Review article
HDAC as onco target: Reviewing the synthetic approaches with SAR study of their inhibitors

https://doi.org/10.1016/j.ejmech.2018.08.073Get rights and content

Highlights

  • Epigenetic modifications such as HDAC act as promising target for treatment of cancer.

  • Overview of synthetic approaches and SARs study of prototype with biological data.

  • Other structural modifications include dual targeting and natural HDAC inhibitors.

Abstract

Even though one is moving towards the success in the discovery of efficient anti-cancer molecules, the drugs used in the treatment of various malignancies are found to possess toxicity and adverse reactivity in the human body that limit their use. The scientists all over the world are engaged in bringing up strategies that aim to develop small molecules that target the abnormal epigenetic factors. The discovery of the role of Histone deacetylases (HDACs) has promised to be a turning point in the treatment of various malignancies. Thus, the invention of potent and safe anticancer therapeutics agents with minimal adverse and side effects are still a major topic of concern and a huge number of research works have been reported in the past few years. This review has been written to discuss on the influence of Histone Deacetylases in cancer malignancies. We have tried to embrace majority of the developments made till date in the field of HDAC and its inhibitors herein. The drugs that are clinically applied, synthesis and SAR study that highlight the chemical groups responsible for evoking the HDAC inhibition and potential of various new classes of HDAC inhibitors (synthetic, hybrid and natural) have also been included.

Introduction

After years of research, the researchers developed a deep-seated knowledge that cancer occurs because of aggressive mutations that occur in the human genome. The supremacy of oncogenes and the suppression of tumor suppressing genes have always been the prime factor in cancer. Pathophysiology of cancer involves genetic factors, metastasis and epigenetic factors. Genetic factors include the heavy emergence of oncogenes and suppression of tumor suppressor genes which may be attributed to mutations that occur as a result of exposure to various carcinogens that may be chemically induced or physically induced. Other than genetic factors, the important one is the epigenetic modifications that involve modifications except the gene mutations. In other words, epigenetic modifications are the one that does not involve any change in nucleotide sequence. They include DNA hypo- and hyper-methylation, modifications in the histone protein and changes in chromosomal framework caused by indecorous expression of certain proteins. Histone proteins can undergo a variety of changes some of which include formylation, methylation, acetylation, phosphorylation, propionylation, butyrylation, hydroxylation etc. Apart from these modifications, a family of HDACs is involved in regulation of chromatin structure and function.

The epigenetic modification not only alter the interaction of the histone with DNA but also affects the ability of chromatin associated complexes to deal with the proof reading mechanism thereby losing their ability to control cell growth and differentiation, so epigenetic modifications like genetic changes can act as drivers for cancer onset and development.

Numerous efforts have been made to synthesize effective anticancer drugs but resistance to the type of chemotherapy employed leads to failure of treatment. Epigenetic changes may be considered as a part consequence of chemo-resistance which leads to failure to treatment of genetic mutations and metastasis. The development of drugs that prevent these epigenetic changes had provided a deep insight into anticancer drug research. One such class of drugs that inhibit a type of epigenetic change is the histone deacetylase inhibitor, which prevents the deacetylation of histone by inhibiting the enzyme histone deacetylase [1]. HATs and HDACs are the class of enzymes that regulate acetylation and deacetylation of the histone proteins (Scheme 1) [2]. The amount of histone acetylation governed by HDAC and HAT (Histone acetyl transferase) along with the post-translational modifications defines a gene code that is identified by the proteins other than the histone proteins involved in the regulation of gene expression. HDACs are also involved in the acetylation of some non-histone proteins such as p53 and other transcription factors which shall be discussed later in the review [3].

HDACs are also involved in a number of other biological pathways such as cellular signal transduction, cellular growth, death and various types of cancer mainly myeloid leukemia [4,5]. It can be said that the levels of lysine residue acetylations of histone 3 and 4 are controlled by the balanced activities of HDAC and HAT on the histone proteins [6]. These are seen in early tumorogenesis which proves the deacetylation and demethylation of the residues (especially the lysine residues) of the histone H4 as the main feature in cancer development [7].

The mechanism underlying histone hypoacetylation in cancer is not known but the hypothesis produced by various researcher states that it is due to the laziness of HATs to acetylate the lysine residues due to impaired DNA or chromosomal dislocations or due to hyper handwork of HDACs [8]. It had been seen that, under stress conditions, tumor suppressor p53 is acetylated both in-vitro and in-vivo by HDAC1 which indicating them to be the key regulators in normal cellular functions and as promising targets for the treatment of malignancies inspiring the researchers to develop anti-HDACs [9].

Even after twenty years of synthetic efforts, only 4 new molecules have been approved by FDA as HDAC inhibitors. Some are still on the urge to leave behind the clinical trials and become epigenetic drug candidates that can be either used as a main drug or an adjuvant with the existing potent anti-cancer drugs to further improve their potency. Valproic acid known for its anti-epileptic activity was tested for its HDAC inhibition due to the known pharmacological profile of the drug. This further increased the curiosity of the researchers and led to the discovery of the first FDA clinically approved drug Vorinostat otherwise known as SAHA i.e., suberoylanilide hydroxamide, added on by another cyclic peptide called Romidepsin. This was followed by Belinostat and Panabinostat. Even though the success of HDAC inhibitors is celebrated for leukemias, they are still a failure in case of solid tumors.

It can be expected that the next generation HDAC inhibitors will provide a light on the required improvements taking into consideration they are delivered in an optimized way. In this review, we mainly pivot on brief knowledge of biological of HDAC and chemistry of presently available HDAC inhibitors, inhibitors in clinical trial and available synthetic schemes with SAR study of several emerging HDAC inhibitors which categorize on the basis of their structure modification such as with modified cap group, linker and different zinc binding groups. Prior to these, we gave some fundamental information in the epigenetic biology of HDACs since the basics of how things work in case of HDACs had to be first recalled.

Section snippets

Classification of HDACs

Till date, eighteen types of human HDAC enzymes have been identified and they are classified into four groups based on their similarity with yeast HDACs. Out of all the classes of HDAC enzyme known, class I, II, and IV HDAC enzymes are metallo-enzymes (zinc dependent) that require zinc metal ion for pronouncing biological activity [[10](b), [10], [10](a)].

SAR study of hydroxamic acid derivatives

SAHA inhibits most of the 11 metal dependent HDAC isoforms. Nonspecific inhibition may account for several mild to severe side effects associated with treatment, including dehydration, thrombocytopenia, anorexia and cardiac arrhythmia. Due to the continual use and side effects associated with HDACi, there has been developing concern for minimizing the side effects by modifying the cap group by using benzimidazole, purine, pyrimidine, lactam and linker such as substituted aliphatic, triazole,

Dual targeting HDAC inhibitors

Hybrid molecules are described as a chemical entity with two (or more than two) pharmacophores which works on disparate or same biological functions or targets via diverse approach. These are designed to optimize biological properties like affinity and selectivity. Due to its advanced mode of action and high selectivity, the hybrid molecules based chemotherapy emerges as a beneficial tool in contemporary trend of anticancer drug discovery [327].

Single target agents can perform excellent during

Natural HDAC inhibitors

Bioactive natural pharmacophores are serendipitous drug candidates, which prompt synthetic strategies for enhancing, improving and helping the drug research and development. It has been found that natural HDAC inhibitors have surfaced as one of the most successful HDAC inhibitors [[356](a), [356](b), [356]]. The exploration of naturally present HDACi has contributed intensely potent inhibition of the deacetylase enzymes. On the basis of structural features, the known natural HDACi are divided

Summary and outlooks

The present review covers the focal points of HDAC inhibitors derivatives as a template for the exploration and advancement of anticancer agents. In recent years much attention has been focused on HDAC, metalloenzyme of multicomponent structure, as one of various cancer specific targets tested. Activities of HDACs have been seen to be regulated on multiple levels, including protein-protein interactions, post-translational modifications (sumoylation, phosphorylation and proteolysis), subcellular

Acknowledgements

Rekha Sangwan highly acknowledges Council of Scientific and Industrial Research (CSIR) for Senior Research Fellowship. Author gratefully acknowledges financial support by Department of Science and Technology (DST), India. This is CDRI communication no 9738.

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