喹啉类mTOR/HDAC双靶抑制剂的设计、合成与体外活性评价

Quinoline Derivatives of mTOR/HDAC Dual-Target Inhibitors:The Design,Synthesis and In vitro Biological Evaluation

为发现新型mTOR/HDAC双靶抑制剂,基于药效团融合策略构建目标分子,并经亲核取代或缩合反应、羟胺解反应制得目标分子。体外抑酶活性测试结果显示,4′-((4-(4-(N-羟基戊酰胺)-哌嗪-1-基)-3-(三氟甲基)苯基)氨基)-[3,6′-二喹啉]-3′-甲酰胺呈现出中等强度的双靶抑酶活性(mTOR、HDAC1、HDAC6的IC_(50)值分别为1444、832、230 nmol/L);4′-((4-(4-(N-羟基乙酰胺)-哌嗪-1-基)-3-(三氟甲基)苯基)氨基)-[3,6′-二喹啉]-3′-甲酰胺对mTOR具有良好的抑制活性(IC_(50)=64 nmol/L)。抗增殖活性测试结果显示,所有目标分子对A549细胞株的增殖抑制活性与阳性对照SAHA、MLN-0128相当或略优;4′-((4-(4-(N-羟基-1-羰基辛酰胺)哌嗪-1-基)-3-(三氟甲基)苯基)氨基)-[3,6′-二喹啉]-3′-甲酰胺对HCT116的抗增殖活性与MLN-0128相当。

To discover novel mTOR/HDAC bi-functional inhibitors,target compounds were designed via a pharmacophore-merging strategy and prepared by nucleophilic substitution or condensation and the following hydroxylaminolysis.As demonstrated by the in vitro enzymatic assay,4′-((4-(4-(N-hydroxypentanamido)-piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-[3,6′-diquinolin]-3′-carboxamide exhibited moderate inhibitory activity against both mTOR and HDAC(mTOR IC_(50)=1444 nmol/L;HDAC1 IC_(50)=832 nmol/L;HDAC6 IC_(50)=230 nmol/L).Besides,4′-((4-(4-(N-hydroxyacetamido)-piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-[3,6′-diquinolin]-3′-carboxamide displayed acceptable inhibitory activity against mTOR(IC_(50)=64 nmol/L).In the anti-proliferative assay,all the synthesized compounds exhibited comparable or superior activity to the positive control SAHA and MLN-0128 against the A549 cell line.Additionally,4′-((4-(4-(N-hydroxy-1-carbonyloctanamido)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-[3,6′-diquinolin]-3′-carboxamide exerted comparable anti-proliferative activity to MLN-0128 against the HCT116 cell line.