Tetrahydro-β-carboline derivatives as potent histone deacetylase 6 inhibitors with broad-spectrum antiproliferative activity.

A series of tetrahydro- β -carboline (TH β C)-based hydroxamic acids were rationally designed and synthesized as novel selective HDAC6 inhibitors (sHDAC6is) by the application of scaffold hopping strategy. Several TH β C analogues were highly potent (IC 50 < 5 nM) and selective against HDAC6 enzyme and exhibited good antiproliferative activity against human multiple myeloma (MM) cell. Molecular docking interpreted the structure activity relationship (SAR). Target engagement of HDAC6 was confirmed in RPMI-8226 cells using the WB assay. In vitro, (1 S , 3 R)-1-(4-chlorophenyl)- N -(4-(hydroxycarbamoyl)benzyl)-2,3,4,9-tetrahydro-1H-pyrido[3, 4- b ]indole-3-carboxamide (14g) showed potent broad antiproliferative activity against various tumors including leukemia, colon cancer, melanoma, and breast cancer cell lines, better than ACY-1215. Moreover, 14g also showed good pharmacokinetics properties in mice via oral administration. [Display omitted] • Potent and selective HDAC6 inhibitors based on 1, 3-disubstituted tetrahydro- β -carboline scaffold. • Chiral variation of TH β C scaffold significantly affects HDAC6 activity and isoform selectivity. • Computational simulations suggested the key interactions between trans 14g and HDAC6. • 14g exhibited promising broad-spectrum antiproliferative activity and pharmacokinetics properties. [ABSTRACT FROM AUTHOR]