Natural products are important leads in drug discovery. The search for effective plant-derived anticancer agents or their synthetic analogues has continued to be of interest to biologists and chemists for a long time. In this report, cytotoxicity and anticancer activity of new synthetic a-methylene-d-lactones was tested against two breast cancer cell lines, invasive, hormone-independent MDA-MB-231 and hormone-dependent MCF-7. Cytotoxicity was examined using MTT assay. The ability to induce apoptosis and changes in mitochondrial membrane potential was studied by flow cytometry. The expression levels of pro-and anti-apoptotic genes were determined by quantitative real-time PCR. Cancer cell migration and invasion were assessed by wound healing and Matrigel assays. Additionally, secretion of proteins associated with invasiveness, metalloproteinase-9 (MMP-9) and urokinase plasminogen activator (uPA) was investigated using commercial ELISA kits and MMP-9 activity by gelatin zymography. A natural sesquiterpene lactone, parthenolide, was used as a positive control. Screening results showed all four analogues to be highly cytotoxic. The most potent compound of the series, 1-isopropyl-2-methylene-1,2-dihydrobenzochromen-3-one, designated DL-3, which reduced the number of viable MDA-MB-231 and MCF-7 cells with the IC 50 values of 5.3 lM and 3.54 lM, respectively, was selected for further research. DL-3 activated the intrinsic pathway of apoptosis, associated with the loss of mitochondrial membrane potential and changes in Bax/Bcl-2 ratio. DL-3 also inhibited the movement of both types of breast cancer cells. Suppression of cell migration and invasion was the result of the decreased secretion of enzymes responsible for the degradation of the extracellular matrix, MMP-9 and uPA. These findings show that the synthetic a-methylene-d-lactone, DL-3, displays potential to be further explored in the development of new anticancer agents.Throughout history, plants have always been an excellent source of pharmaceutical agents used in traditional medicine. More recently, a big number of important drugs have been obtained from plants, either directly, by extracting an active component or, more often, by structural modifications of natural compounds or by the synthesis of their analogues with improved pharmacological properties. Many of the compounds used for cancer chemotherapy, such as the Vinca alkaloids, paclitaxel, camtothecin and etoposide, were originally derived from plants [1], and plants continue to be viewed as major sources for the development of new anticancer drugs.A vast number of biologically significant natural products are characterized by the a-methylene-c-lactone structural motif. Such products are abundant in plants of the Compositae family and possess a broad spectrum of biological activities, ranging from anti-inflammatory, phytotoxic, antibacterial and antifungal to cytotoxic/anticancer [2]. First a-methylene-c-lactones 1 ( fig. 1) were isolated from plants of the Compositae family over 100 years ago, b...
Reactions of [ closo-1-CBH-1-R] (2, R = H, COOH, CH) with PhI(OAc) lead to mixtures of regioisomers [ closo-1-CBH-1-R-6-IPh] (5[6]) and [ closo-1-CBH-1-R-10-IPh] (5[10]) in ratios of ∼3:1 to 1:1, of which the former isomer undergoes selective reactions with nucleophiles (MeCN, pyridine, MeC(═NH)NH, CN). The products and the unreacted 10-isomers 5[10] are separated achieving kinetic resolution of the isomeric iodonium zwitterions. Pure 5[10] is reacted with nucleophiles (pyridine, 4-CHOPyridine, MeNCHS, PhCO, CN, N, I, MeC(═NH)NH, and MeCN), giving substitution products. The mechanism of the substitution is investigated with density functional theory (DFT) methods. Some of the nucleophilic substitution products are transformed further, expanding the scope of available functional groups for the [ closo-1-CBH] anion. Four derivatives are characterized with single-crystal XRD methods: [ closo-1-CBH-10-N] (4[10]a), [ closo-1-CBH-6-NCH] (9[6]a), [ closo-1-CBH-10-NCH] (9[10]a), and [ closo-1-CBH-10-NHC(NH)Me] (10[10]a). Spectroscopic data for selected derivatives are interpreted in terms of transmission of electronic effects through the { closo-1-CB} cluster (NMR) and interaction with substituents (IR, UV). The latter results are compared to those of TD-DFT computational methods.
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