Ring-opened tetrahydro-γ-carbolines display cytotoxicity and selectivity with histone deacetylase isoforms

This study is focused on modification of the indole moiety and the N1-zinc binding domain of tubastatin A, and the effects of such changes on biological activity. Fourteen N-substituted indoles (5–18) were synthesized and structure-activity relationship studies indicated that the change of the tetrahydro-γ-carboline in tubastatin A led to substituted indoles (compounds 7, 11, and 15) which showed significant improvements of selective inhibition for HDAC6 over HDAC1 and HDAC2 in comparison to ACY1215, a compound undergoing clinical trials. In addition, attachment of different hydroxamic acid groups, the zinc binding motif at the N1 position, contributes to the antiproliferative activity in cancer cells. Several synthetic compounds exhibited potent growth inhibition in a broad spectrum of tumor cell lines, induced irreversible growth arrest capacities by suppressing colony formation ability and activated the apoptosis pathway. The data provide compelling evidence that our newly synthesized compounds with type B to D hydroxamic acid groups as the zinc binding motif at the N1 position are potent selective inhibitors of HDAC6 and could be investigated preclinically as potential anticancer drugs. The ring-opened tetrahydro-γ-carbolines (8, 9, 12, 13, and 18) show not only potent antiproliferative activity but also HDAC6 selectivity. [Display omitted] •A series of ring-opened tetrahydro-γ-carbolines were designed and synthesized.•Five compounds (8, 9, 12, 13, and 18) with potent antiproliferative activity were identified.•Compounds 8, 9, 12, 13, and 18 were also potent to inhibit HDAC6 function.