Design, synthesis and anticancer activity of novel valproic acid conjugates with improved histone deacetylase (HDAC) inhibitory activity
Graphical abstract
Introduction
Targeted anticancer agents is one of the most promising strategy for optimizing anticancer therapies to avoid the severe side effects of chemotherapeutic agents such asdose-related side effects, sever systemic toxicity, lack of selectivity or development of drug-resistance [1]. Histone deacetylases (HDACs) represent one of the most important validated cancer targets [2]. Recently, several HDAC inhibitors have been approved worldwide as anticancer agents such as Vorinostat (SAHA) [3], Romidepsin (FK228) [4], Belinostat (PXD101) [5], Panobinostat (LBH-589) [6] and Chidamide (CS055) [7] and many are in clinical trials like Valproic acid (VPA), Butyric acid, Rocilinostat, Practinostate, Givinostat and Entinostat (Fig. 1). Thus, HDAC inhibitors discovery and development are a promising therapeutic approach in drug design for targeting cancer [8], where the three common functional and pharmacophore patterns for design of HDAC inhibitors have been recognized and could be represented as: A) Cap, B) linker, and C) zinc binding group (ZBG) [9] as shown in Fig. 1.
Many HDAC inhibitors were designed and synthesized either via modifying the cap structural entity [10], [11], [12], extension/contraction of the spacer [13], [14], [15], or varying the ZBG by having hydroxamate [16], [17], [18], benzamide [19], [20], thioester [21], [22], thiol based [23], [24], or recently hydrazide [25], [26], [27] based derivatives.
Short-chain fatty acids and their derivatives such as Valproic acid (VPA, 2-propylpentanoic acid), are an important class of HDAC inhibitors. VPA has been widely approved in the treatment of epilepsy and other neuropsychiatric diseases, along with potent anti-cancer activities either as a single agent, or as part of different combination regimens; VPA can acquire synergistic activity with other anticancer agents and also, re-sensitize cells that have acquired resistance [28], [29]. Carboxylic acid group containing molecules were reported as a weak HDAC Inhibitors due to their weak zinc ion binding abilities, when compared to hydroxamic acid or benzamide ZBGs [9]. Additionally, VPA is considered linkerless HDAC inhibitor where carboxylic acid ZBG is directly connected to cap group without any spacer. However, SAR of Carboxylic acids HDAC Inhibitors revealed that short chain fatty acid with 3–6 carbons linker show good HDAC inhibitory [6], [30].
The carboxylic acid and its derivatives play an important role in the biochemistry of living systems as well as in drug development process. This functional group is often part of the pharmacophore of diverse classes of therapeutic agents. In fact, more than 450 carboxylic acid-containing drugs have been marketed worldwide such as non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, anticoagulants, and cholesterol-lowering statins, among others [31], [32].
Carboxylic acid acts as important pharmacophore function group that fulfill the essential criteria for optimal physicochemical and bioavailability rules such as Lipinski’s “Rule of Five” for oral drugs [33] and Astex’s “Rule of Three” for fragment-based lead discovery [34]. In addition, this group has the ability both as hydrogen-bond donors and hydrogen-bond acceptors in a single molecule.
Motivated by the previously mentioned data and in continuous to our drug development program, herein, we extended our approach with Valproic acid, histone deacetylase inhibitors (HDACIs). A new set of VPA conjugates (Fig. 2) containing variable cyclic or acyclic linkers and carboxylic, amide, hydrazide or hydroxamicacid ZBG is designed. This design has the potential to increase binding to HDAC enzyme, consequently enhancing potency and selectivity as well as decreasing toxicity and improvement of bioavailability.
Section snippets
Chemistry
Compounds 2a-k were synthesized as depicted in scheme 1, where Valproic acid was activated as its benzotriazolide derivative 1 following the previously reported procedure [35] and coupled with free amino acids in a mixture of acetonitrile and water (7:3) at 20 °C for 2 h in the presence of 1.5 equivalents of triethylamine to give compounds 2a-h. Compound 1 was also coupled with N and S nucleophiles to yield the corresponding conjugates 2i, 2j and 2k (Scheme 1).
Valproic acid-amino acid
Docking studies
In order to investigate the interaction between valproic acid conjugate target compounds and HDACs, compound 4j was selected for docking into the active site of HDAC 1 (PDB entry: 5ICN), HDAC 2 (PDB code: 4LXZ), HDAC 3 (PDB entry: 4A69), HDAC 4 (PDB entry: 4CBT), HDAC 6 (PDB entry: 5EF8) and HDAC 8 (PDB entry: 3SFH) using Discovery Studio software package with to elucidating the binding mode of these compounds with HDAC enzymes and investigate their similarity to the native ligand (SAHA).
Conclusion
In summary, a series of twenty-fivevalproic acid conjugates 2a-k and 4a-n have been synthesized and were evaluated for their in vitro anti-proliferative activities using the MTT-based assay against four human cancer cell lines including HePG2 (liver), HCT116 (colon), MCF7 (breast) and Hela (cervical) carcinoma cell lines. Compounds 4j (IC50 5.35–14.08 µM) and 4k (IC50 9.62–14.82 µM) displayed the highest and broad-spectrum anti-proliferative activity. Compound 2f showed strong
Chemistry
Starting materials and solvents were purchased from common commercial sources and used without further purification. Melting points were determined on Fisher melting apparatus and are uncorrected. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on Bruker a 400 MHz NMR spectrometer and using DMSO‑d6 as solvent, at Faculty of Science, Zagazig University. Also, 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded on Bruker a 300 MHz NMR spectrometer and using DMSO‑d6 as
Acknowledgments
This project was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, under grant №. (RG-9-166-38). The authors, therefore, gratefully acknowledge DSR technical and financial support.
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