| Objective:Pterocarpin is a subclass of isoflavones family.It is the important effective component of many Chinese medicine.Previous studies suggest that pterocarpan shows antibacterial,anti-cancer,anti-inflammatory,immunosuppressive properties and so on.It has therapeutic effects on Alzheimer’s disease,Parkinson,depression and osteoporosis.Researchers have studied of derivatization on the basic structure of the pterocarpan and activities of derivates.However,there are some shortcomingsincluding undiversified compounds,modest activity,and lack of systematic study about structure-activity relationship.Our laboratory found that Hirtellanine D shows significant activity(IC50=2.5μM)of inhibiting MAGL and it is a significant MAGL inhibitor.Inhibition of MAGL can achieve anti-inflammatory,neuroprotective and anticancer.Thus,Hirtellanine D has the potential to be developed for the treatment of Alzheimer’s disease and anticancer.Considering of previous research and our work,we have designed and synthesized the analogues of pterocarpan based on structure of pterocarpan,and we carried out study on medical chemistry of pterocarpan analogues,proceeded from the molecular mechanism for anticancer activity of MAGL inhibitors.We conducted studies about compounds on the inhibitory activity to MAGL,anticancer activities related to MAGL,antioxidant and immunosuppressive activities,thus the structure-activity relationship of pterocarpan analogues has been explored in above filed of drug development.Method:We designed and synthesized 6,11-dihydrochromeno[4,3-b]indole,6,11-dihydro-5H-benzo[a]carbazole,5,10-dihydroind-eno[1,2-b]indole derivatives based on Hirtellanine D as the leading compound;moreover,the initial screening of these compounds were finished;compounds exhibited good activity would be studied for structural modification and structure-activity relationship.Result:The pterocarpan analogues showed weak inhibitory activity to MAGL.JD3and JD21 have modest inhibitory activities on the proliferation of HeLa with IC509.61μM、16.52μM respectively.Moreover,JD3、JD20、JD21 and JD39 show modest activity of inhibiting HepG2 with IC50 values 15.09μM、12.54μM、6.62μM、9.69μM respectively,among them,JD39 can affect the cell cycle of HepG2.However,compounds exhibited weak immunosuppressive activity and antioxidant activity.In the study of structure-activity relationship onpterocarpan,we found:1)the skeleton of6,11-dihydro-5H-benzo[a]carbazole is more beneficial to the anticancer activity than over the 5,10-dihydroind-eno[1,2-b]indole skeleton;2)the nitrogen hydrogen bond in the indole ring is critical for the anticancer activity;3)the structure feature required for anticancer activity was methoxy group at C-2 of 6,11-dihydro-5H-benzo[a]carbazole Conclusion:JD3,JD20,JD21 and JD39 show modest anticancer activity,and the study of structure-activity relationship provides guidance for structural modification and searching pterocarpan analogues with better bioactivity. |
