Regulation of human hydrolases and its implications in pharmacokinetics and pharmacodynamics.

Hydrolases represent an essential class of enzymes indispensable for the metabolism of various clinically essential medications. Individuals exhibit marked differences in the expression and activation of hydrolases, resulting in significant variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by these enzymes. The regulation of hydrolase expression and activity involves both genetic polymorphisms and nongenetic factors. This review examines the current understanding of genetic and nongenetic regulators of six clinically significant hydrolases, including Carboxylesterase 1 (CES1), Carboxylesterase 2 (CES2), Arylacetamide Deacetylase (AADAC), Paraoxonase 1 (PON1), Paraoxonase 3 (PON3), and Cathepsin A (CTSA). We explore genetic variants linked to the expression and activity of the hydrolases and their effects on the PK and PD of their substrate drugs. Regarding nongenetic regulators, we focus on the inhibitors and inducers of these enzymes. Additionally, we examine the developmental expression patterns and gender differences in the hydrolases when pertinent information was available. Many genetic and nongenetic regulators were found to be associated with the expression and activity of the hydrolases and PK and PD. However, hydrolases remain generally understudied compared to other drug-metabolizing enzymes, such as cytochrome P450s. The clinical significance of genetic and nongenetic regulators has not yet been firmly established for the majority of hydrolases. Comprehending the mechanisms that underpin the regulation of these enzymes holds the potential to refine therapeutic regimens, thereby enhancing the efficacy and safety of drugs metabolized by the hydrolases. Significance Statement Hydrolases play a crucial role in the metabolism of numerous clinically important medications. Genetic polymorphisms and nongenetic regulators can affect hydrolases' expression and activity, consequently influencing the exposure and clinical outcomes of hydrolase substrate drugs. A comprehensive understanding of hydrolase regulation can refine therapeutic regimens, ultimately enhancing the efficacy and safety of drugs metabolized by the enzymes.

Plasma Carboxylesterase 1 Predicts Methylphenidate Exposure: A Proof-of-Concept Study Using Plasma Protein Biomarker for Hepatic Drug Metabolism.

Hepatic drug-metabolizing enzymes (DMEs) play critical roles in determining the pharmacokinetics and pharmacodynamics of numerous therapeutic agents. As such, noninvasive biomarkers capable of predicting DME expression in the liver have the potential to be used to personalize pharmacotherapy and improve drug treatment outcomes. In the present study, we quantified carboxylesterase 1 (CES1) protein concentrations in plasma samples collected during a methylphenidate pharmacokinetics study. CES1 is a prominent hepatic enzyme responsible for the metabolism of many medications containing small ester moieties, including methylphenidate. The results revealed a significant inverse correlation between plasma CES1 protein concentrations and the area under the concentration-time curves (AUCs) of plasma d-methylphenidate (P = 0.014, r = -0.617). In addition, when plasma CES1 protein levels were normalized to the plasma concentrations of 24 liver-enriched proteins to account for potential interindividual differences in hepatic protein release rate, the correlation was further improved (P = 0.003, r = -0.703), suggesting that plasma CES1 protein could explain ~ 50% of the variability in d-methylphenidate AUCs in the study participants. A physiologically-based pharmacokinetic modeling simulation revealed that the CES1-based individualized dosing strategy might significantly reduce d-methylphenidate exposure variability in pediatric patients relative to conventional trial and error fixed dosing regimens. This proof-of-concept study indicates that the plasma protein of a hepatic DME may serve as a biomarker for predicting its metabolic function and the pharmacokinetics of its substrate drugs.

Effect of CES1 genetic variation on enalapril steady-state pharmacokinetics and pharmacodynamics in healthy subjects.

AIMS: Enalapril is a prodrug and needs to be activated by carboxylesterase 1 (CES1). A previous in vitro study demonstrated the CES1 genetic variant, G143E (rs71647871), significantly impaired enalapril activation. Two previous clinical studies examined the impact of G143E on single-dose enalapril PK (10 mg); however, the results were inconclusive. A prospective, multi-dose, pharmacokinetics and pharmacodynamics (PK/PD) study was conducted to determine the impact of the CES1 G143E variant on enalapril steady-state PK and PD in healthy volunteers. METHODS: Study participants were stratified to G143E non-carriers (n = 15) and G143E carriers (n = 6). All the carriers were G143E heterozygotes. Study subjects received enalapril 10 mg daily for seven consecutive days prior to a 72 hour PK/PD study. Plasma concentrations of enalapril and its active metabolite enalaprilat were quantified by an established liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. RESULTS: The CES1 G143E carriers had 30.9% lower enalaprilat Cmax (P = 0.03) compared to the non-carriers (38.01 vs. 55.01 ng/mL). The carrier group had 27.5% lower AUC0-∞ (P = 0.02) of plasma enalaprilat compared to the non-carriers (374.29 vs. 515.91 ng*h/mL). The carriers also had a 32.3% lower enalaprilat-to-enalapril AUC0-∞ ratio (P = 0.003) relative to the non-carriers. The average maximum reduction of systolic blood pressure in the non-carrier group was approximately 12.4% at the end of the study compared to the baseline (P = 0.001). No statistically significant blood pressure reduction was observed in the G143E carriers. CONCLUSIONS: The CES1 loss-of-function G143E variant significantly impaired enalapril activation and its systolic blood pressure-lowering effect in healthy volunteers.

Paramagnetic Carbon Nanosheets with Random Hole Defects and Oxygenated Functional Groups.

Ordered graphitic carbon nanosheets (GCNs) were, for the first time, synthesized by the direct condensation of multifunctional phenylacetyl building blocks (monomers) in the presence of phosphorous pentoxide. The GCNs had highly ordered structures with random hole defects and oxygenated functional groups, showing paramagnetism. The results of combined structural and magnetic analyses indicate that the hole defects and functional groups are associated with the appearance and stabilization of unpaired spins. DFT calculations further suggest that the emergence of stabilized spin moments near the edge groups necessitates the presence of functionalized carbon atoms around the hole defects. That is, both hole defects and oxygenated functional groups are essential ingredients for the generation and stabilization of spins in GCNs.

Oxidative Dehydrogenation of Ethylbenzene into Styrene by Fe-Graphitic Catalysts.

Carbon-based catalysts have attracted much attention for the dehydrogenation (DH) of organic molecules, due to their rich active sites, high conversion efficiency, and selectivity. However, because of their poor stability at high operation temperature and relatively high cost, their practical applications have been limited. Here, we report a simple ball-milling-induced mechanochemical reaction which can introduce iron (Fe) and different functional groups (mostly stable aromatic C═O after heat-treatment) along the edges of graphitic nanoplatelets. The resulting Fe-graphitic nanoplatelets (Fe-XGnPs, X = H, C, N, or V) provide active sites for the oxidative dehydrogenation (ODH) of ethylbenzene into styrene. Among them, Fe-NGnPs (X = N) displayed the highest performance for styrene production at low temperature (∼11.13 mmol g-1 h-1, 450 °C) with high selectivity and durability.

Direct Synthesis of a Covalent Triazine-Based Framework from Aromatic Amides.

There have been extensive efforts to synthesize crystalline covalent triazine-based frameworks (CTFs) for practical applications and to realize their potential. The phosphorus pentoxide (P2 O5 )-catalyzed direct condensation of aromatic amide instead of aromatic nitrile to form triazine rings. P2 O5 -catalyzed condensation was applied on terephthalamide to construct a covalent triazine-based framework (pCTF-1). This approach yielded highly crystalline pCTF-1 with high specific surface area (2034.1 m2 g-1 ). At low pressure, the pCTF-1 showed high CO2 (21.9 wt % at 273 K) and H2 (1.75 wt % at 77 K) uptake capacities. The direct formation of a triazine-based COF was also confirmed by model reactions, with the P2 O5 -catalyzed condensation reaction of both benzamide and benzonitrile to form 1,3,5-triphenyl-2,4,6-triazine in high yield.

A Robust 3D Cage-like Ultramicroporous Network Structure with High Gas-Uptake Capacity.

A three-dimensional (3D) cage-like organic network (3D-CON) structure synthesized by the straightforward condensation of building blocks designed with gas adsorption properties is presented. The 3D-CON can be prepared using an easy but powerful route, which is essential for commercial scale-up. The resulting fused aromatic 3D-CON exhibited a high Brunauer-Emmett-Teller (BET) specific surface area of up to 2247 m2 g-1 . More importantly, the 3D-CON displayed outstanding low pressure hydrogen (H2 , 2.64 wt %, 1.0 bar and 77 K), methane (CH4 , 2.4 wt %, 1.0 bar and 273 K), and carbon dioxide (CO2 , 26.7 wt %, 1.0 bar and 273 K) uptake with a high isosteric heat of adsorption (H2 , 8.10 kJ mol-1 ; CH4 , 18.72 kJ mol-1 ; CO2 , 31.87 kJ mol-1 ). These values are among the best reported for organic networks with high thermal stability (ca. 600 °C).

Defect-Free Encapsulation of Fe0 in 2D Fused Organic Networks as a Durable Oxygen Reduction Electrocatalyst.

Because they provide lower cost but comparable activity to precious platinum (Pt)-based catalysts, nonprecious iron (Fe)-based materials, such as Fe/Fe3C and Fe-N-C, have gained considerable attention as electrocatalysts for the oxygen reduction reaction (ORR). However, their practical application is hindered by their poor stability, which is attributed to the defective protection of extremely unstable Fe nanoparticles. Here, we introduce a synthesis strategy for a stable Fe-based electrocatalyst, which was realized by defect-free encapsulation of Fe nanoparticles using a two-dimensional (2D) phenazine-based fused aromatic porous organic network (Aza-PON). The resulting Fe@Aza-PON catalyst showed electrocatalytic activity (half-wave potential, 0.839 V; Tafel slope, 60 mV decade-1) comparable to commercial Pt on activated carbon (Pt/C, 0.826 V and 90 mV decade-1). More importantly, the Fe@Aza-PON displayed outstanding stability (zero current loss even after 100 000 cycles) and tolerance against contamination (methanol and CO poisoning). In a hybrid Li-air battery test, the Fe@Aza-PON demonstrated performance superior to Pt/C.

Forming a three-dimensional porous organic network via solid-state explosion of organic single crystals.

Solid-state reaction of organic molecules holds a considerable advantage over liquid-phase processes in the manufacturing industry. However, the research progress in exploring this benefit is largely staggering, which leaves few liquid-phase systems to work with. Here, we show a synthetic protocol for the formation of a three-dimensional porous organic network via solid-state explosion of organic single crystals. The explosive reaction is realized by the Bergman reaction (cycloaromatization) of three enediyne groups on 2,3,6,7,14,15-hexaethynyl-9,10-dihydro-9,10-[1,2]benzenoanthracene. The origin of the explosion is systematically studied using single-crystal X-ray diffraction and differential scanning calorimetry, along with high-speed camera and density functional theory calculations. The results suggest that the solid-state explosion is triggered by an abrupt change in lattice energy induced by release of primer molecules in the 2,3,6,7,14,15-hexaethynyl-9,10-dihydro-9,10-[1,2]benzenoanthracene crystal lattice.

Macroporous Inverse Opal-like MoxC with Incorporated Mo Vacancies for Significantly Enhanced Hydrogen Evolution.

The hydrogen evolution reaction (HER) is one of the most important pathways for producing pure and clean hydrogen. Although platinum (Pt) is the most efficient HER electrocatalyst, its practical application is significantly hindered by high-cost and scarcity. In this work, an MoxC with incorporated Mo vacancies and macroporous inverse opal-like (IOL) structure (MoxC-IOL) was synthesized and studied as a low-cost efficient HER electrocatalyst. The macroporous IOL structure was controllably fabricated using a facile-hard template strategy. As a result of the combined benefits of the Mo vacancies and structural advantages, including appropriate hydrogen binding energy, large exposed surface, robust IOL structure and fast mass/charge transport, the synthesized MoxC-IOL exhibited significantly enhanced HER electrocatalytic performance with good stability, with performance comparable or superior to Pt wire in both acidic and alkaline solutions.

An efficient and pH-universal ruthenium-based catalyst for the hydrogen evolution reaction.

The hydrogen evolution reaction (HER) is a crucial step in electrochemical water splitting and demands an efficient, durable and cheap catalyst if it is to succeed in real applications. For an energy-efficient HER, a catalyst must be able to trigger proton reduction with minimal overpotential and have fast kinetics. The most efficient catalysts in acidic media are platinum-based, as the strength of the Pt-H bond is associated with the fastest reaction rate for the HER. The use of platinum, however, raises issues linked to cost and stability in non-acidic media. Recently, non-precious-metal-based catalysts have been reported, but these are susceptible to acid corrosion and are typically much inferior to Pt-based catalysts, exhibiting higher overpotentials and lower stability. As a cheaper alternative to platinum, ruthenium possesses a similar bond strength with hydrogen (∼65 kcal mol-1), but has never been studied as a viable alternative for a HER catalyst. Here, we report a Ru-based catalyst for the HER that can operate both in acidic and alkaline media. Our catalyst is made of Ru nanoparticles dispersed within a nitrogenated holey two-dimensional carbon structure (Ru@C2N). The Ru@C2N electrocatalyst exhibits high turnover frequencies at 25 mV (0.67 H2 s-1 in 0.5 M H2SO4 solution; 0.75 H2 s-1 in 1.0 M KOH solution) and small overpotentials at 10 mA cm-2 (13.5 mV in 0.5 M H2SO4 solution; 17.0 mV in 1.0 M KOH solution) as well as superior stability in both acidic and alkaline media. These performances are comparable to, or even better than, the Pt/C catalyst for the HER.

Edge-selenated graphene nanoplatelets as durable metal-free catalysts for iodine reduction reaction in dye-sensitized solar cells.

Metal-free carbon-based electrocatalysts for dye-sensitized solar cells (DSSCs) are sufficiently active in Co(II)/Co(III) electrolytes but are not satisfactory in the most commonly used iodide/triiodide (I(-)/I3 (-)) electrolytes. Thus, developing active and stable metal-free electrocatalysts in both electrolytes is one of the most important issues in DSSC research. We report the synthesis of edge-selenated graphene nanoplatelets (SeGnPs) prepared by a simple mechanochemical reaction between graphite and selenium (Se) powders, and their application to the counter electrode (CE) for DSSCs in both I(-)/I3 (-) and Co(II)/Co(III) electrolytes. The edge-selective doping and the preservation of the pristine graphene basal plane in the SeGnPs were confirmed by various analytical techniques, including atomic-resolution transmission electron microscopy. Tested as the DSSC CE in both Co(bpy)3 (2+/3+) (bpy = 2,2'-bipyridine) and I(-)/I3 (-) electrolytes, the SeGnP-CEs exhibited outstanding electrocatalytic performance with ultimately high stability. The SeGnP-CE-based DSSCs displayed a higher photovoltaic performance than did the Pt-CE-based DSSCs in both SM315 sensitizer with Co(bpy)3 (2+/3+) and N719 sensitizer with I(-)/I3 (-) electrolytes. Furthermore, the I3 (-) reduction mechanism, which has not been fully understood in carbon-based CE materials to date, was clarified by an electrochemical kinetics study combined with density functional theory and nonequilibrium Green's function calculations.

Two-dimensional polyaniline (C3N) from carbonized organic single crystals in solid state.

The formation of 2D polyaniline (PANI) has attracted considerable interest due to its expected electronic and optoelectronic properties. Although PANI was discovered over 150 y ago, obtaining an atomically well-defined 2D PANI framework has been a longstanding challenge. Here, we describe the synthesis of 2D PANI via the direct pyrolysis of hexaaminobenzene trihydrochloride single crystals in solid state. The 2D PANI consists of three phenyl rings sharing six nitrogen atoms, and its structural unit has the empirical formula of C3N. The topological and electronic structures of the 2D PANI were revealed by scanning tunneling microscopy and scanning tunneling spectroscopy combined with a first-principle density functional theory calculation. The electronic properties of pristine 2D PANI films (undoped) showed ambipolar behaviors with a Dirac point of -37 V and an average conductivity of 0.72 S/cm. After doping with hydrochloric acid, the conductivity jumped to 1.41 × 10(3) S/cm, which is the highest value for doped PANI reported to date. Although the structure of 2D PANI is analogous to graphene, it contains uniformly distributed nitrogen atoms for multifunctionality; hence, we anticipate that 2D PANI has strong potential, from wet chemistry to device applications, beyond linear PANI and other 2D materials.

Unusually Stable Triazine-based Organic Superstructures.

Solid-state reactions have been rapidly gaining popularity in organic chemistry owing to their simplicity, efficiency, and selectivity compared to liquid-phase reactions. Herein, we describe the formation of superstructures through the solid-state reaction of an organic single-crystal. The superstructure of 5,5',5''-(1,3,5-triazine-2,4,6-triyl)triisophthalonitrile (TIPN) can be formed by cyclotrimerization of 1,3,5-tricyanobenzene (TCB) single crystals. The TIPN superstructure was confirmed by single crystal X-ray diffraction and visualized by transmission electron microscopy. The superstructure has hexagonally packed 1-dimensional (1D) channels along the crystal axis. Furthermore, the superstructure arises from interdigitated nitrile interactions in the crystal lattice, and thus has electron-beam tolerance and very high thermal stability.

Antimony-doped graphene nanoplatelets.

Heteroatom doping into the graphitic frameworks have been intensively studied for the development of metal-free electrocatalysts. However, the choice of heteroatoms is limited to non-metallic elements and heteroatom-doped graphitic materials do not satisfy commercial demands in terms of cost and stability. Here we realize doping semimetal antimony (Sb) at the edges of graphene nanoplatelets (GnPs) via a simple mechanochemical reaction between pristine graphite and solid Sb. The covalent bonding of the metalloid Sb with the graphitic carbon is visualized using atomic-resolution transmission electron microscopy. The Sb-doped GnPs display zero loss of electrocatalytic activity for oxygen reduction reaction even after 100,000 cycles. Density functional theory calculations indicate that the multiple oxidation states (Sb(3+) and Sb(5+)) of Sb are responsible for the unusual electrochemical stability. Sb-doped GnPs may provide new insights and practical methods for designing stable carbon-based electrocatalysts.

Nitrogenated holey two-dimensional structures.

Recent graphene research has triggered enormous interest in new two-dimensional ordered crystals constructed by the inclusion of elements other than carbon for bandgap opening. The design of new multifunctional two-dimensional materials with proper bandgap has become an important challenge. Here we report a layered two-dimensional network structure that possesses evenly distributed holes and nitrogen atoms and a C2N stoichiometry in its basal plane. The two-dimensional structure can be efficiently synthesized via a simple wet-chemical reaction and confirmed with various characterization techniques, including scanning tunnelling microscopy. Furthermore, a field-effect transistor device fabricated using the material exhibits an on/off ratio of 10(7), with calculated and experimental bandgaps of approximately 1.70 and 1.96 eV, respectively. In view of the simplicity of the production method and the advantages of the solution processability, the C2N-h2D crystal has potential for use in practical applications.

Graphene nanoplatelets doped with N at its edges as metal-free cathodes for organic dye-sensitized solar cells.

Challenging precious Pt-based electrocatalysts for dye-sensitized solar cells (DSSCs), graphene nanoplatelets that are N-doped at the edges (NGnPs) are prepared via simply ball-milling graphite in the presence of nitrogen gas. DSSCs based on specific nanoplatelets designated "NGnP5" display superior photovoltaic performance (power conversion efficiency, 10.27%) compared to that of conventional Pt-based devices (9.96%). More importantly, the NGnP counter electrode exhibits outstanding electrochemical stability and electrocatalytic activity with a cobalt-complex redox couple.

Direct solvothermal synthesis of B/N-doped graphene.

Heteroatom-doping into graphitic networks has been utilized for opening the band gap of graphene. However, boron-doping into the graphitic framework is extremely limited, whereas nitrogen-doping is relatively feasible. Herein, boron/nitrogen co-doped graphene (BCN-graphene) is directly synthesized from the reaction of CCl4 , BBr3 , and N2 in the presence of potassium. The resultant BCN-graphene has boron and nitrogen contents of 2.38 and 2.66 atom %, respectively, and displays good dispersion stability in N-methyl-2-pyrrolidone, allowing for solution casting fabrication of a field-effect transistor. The device displays an on/off ratio of 10.7 with an optical band gap of 3.3 eV. Considering the scalability of the production method and the benefits of solution processability, BCN-graphene has high potential for many practical applications.

Direct nitrogen fixation at the edges of graphene nanoplatelets as efficient electrocatalysts for energy conversion.

Nitrogen fixation is essential for the synthesis of many important chemicals (e.g., fertilizers, explosives) and basic building blocks for all forms of life (e.g., nucleotides for DNA and RNA, amino acids for proteins). However, direct nitrogen fixation is challenging as nitrogen (N2) does not easily react with other chemicals. By dry ball-milling graphite with N2, we have discovered a simple, but versatile, scalable and eco-friendly, approach to direct fixation of N2 at the edges of graphene nanoplatelets (GnPs). The mechanochemical cracking of graphitic C--C bonds generated active carbon species that react directly with N2 to form five- and six-membered aromatic rings at the broken edges, leading to solution-processable edge-nitrogenated graphene nanoplatelets (NGnPs) with superb catalytic performance in both dye-sensitized solar cells and fuel cells to replace conventional Pt-based catalysts for energy conversion.

Facile, scalable synthesis of edge-halogenated graphene nanoplatelets as efficient metal-free eletrocatalysts for oxygen reduction reaction.

A series of edge-selectively halogenated (X = Cl, Br, I) graphene nanoplatelets (XGnPs = ClGnP, BrGnP, IGnP) were prepared simply by ball-milling graphite in the presence of Cl2, Br2 and I2, respectively. High BET surface areas of 471, 579 and 662 m(2)/g were observed for ClGnP, BrGnP and IGnP, respectively, indicating a significant extent of delamination during the ball-milling and subsequent workup processes. The newly-developed XGnPs can be well dispersed in various solvents, and hence are solution processable. Furthermore, XGnPs showed remarkable electrocatalytic activities toward oxygen reduction reaction (ORR) with a high selectivity, good tolerance to methanol crossover/CO poisoning effects, and excellent long-term cycle stability. First-principle density-functional calculations revealed that halogenated graphene edges could provide decent adsorption sites for oxygen molecules, in a good agreement with the experimental observations.