Inhibitors of histone deacetylase 6 based on a novel 3-hydroxy-isoxazole zinc binding group

Abstract

Histone deacetylase 6 (HDAC6) is an established drug target for cancer treatment. Inhibitors of HDAC6 based on a hydroxamic acid zinc binding group (ZBG) are often associated with undesirable side effects. Herein, we describe the identification of HDAC6 inhibitors based on a completely new 3-hydroxy-isoxazole ZBG. A series of derivatives decorated with different aromatic or heteroaromatic linkers, and various cap groups were synthesised and biologically tested. In vitro tests demonstrated that some compounds are able to inhibit HDAC6 with good potency, the best candidate reaching an IC 50 of 700 nM. Such good potency obtained with a completely new ZBG make these compounds particularly attractive. The effect of the most active inhibitors on the acetylation levels of histone H3 and α- tubulin and their anti-proliferative activity of DU145 cells were also investigated. Docking studies were performed to evaluate the binding mode of these new derivatives and discuss structure-activity relationships.

Anti-multiple myeloma potential of resynthesized belinostat derivatives: an experimental study on cytotoxic activity, drug combination, and docking studies

“…[16][17][18] Various studies have been reported to focus on altering the cap, connective unit (CU), linker, and zinc binding portions of HDAC inhibitors in recent years. [19][20][21][22][23][24][25] In the structure of belinostat, N-hydroxycinnamamide serves as both the ZBG and the linker group. The hydroxamic acid functional group and the E double bond are essential for activity, and exchange of the E double bond to the Z double bond or the triple bond leads to inactive compounds.…”

MiR-129-5p exerts Wnt signaling-dependent tumor-suppressive functions in hepatocellular carcinoma by directly targeting hepatoma-derived growth factor HDGF

“…Thus, miR-129-5p may not only be epigenetically downregulated by miR-129-2 promoter hypermethylation but also by increased histone deacetylation of the miR-129-2 promoter. Since HDACi have a range of undesirable side effects and act relatively unspecific, the targeted application of tumor-suppressive miRNAs is a favorable therapeutic approach [ 49 ]. Notably, several potential miRNA therapies have reached phase I and phase II clinical trials [ 50 , 51 ].…”

Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring

“…The most signicant structural modication was obtained by switching the ZBG to position 2, affording 5, which, to the best of our knowledge, is the most active quinazoline inhibitor reported so far (IC 50 ¼ 12 nM). 13 Based on these premises and relying on our previous work on HDAC6 inhibitors, 2,[15][16][17][18][19] in this study we report the computational design and the synthesis of two structurally novel derivatives containing an aminotriazoloquinazoline (11a) and aminotriazole scaffold (18). The two synthesized compounds were tested in vitro to evaluate their inhibitory activity against HDAC6.…”

“…Based on these premises and relying on our previous work on HDAC6 inhibitors, 2,15–19 in this study we report the computational design and the synthesis of two structurally novel derivatives containing an aminotriazoloquinazoline ( 11a ) and aminotriazole scaffold ( 18 ). The two synthesized compounds were tested in vitro to evaluate their inhibitory activity against HDAC6.…”