Design and Synthesis of Mercaptoacetamides as Potent, Selective, and Brain Permeable Histone Deacetylase 6 Inhibitors

Abstract

A series of nonhydroxamate HDAC6 inhibitors were prepared in our effort to develop potent and selective compounds for possible use in central nervous system (CNS) disorders, thus obviating the genotoxicity often associated with the hydroxamates. Halogens are incorporated in the cap groups of the designed mercaptoacetamides in order to increase brain accessibility. The indole analogue 7e and quinoline analogue 13a displayed potent HDAC6 inhibitory activity (IC 50 , 11 and 2.8 nM) and excellent selectivity against HDAC1. Both 7e and 13a together with their ester prodrug 14 and disulfide prodrugs 15 and 16 were found to be effective in promoting tubulin acetylation in HEK cells. The disulfide prodrugs 15 and 16 also released a stable concentration of 7e and 13a upon microsomal incubation. Administration of 15 and 16 in vivo was found to trigger an increase of tubulin acetylation in mouse cortex. These results suggest that further exploration of these compounds for the treatment of CNS disorders is warranted.

Largazole Analogues as Histone Deacetylase Inhibitors and Anticancer Agents: An Overview of Structure–Activity Relationships

“…[18,19] Interestingly,p otent and selective HDAC6 inhibitors with an a-thioacetimide ZBG have been recently reported for possible use in the treatment of central nervoussystem disorders. [20] Few largazole analogues with ZBGs incorporating an aromatic moiety and as econd heteroatom for metal chelation were reported by Tillekeratne and collaborators. [21] Despite the promising activity of the compounds in enzymatic assays,c ellular assays on HTC-116 colon carcinomac ells revealed GI 50 values at least 100-fold higher than that obtained forl argazole (10 nm).…”

“…This topic is of current interest, as HDAC6 has recently been shown to be a new possible target for the treatment of glioblastoma and multiple myeloma . Interestingly, potent and selective HDAC6 inhibitors with an α‐thioacetimide ZBG have been recently reported for possible use in the treatment of central nervous system disorders …”

Design, synthesis, and biological evaluation of novel derivatives of dithiodiglycolic acid prepared via oxidative coupling of thiols

“…The trityl group was removed by the action of trifluoroacetic acid (TFA) used as a solvent ( 18a–c ) 18 or as a reagent (5 equiv.) in DCM ( 18d–k ) 19 , in the presence of triethylsilane. The reaction was completed in 5–30 min in the former case and took 2–16 h – in the latter.…”

“…In case of compounds 11a–d, f, g, k the reaction mixture was concentrated and the residue was crystallised from hexane-ethyl acetate to give pure disulphides. Compounds 11e, h, i, j precipitated from the reaction mixture and were isolated by filtration and washing with DCM (2 × 5 ml) 19 .…”

The Significance of Nanomedicine in Brain-Targeted Drug Delivery: Crossing Blood-Brain Barriers

“…To address the challenge, the focus of brain researches has been directed towards the development of effective strategies to surpass the BBB over the past three decades. To this end, myriads of strategies to get in the brain have been employed, such as chemical drug delivery [16]; osmotic disruption of BBB [16], ultrasound [17], and nanomedicine based approach [18] among others.…”