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Design, Synthesis, and Docking Study of Acyl Thiourea Derivatives As Possible Histone Deacetylase Inhibitors with a Novel Zinc Binding Group

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Design, Synthesis, and Docking Study of Acyl Thiourea Derivatives As Possible Histone Deacetylase Inhibitors with a Novel Zinc Binding Group Scientia Pharmaceutica Article Design, Synthesis, and Docking Study of Acyl Thiourea Derivatives as Possible Histone Deacetylase Inhibitors with a Novel Zinc Binding Group Duraid H. Al-Amily * and Mohammed Hassan Mohammed Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad, Baghdad 10047, Iraq; [email protected] * Correspondence: [email protected] Received: 1 September 2019; Accepted: 16 October 2019; Published: 22 October 2019 Abstract: Histone deacetylase inhibitors with zinc binding groups often exhibit drawbacks like non-selectivity or toxic effects. Thus, there are continuous efforts to modify the currently available inhibitors or to discover new derivatives to overcome these problems. One approach is to synthesize new compounds with novel zinc binding groups. The present study describes the utilization of acyl thiourea functionality, known to possess the ability to complex with metals, to be a novel zinc binding group incorporated into the designed histone deacetylase inhibitors. N-adipoyl monoanilide thiourea (4) and N-pimeloyl monoanilide thiourea (5) have been synthesized and characterized successfully. They showed inhibition of growth of human colon adenocarcinoma and mouse hepatoblastoma cells with low cytotoxic effect against normal human breast cells. Their binding mode to the active site of several histone deacetylases has been studied by docking and the results gave a preliminary indication that they could be successful histone deacetylase inhibitors. Keywords: histone deacetylase inhibitors; acyl thiourea derivatives; zinc binding group; distance from zinc ion 1. Introduction Histone deacetylases (HDACs) comprise a class of enzymes that catalyze the deacetylation of the "-amino groups of lysine residues at the N-termini of histones [1], proteins that act as a core for DNA compaction into nucleosomes that comprise chromatins [2]. The deacetylation process results in the compaction of nucleosomes and subsequently the repression of gene transcription. Many reports demonstrate that HDACs are overexpressed in several types of cancer [3,4]. Therefore, they represent a valuable target for cancer treatment [5]. In mammalian cells, the identified HDACs represent 18 isoforms and they fall into four major classes (I–IV). Class I includes HDAC1, 2, 3, and 8 while class II includes isoforms 4–7, 9 and 10. Isoform 11 represents class IV. These three classes are zinc-dependent in their activity. The remaining seven isoforms depend on the cofactor nicotine adenine dinucleotide rather than zinc for their catalytic activity and comprise class III [6]. The zinc-dependent classes are most commonly investigated and subjected to inhibition studies as an approach for cancer treatment [7]. HDAC2 is a common example, since its crystallographic structure is well resolved [8]. Early studies on the binding site revealed that it is shaped as an internal tunnel-like cavity having a length of 11 Å. At the bottom of this cavity, a zinc ion is positioned followed by a 14 Å foot-like pocket [9] (Figure1). Lysine residues of histone fit into the tunnel so that they could be deacetylated [10,11]. Sci. Pharm. 2019, 87, 28; doi:10.3390/scipharm87040028 www.mdpi.com/journal/scipharm Sci. Pharm. 2019, 87, 28 2 of 15 Sci. Pharm. 2019, 87, x FOR PEER REVIEW 2 of 16 Sci. Pharm. 2019, 87, x FOR PEER REVIEW 2 of 16 Figure 1. The binding site of histone deacetylase 2. (A) The opening of the tunnel cavity is shown in FigureFigure 1.1. TheThe binding site of h histoneistone deacetylas deacetylasee 2 2.. (A (A) )The The opening opening of of the the tunnel tunnel cavity cavity is isshown shown in which the linker of the inhibitor (cyan) is lying. (B) A side view of the binding site with 30% inwhich which the the linker linker of of the the inhibitor inhibitor (cyan) (cyan) is is lying. lying. (B (B) )A A side side v viewiew of of the binding sitesite withwith 30%30% transparency of the surface to make the whole length of the tunnel (11 Å) visible together with the transparencytransparency ofof thethe surfacesurface toto makemake thethe wholewhole lengthlength ofof thethe tunneltunnel (11(11 Å)Å) visiblevisible togethertogether withwith thethe linker of the inhibitor (forest green). Zinc ion is visible at the deepest end of the tunnel. (C) Mesh linkerlinker ofof thethe inhibitorinhibitor (forest(forest green).green). ZincZinc ionion isis visiblevisible atat thethe deepestdeepest endend ofof the the tunnel. tunnel. ((CC)) MeshMesh surface of the binding site showing the inhibitor inside the 14 Å foot-like pocket. surfacesurface ofof thethe bindingbinding sitesite showingshowing the the inhibitorinhibitor insideinside the the 14 14 Å Å foot-like foot-like pocket. pocket. Accordingly, the design of inhibitors for zinc-dependent HDACs should have a zinc binding Accordingly,Accordingly, the the design design of of inhibitors inhibitors for zinc-dependentfor zinc-dependent HDACs HDACs should sho haveuld ahave zinc a binding zinc binding group group (ZBG) to bind to the zinc ion, a linker chain that mimics acetylated lysine of histone to fit into (ZBG)group to (ZBG) bind to thebind zinc to the ion, zinc a linker ion, chaina linker that chain mimics that acetylated mimics acetylated lysine of histone lysine of to histone fit into the to fit cavity, into the cavity, and a hydrophobic cap to recognize and interact with the outer surface. These are best andthe acavity, hydrophobic and a hydrophobic cap to recognize cap to and recognize interact withand interact the outer with surface. the outer These surface. are best These illustrated are best by illustrated by the classical, FDA-approved inhibitor suberoylanilide hydroxamic acid 1 (SAHA, theillustrated classical, by FDA-approved the classical, inhibitorFDA-approved suberoylanilide inhibitor hydroxamic suberoylanilide acid 1hydroxamic(SAHA, vorinostat) acid 1 (SAHA, [12,13]. vorinostat) [12,13]. vorinostat)Othercommon [12,13]. synthetic inhibitors with ZBG other than hydroxamic acid derivatives include Other common synthetic inhibitors with ZBG other than hydroxamic acid derivatives include entinostatOther2 common(MS-275), synthetic a benzamide, inhibitors and with the short-chainZBG other than aliphatic hydroxamic carboxylic acid acid, derivatives valproic include acid 3 entinostat 2 (MS-275), a benzamide, and the short-chain aliphatic carboxylic acid, valproic acid 3 (Figureentinostat2). 2 (MS-275), a benzamide, and the short-chain aliphatic carboxylic acid, valproic acid 3 (Figure 2). (Figure 2). Figure 2. Common histone deacetylase inhibitors with zinc binding group group.. Figure 2. Common histone deacetylase inhibitors with zinc binding group. The most most common common d disadvantagesisadvantages encountered encountered with with these these classes classes of inhibitors of inhibitors are arerelated related to the to The most common disadvantages encountered with these classes of inhibitors are related to the poorthe poor pharmacokinetic pharmacokinetic profile profile and and enzyme enzyme non non-specificity-specificity of ofhydroxamates, hydroxamates, inin vivo vivo toxicitytoxicity of poor pharmacokinetic profile and enzyme non-specificity of hydroxamates, in vivo toxicity of benzamides duedue toto thethe freefreeo o-amine-amine group, group, and and the the weak weak binding binding of of the the carboxylic carboxylic acids acids to zincto zinc ion ion [5]. benzamides due to the free o-amine group, and the weak binding of the carboxylic acids to zinc ion These[5]. These problems problems encouraged encouraged us to us design to design new new compounds compounds that that keep keep both both the hydrophobicthe hydrophobic cap andcap [5]. These problems encouraged us to design new compounds that keep both the hydrophobic cap andlinker linker but withbut with a new, a new, unique unique ZBG. ZBG. and linker but with a new, unique ZBG. Acyl thiourea derivatives can coordinate metals in either a bidentate fashion through both the Acyl thiourea derivatives can coordinate metals in either a bidentate fashion through both the carbonyl oxygen and the thiocarbonyl sulfur [14,15] [14,15],, or a monodentate fashion via the thiocarbonyl carbonyl oxygen and the thiocarbonyl sulfur [14,15], or a monodentate fashion via the thiocarbonyl sulfur only [[16,17]16,17] (Figure3 3).). ThioureaThiourea itselfitself cancan coordinatecoordinate metalsmetals throughthrough itsits sulfursulfur oror throughthrough oneone sulfur only [16,17] (Figure 3). Thiourea itself can coordinate metals through its sulfur or through one of its nitrogen atomsatoms [[1818–2020]].. of its nitrogen atoms [18–20]. Sci. Pharm. 2019, 87, 28 3 of 15 Sci. Pharm. 2019, 87, x FOR PEER REVIEW 3 of 16 Sci. Pharm. 2019, 87, x FOR PEER REVIEW 3 of 16 Figure 3. Coordination modes of acyl thiourea derivative with metal ions as bidentate (a) or Figure 3.3.Coordination Coordination modes modes of acylof acyl thiourea thiourea derivative derivative with metal with ions metal as bidentate ions as ( abidentate) or monodentate (a) or monodentate (b). monodentate(b). (b). Here,Here, we we wish wish to to describe describe for for the the first firstfirst tim timetimee the the synthesis synthesis of of two two novel novel substituted substituted acyl acyl thiourea thiourea derivativesderivatives (compounds (compounds(compounds4 and44 andand5, Figure 55, , FigureFigure4) as possible 44) ) asas possible inhibitorspossible inhibitorsinhibitors for zinc-dependent forfor zinczinc-dependent- histonedependent deacetylase
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