Synthesis and biological evaluation of 4-methylideneisoxazolidin-5-ones – A new class of highly cytotoxic α-methylidene-γ-lactones
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- 作者：Marek Ró ; ż ; alski ; Urszula Krajewska ; Mariusz Panczyk ; Marek Mirowski ; Barbara Ró ; ż ; alska ; Tomasz Wą ; sek ; Tomasz Janecki
- 关键词：Methylideneisoxazolidinones ; Cytotoxicity ; Apoptosis ; Multidrug resistance ; Antimicrobial activity
- 刊名：European Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：February 2007
- 年：2007
- 卷：42
- 期：2
- 页码：248-255
- 全文大小：377 K
文摘
Two 4-methylideneisoxazolidin-5-ones (4a,b), which are α-methylidene-γ-lactones containing a nitrogen atom in the lactone ring, were synthesized. Their cytotoxic properties were evaluated against promyelocytic leukemia HL-60 cells. Both 4a and 4b exhibited relatively high cytotoxic activity with an IC50 of 4.1 and 5.4 μM, respectively. Caspase-3 activity assay revealed that both isoxazolidinones (4) were able to induce apoptosis process in time- and concentration-dependent manner. Using multiplex PCR analysis, it was observed that 4 caused distinct inhibition of BCL-2 gene expression. Expression of BAX, a pro-apoptotic gene remained unchanged. It was also found that 4a,b did not induce the expression of MDR1 and MRP1 genes, related to multidrug resistance. In addition, cytotoxicity data obtained for drug-sensitive and drug-resistant HL-60 ADR cells revealed that the investigated compounds were poor substrates for transport by MRP1 efflux pump, suggesting that they might be useful for treating drug-resistant tumors. Furthermore, antimicrobial properties of 4a,b were evaluated. They showed significant activity against fungi Candida albicans, but only a weak activity against all tested Gram-positive and Gram-negative bacterial strains.