Structure–Function Analysis of the Conserved Tyrosine and Diverse π‑Stacking among Class I Histone Deacetylases: A QM (DFT)/MM MD Study

Discovery of the isoform-selective histone deacetylases (HDACs) inhibitors is of great medical importance and still a challenge. The comparison studies on the structure–function relationship of the conserved residues, which are located in the linker binding channel among class I HDACs (including 4 isoforms: HDAC1/2/3/8), have been carried out by using <i>ab initio</i> QM/MM MD simulations, a state-of-the-art approach to simulate metallo-enzymes. We found that the conserved tyrosine (Y303/308/286/306 in HDAC1/2/3/8, respectively) could modulate the zinc-inhibitor chelation among all class I HDACs with different regulatory mechanisms. For HDAC1/2/3 selective-inhibitor benzamide, the conserved tyrosine could modulate the coordinative ability of the central atom (Zn²⁺), while for pan-inhibitor SAHA, the conserved tyrosine could increase the chelating ability of the ligand (SAHA). Moreover, it is first found that the conserved tyrosine is correlated with the intertransformation of π–π stacking styles (parallel shift vs T-shaped) by the aromatic ring in benzamide and the two conserved phenylalanine residues of HDACs. In addition, the catalytic roles of the conserved tyrosine in stabilizing the transition state and intermediate are further revealed. These findings provide useful molecular basis knowledge for further isoform-selective inhibitor design among class I HDACs

One-Pot Synthesis of Deuterated Aldehydes from Arylmethyl Halides

A facile, one-pot approach for synthesizing deuterated aldehydes from arylmethyl halides was developed using D₂O as the deuterium source. The efficient process is realized by a sequence of formation, H/D exchange, and oxidation of pyridinium salt intermediates. The mild and air-compatible reaction conditions enable efficient synthesis of diverse deuterated aldehydes with high deuterium incorporation

Design, Synthesis, and Evaluation of Multitarget-Directed Resveratrol Derivatives for the Treatment of Alzheimer’s Disease

A series of multitarget-directed resveratrol derivatives was designed and synthesized for the treatment of Alzheimer’s disease (AD). In vitro studies indicated that most of the target compounds exhibit significant inhibition of self-induced β-amyloid (Aβ) aggregation and Cu­(II)-induced Aβ_1–42 aggregation and acted as potential antioxidants and biometal chelators. In particular, compounds <b>5d</b> and <b>10d</b> are potential lead compounds for AD therapy (<b>5d</b>, IC₅₀ = 7.56 μM and <b>10d</b>, IC₅₀ = 6.51 μM for self-induced Aβ aggregation; the oxygen radical absorbance capacity assay using fluorescein (ORAC-FL) values are 4.72 and 4.70, respectively). Moreover, these compounds are capable of disassembling the highly structured Aβ fibrils generated by self- and Cu­(II)-induced Aβ aggregation. Furthermore, <b>5d</b> crossed the blood–brain barrier (BBB) in vitro and did not exhibit any acute toxicity in mice at doses of up to 2000 mg/kg. Taken together, the data indicate that <b>5d</b> is a very promising lead compound for AD

Computational Design of a Time-Dependent Histone Deacetylase 2 Selective Inhibitor

Development of isoform-selective histone deacetylase (HDAC) inhibitors is of great biological and medical interest. Among 11 zinc-dependent HDAC isoforms, it is particularly challenging to achieve isoform inhibition selectivity between HDAC1 and HDAC2 due to their very high structural similarities. In this work, by developing and applying a novel de novo reaction-mechanism-based inhibitor design strategy to exploit the reactivity difference, we have discovered the first HDAC2-selective inhibitor, β-hydroxymethyl chalcone. Our bioassay experiments show that this new compound has a unique time-dependent selective inhibition on HDAC2, leading to about 20-fold isoform-selectivity against HDAC1. Furthermore, our ab initio QM/MM molecular dynamics simulations, a state-of-the-art approach to study reactions in biological systems, have elucidated how the β-hydroxymethyl chalcone can achieve the distinct time-dependent inhibition toward HDAC2

Prenylated Coumarins: Natural Phosphodiesterase‑4 Inhibitors from <i>Toddalia asiatica</i>

Bioassay-guided fractionation of the ethanolic extract of the roots of <i>Toddalia asiatica</i> led to the isolation of seven new prenylated coumarins (<b>1</b>–<b>7</b>) and 14 known analogues (<b>8</b>–<b>21</b>). The structures of <b>1</b>–<b>7</b> were elucidated by spectroscopic analysis, and their absolute configurations were determined by combined chemical methods and chiral separation analysis. Compounds <b>1</b>–<b>5</b>, named toddalin A, 3‴-<i>O</i>-demethyltoddalin A, and toddalins B–D, represent an unusual group of phenylpropenoic acid-coupled prenylated coumarins. Compounds <b>1</b>–<b>21</b> and four modified analogues, <b>10a</b>, <b>11a</b>, <b>13a</b>, and <b>17a</b>, were screened by using tritium-labeled adenosine 3′,5′-cyclic monophosphate ([³H]-cAMP) as substrate for their inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds <b>3</b>, <b>8</b>, <b>10</b>, <b>10a</b>, <b>11</b>, <b>11a</b>, <b>12</b>, <b>13</b>, <b>17</b>, and <b>21</b> exhibited inhibition with IC₅₀ values less than 10 μM. Toddacoumalone (<b>8</b>), the most active compound (IC₅₀ = 0.14 μM), was more active than the positive control, rolipram (IC₅₀ = 0.59 μM). In addition, the structure–activity relationship and possible inhibitory mechanism of the active compounds are also discussed

Presentation_1_Structure-Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel PDE10 Inhibitors With Antioxidant Activities.PDF

<p>Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of 13 designed compounds showed good PDE10 inhibition at the concentration of 1.0 μM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.</p

Palladium-Catalyzed Decarboxylative Acylation of <i>N</i>‑Nitrosoanilines with α‑Oxocarboxylic Acids

A palladium-catalyzed oxidative C–H bond decarboxylative acylation of <i>N</i>-nitrosoanilines using α-oxocarboxylic acid as the acyl source is described. The catalyst Pd­(OAc)₂ and oxidant (NH₄)₂S₂O₈ enabled <i>ortho</i>-acylation of <i>N</i>-nitrosoanilines at room temperature, affording an array of <i>N</i>-nitroso-2-aminobenzophenones in moderate to excellent yields

Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of Alzheimer’s disease

<p>Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer’s disease (AD). To discover multifunctional anti-AD agents with capability of PDE9 inhibition and antioxidant activity, a series of novel pyrazolopyrimidinone derivatives, coupling with the pharmacophore of antioxidants such as ferulic and lipolic acids have been designed with the assistance of molecular docking and dynamics simulations. Twelve out of 14 synthesised compounds inhibited PDE9A with IC₅₀ below 200 nM, and showed good antioxidant capacities in the ORAC assay. Compound <b>1h,</b> the most promising multifunctional anti-AD agent, had IC₅₀ of 56 nM against PDE9A and good antioxidant ability (ORAC (trolox) = 3.3). The selectivity of <b>1h</b> over other PDEs was acceptable. In addition, <b>1h</b> showed no cytotoxicity to human neuroblastoma SH-SY5Y cells. The analysis on structure-activity relationship (SAR) and binding modes of the compounds may provide insight into further modification.</p

Prostaglandin Derivatives: Nonaromatic Phosphodiesterase‑4 Inhibitors from the Soft Coral <i>Sarcophyton ehrenbergi</i>

Ten new prostaglandin derivatives (PGs), sarcoehrendins A–J (<b>1</b>–<b>10</b>), together with five known analogues (<b>11</b>–<b>15</b>) were isolated from the soft coral <i>Sarcophyton ehrenbergi</i>. Compounds <b>4</b>–<b>8</b> represented the first examples of PGs featuring an 18-ketone group. The structures including the absolute configurations were elucidated on the basis of spectroscopic analysis and chemical evidence. All of the isolates and six synthetic analogues (<b>3a</b>, <b>3b</b>, <b>4a</b>, and <b>11a</b>–<b>11c</b>) were screened for inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds <b>2</b>, <b>10</b>, <b>11a</b>, <b>11b</b>, and <b>13</b>–<b>15</b> exhibited inhibition with IC₅₀ values less than 10 μM, and compound <b>15</b> (IC₅₀ = 1.4 μM) showed comparable activity to the positive control rolipram (IC₅₀ = 0.60 μM). The active natural PGs (<b>2</b>, <b>10</b>, and <b>13</b>–<b>15</b>) represent the first examples of PDE4 inhibitors without an aromatic moiety, and a preliminary structure–activity relationship is also proposed

The Molecular Basis for the Selectivity of Tadalafil toward Phosphodiesterase 5 and 6: A Modeling Study

Great attention has been paid to the clinical significance of phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil, tadalafil, and vardenafil widely used for erectile dysfunction. However, sildenafil causes side effects on visual functions since it shows similar potencies to inhibit PDE5 and PDE6, whereas tadalafil gives a high selectivity of 1020-fold against PDE6. Till now, their molecular mechanisms of selectivity of PDE5 versus PDE6 have remained unknown in the absence of the crystal structure of PDE6. In order to elucidate its isoform-selective inhibitory mechanism, a 3D model of PDE6 was constructed by homology modeling, and its interaction patterns with tadalafil plus sildenafil were exploited by molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. The present work reveals that tadalafil exhibits a less negative predicted binding free energy of −35.21 kcal/mol with PDE6 compared with the value of −41.12 kcal/mol for PDE5, which suggests that tadalafil prefers PDE5 rather than PDE6 and confers a high selectivity for PDE5 versus PDE6. The binding free energy results for tadalafil were consistent with external bioassay studies (IC₅₀ = 5100 and 5 nM toward PDE6 and PDE5, respectively). Two important residues from the Q₂ pockets (Val782 and Leu804 in PDE5 and their corresponding Val738 and Met760 in PDE6) were further identified to account for the high selectivity of tadalafil for PDE5 versus PDE6. These findings have shed light on the continuous puzzle of why sildenafil (IC₅₀ = 74 and 6 nM toward PDE6 and PDE5, respectively) causes visual disorders because of its poor selectivity but tadalafil does not. In addition, the homology model of PDE6 can be used to design more potent and selective second-generation PDE5 inhibitors with less inhibitory potency against PDE6