Design,Synthesis And Biological Evaluation Of Phenylacetyl-Tetrahydro-?-carboline In Acute Promyelocytic Leukemia

Acute promyelocytic leukemia(APL)is a special subtype of acute myeloid leukemia(AML-M3).Its clinical manifestations include occurring serious bleeding,so it was once considered a very dangerous disease.About 98%APL patients have PML-RARa,which be thought the main APL pathogenesis.At present,the chemotherapy of all-trans retinoic acid(ATRA)combined arsenic trioxide(ATO)is still the first-line treatment of APL,which the complete remission rate(CR)reaches more than 90%.However,about 5%-10%APL patients who achieved CR will change to relapsed APL.So it is critical to explore more candidate drugs for the treatment of APL resistance.Our preliminary study found compound LG-362B was able to target the PML-RARa and inhibit the abnormal proliferation of promyelocytic cells specifically,while its structure-activity relationship was not yet clear,anti-cancer activity and physicochemical properties still need to improve.So we fulfilled a series of compound designs and got some advantage groups,such as trihydroxy piperidinyl,propanolamine substituents and so on.Herein,we introduced the dominant groups into our designs and assessed their inhibitory activity at the cellular level.Compound 29 not only appeared obvious inhibitory activity,but also it showed relative activities in the induction of apoptosis and cell cycle arrest.Besides,its physicochemical properties had been greatly improved.Finally,we summarized the overall structure-activity relationship,which be able to provide a reference for the follow-up study.