit mitochondrial protein synthesis [ 156 ], altering the fine homeostasis of this organelle, thus generating ROS and inducing apoptosis in cancer cells [ 157 , 158 , 159 ].…”

Development and Validation of Stability-Indicating Assay Method for a Novel Oxazolidinone (PH-192) with Anticonvulsant Activity by Using UHPLC-QToF-MS

“…Oxazolidinone derivatives are exemplified by the presence of a five-membered heterocyclic ring system which has been identified as an important pharmacophoric group associated with the pharmacological properties of some clinically used drugs, namely, antibacterial, anticoagulant, and psychoactive agents [ 4 , 6 , 7 , 8 , 9 , 10 ]. Furthermore, systematic structural modification around the phenyl-oxazolidinone scaffold has yielded novel compounds with anticancer, antiepileptic, antithyroid, and more recently 5-lipoxygenase inhibitory properties [ 9 , 11 , 12 , 13 , 14 , 15 ]. The oxazolidinone-containing antibacterial agents, namely, linezolid 1 and tedizolid (2, Figure 1 ), have demonstrated clinical success with regards to their efficacy and safety profiles against susceptible and resistant Gram-positive cocci [ 16 , 17 , 18 , 19 ].…”