tert‐Butylcarbamate‐Containing Histone Deacetylase Inhibitors: Apoptosis Induction, Cytodifferentiation, and Antiproliferative Activities in Cancer Cells

Abstract

Herein we report novel pyrrole- and benzene-based hydroxamates (8, 10) and 2'-aminoanilides (9, 11) bearing the tert-butylcarbamate group at the CAP moiety as histone deacetylase (HDAC) inhibitors. Compounds 8 b and 10 c selectively inhibited HDAC6 at the nanomolar level, whereas the other hydroxamates effected an increase in acetyl-α-tubulin levels in human acute myeloid leukemia U937 cells. In the same cell line, compounds 8 b and 10 c elicited 18.4 and 21.4 % apoptosis, respectively (SAHA: 16.9 %), and the pyrrole anilide 9 c displayed the highest cytodifferentiating effect (90.9 %). In tests against a wide range of various cancer cell lines to determine its antiproliferative effects, compound 10 c exhibited growth inhibition from sub-micromolar (neuroblastoma LAN-5 and SH-SY5Y cells, chronic myeloid leukemia K562 cells) to low-micromolar (lung H1299 and A549, colon HCT116 and HT29 cancer cells) concentrations. In HT29 cells, 10 c increased histone H3 acetylation, and decreased the colony-forming potential of the cancer cells by up to 60 %.

Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models

“…35 Compound C1A, reported by Kaliszczak et al also displays excellent growth inhibition of neuroblastoma cells. SK-OV-3 cells, IC 50 = 40 μM) pointing towards potentially high sensitivity of the neuroblastoma cells to HDAC6 inhibition.…”

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

“…Several epigenetic inhibitors have been developed and shown to induce differentiation, growth arrest, or apoptosis in tumor cells [7][8][9][10][39][40][41]. Among them, we previously characterized the thiazole derivative CPTH6, as a novel HAT inhibitor that activates the apoptotic program and modulates the autophagic flux in human tumor cell lines [11,12].…”

Drugging the HDAC6–HSP90 interplay in malignant cells

“…In histiocytoma cells, 5 mM of 8b caused apoptosis rates similar to 5 mM of the pan-HDACi suberoylanilide hydroxamic acid (SAHA, also known as vorinostat), and 8b depleted S-phase cells more strongly than all other HDACi. Unexpectedly, these favorable properties of 8b did not correlate with its ability to cause a-tubulin hyperacetylation [32]. It is possible that 8b does not target the catalytic domain of HDAC6 required for deacetylation of a-tubulin, and this may cause the strong effect of this HDAC6-specific agent against leukemic cells.…”

“…ACY-1215 is cytotoxic for cultured and primary cells from patients suffering from MM [31]. HA HDACi with a tert-butylcarbamate group at the cap moiety can also act selectively on HDAC6 [32]. Compound 8b ( Table 2) caused a 50% growth inhibition of CML cells at 3.1 mM.…”

“…HDAC6 also binds and stabilizes the pentaspan membrane glycoprotein CD133 and promotes this schematic segmentation like ''capless'' HDAC6i (BRD9757) [25] (H), or inhibitors lacking a ZBG (menadione) [26] (I) have been reported. Nexturastat A [27], C1A [28] or 8b [32] are further examples for the most prominent group of inhibitors, containing a HA as ZBG (J -M). Compound 29, also bearing a HA as a ZBG has been designed as a chimeric, dual HSP90 and HDAC6 inhibitor [63] (M).…”