Design, Synthesis and Antitumor Activity of 2-methylene-5-substitutedmethylenecyclopentanones
|School||Shenyang Pharmaceutical University|
|Keywords||2 - methylene-5 - substituted methylene cyclopentanone Structure-Activity Relationship The anti-tumor activity GSH Binding Induced apoptosis|
QSAR Studies on the natural antitumor terpenoids system , we found that the α-methylene cyclopentanone or α-methylene - γ - butyrolactone is the vast majority of times sesquiterpene class or diterpenoid compounds With the essential structure of the anti-tumor activity . We found that 2 - methylene-5 - substituted benzene methylenecyclopentyl ketones depletion of glutathione (reduced glutathione, GSH) , inhibition of glutathione -S-transferase enzymes (glutathione-S- , transferaseπ , GSTπ ) of activity and promote apoptosis of tumor cells three showed strong activity , but also has good chemical stability . For further study of the mechanism of action of these compounds , the structure-activity relationships and enhance the anti-tumor activity replace methylene section on the system structural modification and transformation , we designed and synthesized 22 - methylene-5 - substituted methylidenecyclopent ketones (B-1 ~ B-22), the structure was confirmed by IR , 1 sup> H- NMR and MS spectra data conclusive evidence , 20 have not been reported , the new compounds. WB852 as a positive control , the growth inhibition of the MTT assay of the target compound B - 1 to B -22 of human breast cancer cells T47D and MDA-MB231 , B -11 to B -15 , B -18 , B -20 and B-22 , etc. compound 8 shows a good activity, and the B-14 and B-15 activity is preferably on the T47D IC 50 sub > values ??were 0.64 and 0.98 . AO and EB double staining method for the determination of the B-14 induced leukemia HL60 cells apoptotic activity , concentration 3μM , apoptosis rate was 80% ; using UV spectrophotometric method for the determination of the B-14 and extracellular GSH binding rate , a concentration of 40 μm , binding rate of 84%, preliminary corresponds to the mechanism of action of the above results with such compounds . The preliminary structure-activity relationship of : 2 - methylene-5 - substituted methylcyclopentyl ketone compounds on the phenyl ring of the benzylidene , mono-substituted hydroxy or alkoxy , the activity of the compounds is weak ; replaced by a hydroxy and methoxy bis strong activity , the compounds ; 2 - methylene-5 - alkoxy - methylene- cyclopentanone , and 2 - sub- methyl-5 - (4 - substituted diphenylmethylene ) cyclopentyl ketone activity of the compounds is weak . Depth pharmacological studies are ongoing .