Current Medicinal Chemistry - Volume 24, Issue 37, 2017

Histone deacetylases (HDACs) are epigenetic enzymes creating the transcriptionally inactive state of chromatin by erasing acetyl moiety from histone and non-histone substrates. HDAC6 modulates several biological pathways in dividing cells as well as in post-mitotic neurons, and has been implicated in the pathophysiology of neurodegeneration. The distinct cellular functions and survival in these cells are reliant on HDAC6-mediated processes including intracellular trafficking, chaperone-mediated stress responses, anti-oxidation and protein degradation. Consequently, the interest in HDAC6 as a promising therapeutic target to tackle neurodegenerative disorders has escalated markedly over the last decade. Taking these grim facts into consideration, the current article focuses on structural organization of HDAC6. Importantly, we discuss the general role of HDACs in cognition and neuronal death. Further, we describe the unique involvement of HDAC6 in eliminating protein aggregates, oxidative stress and mitochondrial transport. Moreover, the article rigorously details how the impaired activity of HDAC6 culminates in neurodegenerative complications like Alzheimer disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Lastly, we provide crystal clear view regarding the fascinating research areas which may lead to the development of novel small-molecules for enhanced therapeutic benefit against these therapeutically arduous neurodegenerative maladies.

Histone acetyltransferases (HATs) are epigenetic drivers that catalyze the acetyl transfer from acetyl-CoA to lysines of both histone and non-histone substrates and thereby induce transcription either by chromatin remodeling or direct transcription factor activation. Histone deacetylases (HDACs) conduct the reverse reaction to counter HAT activity. Physiological processes such as cell cycle progression or apoptosis require a thoroughly balanced equilibrium of the interplay between acetylation and deacetylation processes to maintain or, if required, alter the global acetylome status. Aberrant HAT activity has recently been demonstrated to play a crucial role in the progression of various diseases such as prostate, lung, and colon cancers as well as glioblastomas and neurodegenerative diseases. Recent investigations have aimed for the identification of HAT modulators to further decipher the complexity of acetyl transferase related signaling cascades and discover potential leads for drug design approaches. HDACs have been extensively characterized and targeted by small molecules, including four FDA-approved HDAC inhibitors; in contrast, HATs have not been active targets for therapeutic development. This review will summarize the status of HAT associated diseases and the arsenal of currently known and available HAT inhibitors with respect to their discovery, further improvements, and current applications.

Histone deacetylases (HDACs) influence diverse cellular processes and may contribute to tumor development and progression by multiple mechanisms. Class I HDACs are often overexpressed in cancers contributing to a genome-wide epigenetic state permitting increased proliferation, and diminished apoptosis and cell differentiation. Class IIA and IIB isoenzymes may likewise contribute to tumorigenesis as components of specific intranuclear repressor complexes or regulators of posttranslational protein modifications. As HDAC inhibitors may counteract these tumorigenic effects several of these compounds are currently tested in clinical trials. HDAC inhibitors are also considered for urothelial carcinoma, where novel therapeutic drugs are urgently required. However, only modest antineoplastic activity has been observed with isoenzyme-unspecific pan-HDAC inhibitors. Therefore, inhibition of specific HDAC isoenzymes might be more efficacious and tumor-specific. Here, we systematically review knowledge on the expression, function and suitability as therapeutic targets of the 11 classical HDACs in UC. Overall, the class I HDACs HDAC1 and HDAC2 are the most promising targets for antineoplastic treatment. In contrast, targeting HDAC8 and HDAC6 is likely to be of minor relevance in urothelial carcinoma. Class IIA HDACs like HDAC4 require further study, since their downregulation rather than upregulation could be involved in urothelial carcinoma pathogenesis.

Background: Histone deacetylases (HDACs) play key roles in many biological phenomena and HDAC inhibition has been proved to be an effective strategy in cancer therapy. Over the last few decades, a plethora of structurally diverse HDAC inhibitors have been reported for a broad range of tumor indications. Among them, macrocyclic HDAC inhibitors, including cyclic peptides, depsipeptides and peptidomimetics, etc., have drawn lots of interests because of the fact that macrocyclic HDAC inhibitors have the potential for member or isoform selective inhibition. Conclusion: Macrocyclic HDAC inhibitors present an excellent opportunity for the selective modulation of HDAC inhibitors due to their complex recognition cap group moieties. However, compared with the structurally simpler synthetic HDAC inhibitors, efforts to develop macrocyclic HDAC inhibitors have been so far modestly successful with only one compound (romidepsin) approved for the cancer treatment. Development of macrocyclic HDAC inhibitors are hampered by the complex reaction schemes required for their synthesis. We expect that in the near future, more macrocyclic HDAC inhibitors will be identified from natural products; and further modification or SAR studies will be made on these or already known natural macrocyclic HDAC inhibitors. More selective drug-like macrocyclic HDAC inhibitors will be designed and identified after understanding the interactions between the ligand and the HDACs.

Tuberculosis (TB) accounts for millions of deaths worldwide every year. Diverse survival strategies adopted by Mycobacterium tuberculosis (Mtb) have substantially hindered the existing anti-TB regimen thereby leading to multidrug-resistant (MDR) and extremely drug-resistant (XDR) strains of TB. The steady decrease in current antibiotics’ efficacy against these adversities is an indicator that their adequate replenishment in future is almost impossible, placing society on the precipice of a catastrophe. Over the past many years, researchers have been continuously generating new armamentarium of anti- TB drugs by tailoring the properties of available drugs or designing completely new agents. One of these emerging and successful synthetic techniques is molecular hybridization (MH) that involves the integration of different pharmacophoric subunits to form a new prototype with the ability to be recognized by multiple receptors. In most cases, the resultant conjugates have been reported to exhibit superior biological activity profiles relative to their parent molecules which is attributed to their different or dual modes of action. Accordingly, several new effective anti-TB scaffolds have been synthesized using this approach, and are well cited in literature. In this review, we provide a summarized account of the chemical strategies optimistically focused to develop new molecular assemblies for TB via MH approaches. Additionally, the structure activity relationships revealed from different biological assays is systematically discussed.