pci-34051 and Neoplasms

The indole scaffold is one of the most widespread heterocycles in the naturally occurring and synthetic bioactive compounds including anticancer agents. Due to its biodiversity and versatility, it has been a highly privileged motif for the target-based design and development of anticancer agents. In the last decade, many researchers have reported various indole-based compounds with distinct mechanisms involved in producing potential anticancer activities, indicating the importance of indole motif in the anticancer drug development. The present article aims to review the current application of indole core in the design of new anticancer agents that may act via various targets such as histone deacetylases (HDACs), sirtuins, PIM kinases, DNA topoisomerases and σ receptors. Targeting these enzymes or receptors in cancer cells by indole-derived compounds can be a powerful tool for the management of cancer.

Topics: Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Design; Humans; Indoles; Molecular Structure; Neoplasms; Structure-Activity Relationship

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.

Topics: Animals; Antineoplastic Agents; Biological Products; Chemistry Techniques, Synthetic; Drug Discovery; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Models, Molecular; Molecular Targeted Therapy; Neoplasms; Structure-Activity Relationship

Topics: Animals; Antineoplastic Agents; Apoptosis; Binding Sites; Cell Cycle Checkpoints; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Histone Deacetylases; Humans; Mice; Mice, SCID; Molecular Docking Simulation; Neoplasms; PPAR gamma; Repressor Proteins; Structure-Activity Relationship; Thiazolidinediones; Transcriptional Activation; Transplantation, Heterologous

Histone deacetylases (HDACs) are representative targets for the natural and synthetic chemicals used to transform cells to confer antitumor properties. In the current study, curcumin and hydroxamate-derivative PCI-34058-bound HDAC1 were subjected to atomistic simulation. The results support the view that fitting of curcumin and PCI-34058 within the HDAC1 pocket depends on extensive interactions between the aromatic moieties of the inhibitors and the extensive network of aromatic amino acid side chains lining the pocket of HDAC1. The interaction forces a local perturbation of the coiled structures connecting the pocket residues resulting in ligand-induced tightening of the pocket. In addition to the competitive occupancy of the histone-acetyl-lysine binding pocket by the inhibitors, interference with the in-pocket aspartate-histidine (ASP-HIS) charge relay system was also observed in inhibitor-bound HDAC1 systems. In conclusion, curcumin and PCI-34058-mediated ligand-dependent HDAC1 tunnel closure interferes negatively with the ASP-HIS charge relay system in HDAC1. Future design of HDAC inhibitors may benefit from optimizing competitive interaction with the ligand site and interference with the charge relay system.

Topics: Amino Acid Sequence; Catalytic Domain; Curcumin; Histone Deacetylase 1; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Indoles; Ligands; Models, Molecular; Neoplasms