Design, synthesis, and biological evaluation of tetrahydroisoquinoline based hydroxamate derivatives as HDAC 6 inhibitors for cancer therapy

A series of novel tetrahydroisoquinoline (THIQ) compounds were synthesized and evaluated as histone deacetylase 6 (HDAC 6) inhibitors. The compounds are designed based on various aromatic groups serv-ing as cap group, tetrahydroisoquinoline is used as a linker, and hydroxamic acid acts as a metal-binding group. A total of thirty-one novel THIQ analogues are designed and synthesized (B1-B31). The structures of the synthesized compounds are confirmed using 1 H NMR, 13 C NMR, LC-MS, and elemental analysis. The characterized compounds are screened for their inhibition against Class I HDAC8, Class IIa HDAC4 and Class IIb HDAC6. Several of these compounds exhibited potent antiproliferative activities in multiple tumor cell lines. Among the compounds tested B10 and B24 were found to be most potent selective in-hibitors of HDAC 6 with IC50 values of 0.3 mu M and 0.4 mu M respectively. B21 and B24 remarkably blocked colony formation in MCF-7 cancer cells. Inhibition of cancer cell proliferation by B21 and B24 involved cell cycle arrest in G1 phase and apoptotic death of the cancer cells.(c) 2023 Elsevier B.V. All rights reserved.