Design, Synthesis And Antitumor Activity Of 2-methylene-5-substitutedmethylenecyclopentanones

Through studying structure-activity relationship (SAR) of the natural terpenoid, which have anti-tumour activity, it is found thatα-methylene cyclopentanone appearing in diterpenes and a-methylene-γ-lactones appearing in sesquiterpenesare functional groups to mediate anti-tumour activity. After simplifying and modifying these nature compounds, Prof. Ji and his colleagues designed and synthesized a series of 2-substituedaminomethyl-5-(E)-substitut-edmethylenecylopentanones (cyclohexanones). As one of the representatives, WB852, has significant anti-tumour activtity. In recent research, we have found 2-methylene-5-substitutedphenylmethylenecylopentanones have significant activities in exhausting GSH, inhibiting the activity of GSTπand inducing tumor cell apoptosis and are stable in squeous solution stabilization.In order to study antitumor mechanismand SAR these compounds, 5-substitutedmethylene group was modified systemically and 22 2-methylene-5-substitutedmethylene cylopentanones (B-l~B-22) were designed synthesized, which structure have been characterized by the application of IR, MS and ~1H-NMR spectra.Using WB852 as a positive comparison, the growth inhibition of the target compound (B-1-B-22) in breast cancer cells T47D and MDA-MB231 was tested with MTT method. The results showed that 8 compounds B-11-B-15, B18, B-20～B-22, especially B-14 and B-15 which IC50 values were 0.64 and 0.98 separately, had significant activities. The apoptosis-inducing activity of B-14 to HL60 cells was evaluated through AO and EB double decoration assay(apoptosis rate = 80%) and GSH-binding ability in vitro was tested by UV/VIS spectrophotometry (binding rate = 84% at 40μM of B-14). These results supported the anticipated antitumor mechanism.The SAR was showed as fowllows: 2-methylene-5-substitutedphenylmethyllenecylopen-tanones was monosubstitued by hydroxyl or alkoxyl group has tiny activity; the activity was increased after 2-methylene-5-substitutedphenylmethylenecylopentanones by hydroxyl and methoxyl group simultaneously; unfortunately 2-methylene-5-aldylmethenecylopentanone and 2-methylene-5-diphenylmethylenecyclopentanone is less activity. Pharmacological tests are being intensively studied.