Hedaya Omar M, Mathew Princy M, Mohamed Fatima H, Phillips Oludotun A, Luqmani Yunus A
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Safat 13110, Kuwait.
Mol Med Rep. 2016 Apr;13(4):3311-8. doi: 10.3892/mmr.2016.4938. Epub 2016 Feb 23.
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.
面对现有抗生素的耐药性不断增加的情况，恶唑烷酮类药物（以利奈唑胺为代表）已被开发为有前景的抗菌剂，但可能还有其他有益作用。在本研究中，研究了一系列5-（1H-1,2,3-三唑基）甲基-、5-乙酰氨基甲基-吗啉代和N-取代哌嗪基恶唑烷酮衍生物，以确定它们对真核细胞是否有活性。采用经细胞计数验证的MTT法，评估9种恶唑烷酮衍生物（浓度为100 nM - 10 μM）对MCF7人乳腺癌细胞增殖的影响。然后在MDA231乳腺癌细胞上测试三种活性最高的化合物。通过流式细胞术评估凋亡程度来确定所选衍生物的细胞毒性。使用伤口愈合和琼脂糖侵袭试验在MDA231细胞上评估这些化合物的抗转移潜力。含有4-N-（2-氯肉桂酰基）、4-N-（4-硝基苯甲酰基）和4-N-甲基磺酰基部分的5-三唑基甲基哌嗪基恶唑烷酮衍生物对癌症表现出最有效的细胞生长抑制活性，抑制增殖高达70%，与其对金黄色葡萄球菌的抗菌活性顺序相同，但浓度更高。出乎意料的是，几种衍生物在100 nM时刺激增殖，远低于其抗菌最低抑菌浓度。某些化合物还抑制了MDA231细胞的运动性和侵袭性。三种测试衍生物对真核细胞系无影响，表明它们对细菌具有优先活性。两种化合物实际上刺激了真核细胞增殖。其余三种对癌细胞表现出有效的细胞生长抑制活性，在低浓度和高浓度下反应不同，这可能表明在真核细胞上有多个靶点。后一种化合物可能用作抗癌剂。
