Comparison of Anti-Invasive Activity of Parthenolide and 3-Isopropyl-2-Methyl-4-Methyleneisoxazolidin-5-One (MZ-6) - A New Compound with α-Methylene-γ-Lactone Motif - on Two Breast Cancer Cell Lines

• Published in: Chemical biology & drug design 2012-01, Vol.79 (1), p.112-120
• Main Authors: Wyrębska, Anna, Gach, Katarzyna, Szemraj, Janusz, Szewczyk, Karolina, Hrabec, Elżbieta, Koszuk, Jacek, Janecki, Tomasz, Janecka, Anna
• Format: Article
• Language: English
• Subjects: anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Movement; Cell Survival - drug effects; Female; gene expression; Humans; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - toxicity; Lactones - chemistry; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; metastasis; Neoplasm Invasiveness; sesquiterpene lactones; Sesquiterpenes - chemical synthesis; Sesquiterpenes - chemistry; Sesquiterpenes - toxicity; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - metabolism; wound healing assay
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/j.1747-0285.2011.01257.x

The biological activities of parthenolide, a sesquiterpene lactone isolated from feverfew, have been attributed to the presence of the α‐methylene‐γ‐lactone skeleton. The lactone skeleton can react via the Michael type addition with sulfhydryl groups of enzymes and other functional proteins, interfering with key biological processes in the cell. In the present study, we describe an efficient method of preparation of 3‐isopropyl‐2‐methyl‐4‐methyleneisoxazolidin‐5‐one (MZ‐6), a synthetic compound with α‐methylene‐γ‐lactone ring, as in parthenolide, additionally modified by introduction of a nitrogen atom. Furthermore, we investigated the cytotoxic activity and anti‐metastatic potential of MZ‐6 in comparison with parthenolide. Both compounds showed considerable cytotoxicity against breast cancer MCF‐7 and MDA‐MB‐231 adenocarcinoma cells in vitro and were then evaluated for their anti‐metastatic potential. The experimental results showed that MZ‐6 and parthenolide suppressed, to a similar degree, migration of MCF‐7, but not more aggressive MDA‐MB‐231 cells. In both cell lines, tested compounds down‐regulated mRNA and protein levels of metalloproteinase‐9 and urokinase plasminogen activator, the key proteases involved in the degradation of extracellular matrix and dissemination of cancer cells. The obtained results indicate that simple analogs of α‐methylene‐γ‐lactones can be good substitutes for more complex structures isolated from plants. Cytotoxic activity and anti‐metastatic potential of parthenolide and MZ‐6, a simple analog of parthenolide with the same α‐methylene‐γ‐lactone motif, have been investigated. Efficient synthesis of MZ‐6, has been described.