Design, synthesis, and in vitro biological evaluation of novel HDAC inhibitors bearing C-1 phenyl substituted tetrahydroisoquinoline Cap moiety as anti-tumor therapeutic agents

Herein, a structurally novel class of histone deacetylase (HDAC) inhibitors featuring the C-1 phenyl substituted tetrahydroisoquinoline Cap moiety were designed, synthesized, biologically evaluated in vitro and structure-activity relationship (SAR) study. A majority of compounds exhibited potent inhibitory activity against both HDAC6 and HDAC1 with IC₅₀ in the two-digit nanomolar. The representative compound in this series, 9g, demonstrated IC₅₀ values of 1.89 ± 0.08, 0.63 ± 0.05, and 2.31 ± 0.06 μM against A549, RPMI 8226 and HepG2 cell line, respectively. The apoptosis assay demonstrated that 9g exerted excellent effects in promoting cancer cell apoptosis. It was found that 9g arrested RPMI 8226 cells in G0/G1 phase in a concentration-dependent manner. Additionally, 9g also induce upregulation of acetylation levels in Histone H3 and α-Tubulin at the concentration as low as 1 μM. All above, 9g merits further structural modification as a lead compound.