Heterocyclic ketones as inhibitors of histone deacetylase

Several heterocyclic ketones were investigated as potential inhibitors of histone deacetylase. Nanomolar inhibitors such as 22 and 25 were obtained, the anti-proliferative activity of which were shown to be mediated by HDAC inhibition.     

Trifluoromethyl ketones as inhibitors of histone deacetylase

Trifluoromethyl ketones were found to be inhibitors of histone deacetylases (HDACs). Optimization of this series led to the identification of submicromolar inhibitors such as 20 that demonstrated antiproliferative effects against the HT1080 and MDA 435 cell lines.     

Synthesis,evaluation and molecular modeling of cyclic tetrapeptide histone deacetylase inhibitors as anticancer agents

Histone deacetylase inhibitors (HDACIs) are a promising class of anticancer agents. To examine whether a slight change in the recognition domain could alter their inhibitory activity, we synthesized a series of cyclo(?l ‐Am7(S2Py)‐Aib‐l ‐Phe(n‐Me)‐d ‐Pro)derivatives and evaluated their HDAC inhibitory and anticancer activities. The peptides exhibited potent HDAC inhibitory activity and inhibited three human cancer cell lines with IC₅₀ in the micromolar range. Docking and molecular dynamics simulation were conducted to explore the interaction mechanisms of class I and II HDACs with these inhibitors. It revealed that the zinc ion in the active site coordinated five atoms of HDACs and the sulfur atom of the inhibitor. The metal binding domains of these compounds interacted with HDAC2, and the surface recognition domains of these compounds interacted with HDAC4 through hydrogen bonding. The hydrophobic interactions also provided favorable contributions to stabilize the complexes. The results obtained from this study would be helpful for us to design some novel cyclic tetrapeptides that may act as potent HDACIs. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.     

Synthesis and biological evaluation of histone deacetylase inhibitors that are based on FR235222: a cyclic tetrapeptide scaffold

We outline the synthesis of six novel derivatives that are based on a recently discovered HDAC inhibitor FR235222. Our work is the first report utilizing a novel binding element, guanidine, as metal coordinators in HDAC inhibitors. Further, we demonstrate that these compounds show cytotoxicity that parallels their ability to inhibit deacetylase activity, and that the most potent compounds maintain an L-Phe at position 1, and a D-Pro at position 4. Both inhibition of HDAC activity and cytotoxicity against the pancreatic cancer cell line BxPC3 are exhibited by these compounds, establishing that a guanidine unit can be utilized successfully to inhibit HDAC activity.     

Novel pyrrole-containing histone deacetylase inhibitors endowed with cytodifferentiation activity

A novel series of aroyl-pyrrolyl-hydroxy-amides (APHAs) active as histone deacetylase (HDAC) inhibitors has been reported. The new derivatives were designed by replacing the benzene ring of the prototype 1 with both aromatic and aliphatic, monocyclic and polycyclic rings (compounds 3a-i), or by inserting a number of substituents on the methylene linker of 1 (compounds 4a-l). Compounds 3a-i and 4a-l were active at sub-micromolar level against the maize deacetylases HD1-B (class I), HD1-A (class II), and HD2. Tested at 5 microM against human HDAC1 and HDAC4, 3b, 4a, and 4j showed significant HDAC1 inhibition, whereas on HDAC4 only 4a was highly effective. On the human leukemia U937 cell line, the same compounds did not alter the cell cycle phases and failed in inducing apoptosis. However, they displayed granulocytic differentiation at 5 microM, with 3b being the most potent (76% CD11c positive cells). Tested to evaluate their effects on histone H3 and alpha-tubulin acetylation, 3b and 4a showed high H3 acetylation, whereas 4a and 4b were the most potent with alpha-tubulin as a substrate.     

Novel histone deacetylase inhibitors: N-hydroxycarboxamides possessing a terminal bicyclic aryl group

Utilizing tranexamic acid as a starting material, a series of N-hydroxycarboxamides were synthesized in order to seek new histone deacetylase (HDAC) inhibitors. Further structure optimization involving the replacement of the 1,4-cyclohexylene group with the 1,4-phenylene group yielded the promising HDAC inhibitors which possess a terminal bicyclic aryl amide.     

Potent histone deacetylase inhibitors: N-hydroxybenzamides with antitumor activities

The screening tests of N-hydroxybenzamides for their HDAC-inhibitory activities led to the discovery of the promising compounds with a 2-naphthylcarbonyl group and with a 1,4-biphenylcarbonyl group. These compounds were further modified to optimize their physico-chemical profile. As a result, the inhibitor with a 6-amino-2-naphthylcarbonyl was obtained, which showed not only promising growth inhibitions against a panel of tumor cells, but also an improved water solubility. It exhibited the maximal 185% of survival rate (%T/C) in a in vivo experiment with P388 cell-inoculated mice.     

Alpha-mercaptoketone based histone deacetylase inhibitors

In an effort to discover novel non-hydroxamic acid histone deacetylase (HDAC) inhibitors, a novel alpha-mercaptoketone was identified in a high-throughput screen. Lead optimization of the screening hit, led to a number of potent HDAC inhibitors. In particular, alpha-mercaptoketone 19y (KD5150) exhibited nanomolar in vitro activity and inhibition of tumor growth in vivo.     

Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors

In an effort to identify HDAC isoform selective inhibitors, we designed and synthesized novel, chiral 3,4-dihydroquinoxalin-2(1H)-one and piperazine-2,5-dione aryl hydroxamates showing selectivity (up to 40-fold) for human HDAC6 over other class I/IIa HDACs. The observed selectivity and potency (IC₅₀ values 10–200 nM against HDAC6) is markedly dependent on the absolute configuration of the chiral moiety, and suggests new possibilities for use of chiral compounds in selective HDAC isoform inhibition.     

Sulfamides as novel histone deacetylase inhibitors

The sulfamide moiety has been utilized to design novel HDAC inhibitors. The potency and selectivity of these inhibitors were influenced both by the nature of the scaffold, and the capping group. Linear long-chain-based analogs were primarily HDAC6-selective, while analogs based on the lysine scaffold resulted in potent HDAC1 and HDAC6 inhibitors.     

Novel alkoxyamide-based histone deacetylase inhibitors reverse cisplatin resistance in chemoresistant cancer cells

Although histone deacetylase inhibitors (HDACi) have shown promising antitumor effects in specific types of blood cancer, their effects on solid tumors are limited. Previously, we developed LMK235 (5), a class I and class IIb preferential HDACi with chemosensitizing effects on breast cancer, ovarian cancer and HNSCC. Based on its promising effects on solid tumor cells, we modified the cap group of 5 to improve its anticancer activity. The tri- and dimethoxy-phenyl substituted compounds 13a and 13d turned out to be the most potent HDAC inhibitors of this study. The isoform profiling revealed a dual HDAC2/HDAC6 inhibition profile, which was confirmed by the acetylation of α-tubulin and histone H3 in Cal27 and Cal27CisR. In combination with cisplatin, both compounds enhanced the cisplatin-induced cytotoxicity via caspase-3/7 activation. The effect was more pronounced in the cisplatin resistant subline Cal27CisR. The pretreatment with 13d resulted in a complete resensitisation of Cal27CisR with IC₅₀ values in the range of the parental cell line. Therefore, 13d may serve as an epigenetic tool to analyze and modulate the cisplatin resistance of solid tumors.     

Design of novel histone deacetylase inhibitors

Histone deacetylase (HDAC) inhibitors that target Class I and Class II HDACs are of synthetic and therapeutic interest and ongoing clinical studies indicate that they show great promise for the treatment of cancer. Moreover, Zolinza (vorinostat) was recently approved by the FDA for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma [Nat. Rev. Drug Disc. 2007, 6, 21]. As part of a broader effort to more fully explore the structure-activity relationships (SAR) of HDAC inhibitors, we sought to identify novel HDAC inhibitor structures through iterative design by utilizing low affinity ligands as synthetic starting points for SAR development. Novel and potent HDAC inhibitors have been identified using this approach and herein we report the optimization of the recognition elements of a novel series of malonyl-derived HDAC inhibitors.     

Targeting inflammation in heart failure with histone deacetylase inhibitors

Cardiovascular insults such as myocardial infarction and chronic hypertension can trigger the heart to undergo a remodeling process characterized by myocyte hypertrophy, myocyte death and fibrosis, often resulting in impaired cardiac function and heart failure. Pathological cardiac remodeling is associated with inflammation, and therapeutic approaches targeting inflammatory cascades have shown promise in patients with heart failure. Small molecule histone deacetylase (HDAC) inhibitors block adverse cardiac remodeling in animal models, suggesting unforeseen potential for this class of compounds for the treatment of heart failure. In addition to their beneficial effects on myocardial cells, HDAC inhibitors have potent antiinflammatory actions. This review highlights the roles of HDACs in the heart and the potential for using HDAC inhibitors as broad-based immunomodulators for the treatment of human heart failure.     

Zinc binding groups for histone deacetylase inhibitors

Zinc binding groups (ZBGs) play a crucial role in targeting histone deacetylase inhibitors (HDACIs) to the active site of histone deacetylases (HDACs), thus determining the potency of HDACIs. Due to the high affinity to the zinc ion, hydroxamic acid is the most commonly used ZBG in the structure of HDACs. An alternative ZBG is benzamide group, which features excellent inhibitory selectivity for class I HDACs. Various ZBGs have been designed and tested to improve the activity and selectivity of HDACIs, and to overcome the pharmacokinetic limitations of current HDACIs. Herein, different kinds of ZBGs are reviewed and their features have been discussed for further design of HDACIs.     

Discovery of histone deacetylase 8 selective inhibitors

We have developed an efficient method for synthesizing candidate histone deacetylase (HDAC) inhibitors in 96-well plates, which are used directly in high-throughput screening. We selected building blocks having hydrazide, aldehyde and hydroxamic acid functionalities. The hydrazides were coupled with different aldehydes in DMSO. The resulting products have the previously identified ‘cap/linker/biasing element’ structure known to favor inhibition of HDACs. These compounds were assayed without further purification. HDAC8-selective inhibitors were discovered from this novel collection of compounds.     

Design and synthesis of phthalimide-type histone deacetylase inhibitors

Several hydroxamic acid derivatives with a substituted phthalimide group as a linker and/or cap structure, prepared during structural development studies based on thalidomide, were found to have histone deacetylase (HDAC)-inhibitory activity. Structure-activity relationship studies indicated that nature of the substituent introduced at the phthalimide nitrogen atom, introduction of a hydroxamic acid structure, and distance between the N-hydroxyl group and the cap structure are important for HDAC-inhibitory activity.