Discovery and development of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as Bcl-2/Mcl-1 inhibitors

[Display omitted] •Novel tetrahydroisoquinoline derivatives were developed based on compound 1.•Active compounds potently bound to Bcl-2 and Mcl-1protein, but not to Bcl-XL.•Active compounds showed anti-proliferative effects on tested cancer cells.•11t dose-dependently induced Jurkat cell apoptosis and caspase-3 activation. Bcl-2 family proteins play a vital role for cancer cell in escaping apoptosis, and small-molecule anti-apoptotic Bcl-2 protein inhibitors have been developed as new anticancer therapies. In current study, a series of substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were developed based on the lead compound 1 (Ki = 5.2 µM against Bcl-2 protein). The fluorescence polarization assays suggested that active compounds possessed potent binding affinities to both Bcl-2 and Mcl-1 protein, but had minor or no binding affinities to Bcl-XL protein. MTT assays showed that these compounds had certain anti-proliferative activities against cancer cells. Furthermore, it was found that active compound 11t could induce cell apoptosis and caspase-3 activation in a dose-dependent manner in Jurkat cells.