| Non-small cell lung cancer(NSCLC)is the major histologic subtype of lung cancers which is the main cause of cancer-related death worldwide.Cisplatin is one of the first-line chemotherapeutic agents,however,the continuous exposure to cisplatin often results in the development of acquired multidrug resistance which can be caused by numerous mechanisms.The tremendous complexity of chemoresistance and living systems made it a great challenge to reverse the resistance.The resistance could be partly reversed by the combination of anticancer agents with Verapamil or Tamoxifen,and some new compounds have been reported to reverse the resistance via different mechanisms.In clinical treatment of advanced NSCLC,however,the chemoresistance is still very serious.Histone deacetylases(HDAC)inhibitors have been successfully applied in clinical treatment and show synergistic effects with various anticancer drugs.Cancer stem cells(CSC)are related to chemoresistance and relapses of cancer.Belinostat,a HDAC inhibitor,has been reported to circumvent the resistance in NSCLC through inhibition of both ABCC2 and DNA repair-mediated mechanisms.Meanwhile,drug-resistant NSCLC displayed the enhanced expressions of CSC transcription factors.Therefore,HDAC and Smoothened protein,a key protein in Hh signal pathway of CSC,were selected as the target and novel compounds were designed via principle of hybridization based on Belinostat and Vismodegib.Five series of novel N-hydroxypropenamides were designed and molecular docking studies were employed to verify the designing.Based on the molecular docking results,58 compounds with acceptable docking score were synthesized via Heck,Negish,Knoevenagel,Sandmeyer reaction et al.And a synthetic route to 3-formylbenzenesulfonyl chlorides from the corresponding benzaldehydes has been developed.The key step in this procedure is the conversion of aldehyde bisulfite adducts to target compounds via a two-stage reaction in the presence of Na2SO4.Eight 3-formylbenzenesulfonyl chloride derivatives were prepared by this method and identified by chemical derivatization method.Some of the designed compounds exhibited acceptable inhibitory effect on HDAC,which is better than belinostat in the level of 10 μM.The IC50 of compound a5,a7 and d8 are 0.17 μM,0.25 μM and 0.20 μM,respectively.The expression of transcription factor Gli1 of Hh signaling pathway in A549 cells can be downregulated by compounds a3,a5,a7,b9,bll,b13,b15 and d4 in the level of 5 μM.And the expression of Glil was reduced by 87.1%by compound a5.Therefore,we believe that compound a5 can inhibit both HDAC and Hh signaling pathway. |
