Mercaptoacetamide: A promising zinc-binding group for the discovery of selective histone deacetylase 6 inhibitors

A Review of Progress in Histone Deacetylase 6 Inhibitors Research: Structural Specificity and Functional Diversity

“…In particular, the chemodiversity of HDAC6 inhibitors is preferentially manifest in the diverse array of capping groups, followed by somewhat conserved linkers and ZBGs. 44,45 Interestingly, people like to utilize the skeleton of old drugs as the capping groups when designing HDAC6 inhibitors bearing long aliphatic linkers, which might attribute to the flexible alkyl chain being favored for the steric complementarity between the capping groups and the three-dimensional contours of the L1 and L2 loop pockets of the HDAC6 active site. 44 In contrast, phenylhydroxamates displayed much more tolerance to different capping groups, along with the hydroxamate moiety binding with Zn 2 + in monodentate coordination, and the aromatic ring formed double π stacking interactions with P583 and P643.…”

“…184 Compared with hydroxamate, mercaptoacetamide showed good pharmacological effects and druglike properties and was unlikely to cause mutagenicity. 45 In their study, compounds 76 and 77, containing indole and quinoline capping groups, respectively, showed high potency toward HDAC6 (IC 50 = 11, 2.8 nM) and excellent selectivity over HDAC1 (Figure 27). Notably, dichlorine substituents were able to increase the lipophilicity of compounds, thus increasing the brain accessibility.…”

“…Therefore, modifying the cap, varying the linker, or altering the ZBG are common strategies to improve selectivity . Particularly, given the unique three-dimensional contour of the HDAC6 active site, the chemodiversity of HDAC6 inhibitors is preferentially manifest in the diverse array of capping groups, followed by somewhat conserved linkers and ZBGs. , With this in mind, we classified HDAC6 inhibitors according to different ZBGs (hydroxamic acids or novel binding groups) and linkers (according to structural rigidity) and then summarized in detail the various capping groups. , …”

Synthesis and structure‐activity relationship of thiol‐based histone deacetylase 6 inhibitors

“…Compound 1 shows excellent inhibitory activity against HDAC6, 7.2 nM, equivalent to the positive control Ricolinostat. Mercaptoacetamide, as a highly efficient group, chelates with the zinc ion in a bidentate fashion (Tavares et al, 2021). Compound 2 introduces mercaptoacetamide and inhibits HDAC6 with moderate potency of 40 nM.…”

Inverse Correlation Between Alzheimer’s Disease and Cancer: Short Overview

“…For example, Song et al [122] reviewed that myricetin which possesses some biological activities such as antitumor, anti-inflammatory inhibits the proliferation of various cancer cells (e.g., the liver, breast, ovarian, colon, thyroid, prostate, lung cancer, leukemia, glioma, human placental choriocarcinoma) and has antineurodegenerative activity. Tavares et al [123] pointed that mercaptoacetamide-based histone deacetylase inhibitors have some anti-tumor effects (e.g., prostate cancer) and might be considered as a potential therapeutic target for neurodegenerative disorder's such as AD due to promoting dendritic spine density, leading to decrease in human Aß40, Aß42, and phosphorylated tau (Thr181) levels, and impacts Aß levels by downregulating Aß-production pathways while upregulating Aß clearance pathways. Cerium oxide nanoparticles (CNPs) have also anti-cancer properties and protects against Alzheimer's disease.…”