Natural Amino Acid-Bearing Carbamate Prodrugs of Daidzein Increase Water Solubility and Improve Phase II Metabolic Stability for Enhanced Oral Bioavailability.

Daidzein (DAN) is an isoflavone, and it is often found in its natural form in soybean and food supplements. DAN has poor bioavailability owing to its extremely low water solubility and first-pass metabolism. Herein, we hypothesized that a bioactivatable natural amino acid-bearing carbamate prodrug strategy could increase the water solubility and metabolic stability of DAN. To test our hypothesis, nine amino acid prodrugs of DAN were designed and synthesized. Compared with DAN, the optimal prodrug (daidzein-4'-O-CO-N-isoleucine, D-4'-I) demonstrated enhanced water solubility and improved phase II metabolic stability and activation to DAN in plasma. In addition, unlike the passive transport of DAN, D-4'-I maintained high permeability via organic anion-transporting polypeptide 2B1 (OATP2B1)-mediated transport. Importantly, D-4'-I increased the oral bioavailability by 15.5-fold, reduced the gender difference, and extended the linear absorption capacity in the pharmacokinetics of DAN in rats. Furthermore, D-4'-I exhibited dose-dependent protection against liver injury. Thus, the natural amino acid-bearing carbamate prodrug strategy shows potential in increasing water solubility and improving phase II metabolic stability to enhance the oral bioavailability of DAN.

Multifunctional Ni-NPC Single-Atom Nanozyme for Removal and Smartphone-Assisted Visualization Monitoring of Carbamate Pesticides.

A multifunctional single-atom nanozyme, denoted as 3D Ni,N-codoped porous carbon (Ni-NPC), was devised that exhibits remarkable adsorption capabilities and a repertoire of enzyme mimetic functions (oxidase- and peroxidase-like). These attributes stem from the distinctive mesoporous thin-shell structure and well-dispersed Ni sites. The efficient adsorption capacity of Ni-NPC was assessed with respect to three carbamate pesticides (CMPs): metolcarb, carbaryl, and isoprocarb. Moreover, a colorimetric detection method for CMP was established based on its robust peroxidase-like catalytic activity and sequential catalytic interactions with acetylcholinesterase. Furthermore, a portable colorimetric sensor based on a hydrogel sphere integrated with a smartphone platform was devised. This sensor enables rapid, on-site, and quantitative assessment of CMP, boasting an extraordinarily low detection limit of 1.5 ng mL-1. Notably, this sensor was successfully applied to the analysis of CMP levels in lake water and vegetable samples (pakchoi and rape), propelling the progress of real-time detection technologies in food and environment monitoring.

Panaxadiol carbamate derivatives: Synthesis and biological evaluation as potential multifunctional anti-Alzheimer agents.

It is reported that panaxadiol has neuroprotective effects. Previous studies have found that compound with carbamate structure introduced at the 3-OH position of 20 (R) -panaxadiol showed the most effective neuroprotective activity with an EC50 of 13.17 µM. Therefore, we designed and synthesized a series of ginseng diol carbamate derivatives with ginseng diol as the lead compound, and tested their anti-AD activity. It was found that the protective effect of compound Q4 on adrenal pheochromocytoma was 80.6 ±â€¯10.85 % (15 µM), and the EC50 was 4.32 µM. According to the ELISA results, Q4 reduced the expression of Aß25-35 by decreasing ß-secretase production. Molecular docking studies revealed that the binding affinity of Q4 to ß-secretase was -49.67 kcal/mol, indicating a strong binding affinity of Q4 to ß-secretase. Western blotting showed that compound Q4 decreased IL-1ß levels, which may contribute to its anti-inflammatory effect. Furthermore, compound Q4 exhibits anti-AD activities by reducing abnormal phosphorylation of tau protein and activation of the mitogen activated protein kinase pathway. The learning and memory deficits in mice treated with Q4in vivo were significantly alleviated. Therefore, Q4 may be a promising multifunctional drug for the treatment of AD, providing a new way for anti-AD drugs.

Development of a Pt-graphene nanocomposite-based solid-phase extraction coupled with ultra-performance liquid chromatography-tandem mass spectrometry for the determination of carbamate pesticides in fish.

In the present work, a potential solid-phase extraction (SPE) material based on graphene anchored with platinum nanoparticles (Pt-Graphene) was prepared and characterized by scanning electron micrographs and transmission electron micrograph. The carbamates residues in fish were enriched by SPE filled with Pt-Graphene and detected by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The proposed extraction protocol exhibited satisfactory recoveries (76.5-115.6%), low limit of quantitation values in µg kg-1 level, and good precision for the studied ten carbamates. These results demonstrated the feasibility of the proposed protocol. The developed Pt-Graphene nanoparticles showed excellent performance for extracting analytes at trace levels, indicating that it could be used as a potential SPE sorbent in food residue analysis.

Synthesis of Unnatural α-Amino Acids from (Pyridin-2-yl) Carbamate via CIPE-Induced Carbonyl Migration.

Synthetic methods of unnatural α-amino acids have always been the focus of extensive research due to their significant bioactivities. However, convenient transition-metal-free catalyzed methods are still in demand. Herein, we report a novel strategy for the construction of an unnatural α-amino acid skeleton via intramolecular rearrangement of carbamates, which are readily available from amines and their common protecting groups. This rearrangement could afford a variety of amino ester products in up to 98% yield, even in gram-scale reaction. The reaction mechanism was studied in detail through experiments and theoretical calculations. The complex-induced proximity effect (CIPE) from the 2-pyridyl group is shown to be indispensable for this transformation.

Microbial elimination of carbamate pesticides: specific strains and promising enzymes.

Carbamate pesticides are widely used in the environment, and compared with other pesticides in nature, they are easier to decompose and have less durability. However, due to the improper use of carbamate pesticides, some nontarget organisms still may be harmed. To this end, it is necessary to investigate effective removal or elimination methods for carbamate pesticides. Current effective elimination methods could be divided into four categories: physical removal, chemical reaction, biological degradation, and enzymatic degradation. Physical removal primarily includes elution, adsorption, and supercritical fluid extraction. The chemical reaction includes Fenton oxidation, photo-radiation, and net electron reduction. Biological degradation is an environmental-friendly manner, which achieves degradation by the metabolism of microorganisms. Enzymatic degradation is more promising due to its high substrate specificity and catalytic efficacy. All in all, this review primarily summarizes the property of carbamate pesticides and the traditional degradation methods as well as the promising biological elimination. KEY POINTS: • The occurrence and toxicity of carbamate pesticides were shown. • Biological degradation strains against carbamate pesticides were presented. • Promising enzymes responsible for the degradation of carbamates were discussed.

Screening the biological properties of transition metal carbamates reveals gold(I) and silver(I) complexes as potent cytotoxic and antimicrobial agents.

We report a screening study aimed to assess for the first time the air- and water-stability and the biological potential of simple metal-carbamates. These molecular metallic species are based on elements belonging to the groups 4-5, 7-9 and 11, and tin, and are easily available from inexpensive reagents. Complexes [Ag(O2CNEt2)] (13-Ag) and [Au(O2CNMe2)(PPh3)] (14-Au) resulted substantially stable in aqueous media and exhibited a potent in vitro cytotoxicity. Especially 13-Ag revealed a significant selectivity against the A549 lung adenocarcinoma and the A2780 ovarian cancer cell lines with respect to the noncancerous HEK293 cell line. Generation of ROS (reactive oxygen species) and mitochondrial membrane depolarization were recognized for 13-Ag and 14-Au; notwithstanding, the cell death mechanism is different in the two cases: apoptosis and cell cycle arrest in G0/G1 phase for 13-Ag; necroptosis and cell cycle arrest in S phase for 14-Au. Both 13-Ag and 14-Au are endowed with antibacterial activity, which is relatively stronger for 13-Ag towards Gram negative and for 14-Au towards Gram positive strains, respectively.

Targeted Fluorogenic Cyanine Carbamates Enable In Vivo Analysis of Antibody-Drug Conjugate Linker Chemistry.

Antibody-drug conjugates (ADCs) are a rapidly emerging therapeutic platform. The chemical linker between the antibody and the drug payload plays an essential role in the efficacy and tolerability of these agents. New methods that quantitatively assess the cleavage efficiency in complex tissue settings could provide valuable insights into the ADC design process. Here we report the development of a near-infrared (NIR) optical imaging approach that measures the site and extent of linker cleavage in mouse models. This approach is enabled by a superior variant of our recently devised cyanine carbamate (CyBam) platform. We identify a novel tertiary amine-containing norcyanine, the product of CyBam cleavage, that exhibits a dramatically increased cellular signal due to an improved cellular permeability and lysosomal accumulation. The resulting cyanine lysosome-targeting carbamates (CyLBams) are ∼50× brighter in cells, and we find this strategy is essential for high-contrast in vivo targeted imaging. Finally, we compare a panel of several common ADC linkers across two antibodies and tumor models. These studies indicate that cathepsin-cleavable linkers provide dramatically higher tumor activation relative to hindered or nonhindered disulfides, an observation that is only apparent with in vivo imaging. This strategy enables quantitative comparisons of cleavable linker chemistries in complex tissue settings with implications across the drug delivery landscape.

Novel cannabidiol-carbamate hybrids as selective BuChE inhibitors: Docking-based fragment reassembly for the development of potential therapeutic agents against Alzheimer's disease.

Cannabidiol (CBD) and rivastigmine have been launched as drugs for treating dementia and cholinesterases (ChEs) are ideal drug targets. This study focused on developing novel ChE inhibitors as drug leads against dementia through molecular modeling and fragment reassembly approaches. A potent carbamate fragment binding to active site gorge of BuChE was found via a docking-based structural splicing approach, thus, 17 novel compounds were designed by structural reassembly. Compound C16 was identified as a highly selective potent BuChE inhibitor (IC50 = 5.3 nM, SI > 4000), superior to CBD (IC50 = 0.67 µM). C16 possessed BBB penetrating ability, benign safety, neuroprotection, antioxidant and pseudo-irreversible BuChE inhibition (Kd = 13 nM, k2 = 0.26 min-1), showing good drug-like properties. In vivo studies confirmed that C16 significantly ameliorated the scopolamine-induced cognition impairment, almost entirely recovered the Aß1-42 (icv)-impaired cognitive function to the normal level, showed better behavioral performance than donepezil and good anti-amyloidogenic effect. Hence, the potential BuChE inhibitor C16 can be developed as a promising disease-modifying treatment of AD.

Identifying requirements for RSK2 specific inhibitors.

Identifying isoform-specific inhibitors for closely related kinase family members remains a substantial challenge. The necessity for achieving this specificity is exemplified by the RSK family, downstream effectors of ERK1/2, which have divergent physiological effects. The natural product, SL0101, a flavonoid glycoside, binds specifically to RSK1/2 through a binding pocket generated by an extensive conformational rearrangement within the RSK N-terminal kinase domain (NTKD). In modelling experiments a single amino acid that is divergent in RSK3/4 most likely prevents the required conformational rearrangement necessary for SL0101 binding. Kinetic analysis of RSK2 association with SL0101 and its derivatives identified that regions outside of the NTKD contribute to stable inhibitor binding. An analogue with an n-propyl-carbamate at the 4" position on the rhamnose moiety was identified that forms a highly stable inhibitor complex with RSK2 but not with RSK1. These results identify a SL0101 modification that will aid the identification of RSK2 specific inhibitors.

Electrochemical detection of carbendazim with mulberry fruit-like gold nanocrystal/multiple graphene aerogel and DNA cycle amplification.

An aptasensor for electrochemical detection of carbendazim is reported with mulberry fruit-like gold nanocrystal (MF-Au)/multiple graphene aerogel (MGA) and DNA cycle amplification. HAuCl4 was reduced by ascorbic acid in a CTAC solution containing KBr and KI and formed trioctahedron gold nanocrystal. The gold nanocrystal underwent structural evolution under enantioselective direction of L-cysteine. The resulting MF-Au shows a mulberry fruit-like nanostructure composed of gold nanocrystals of about 200 nm as the core and many irregular gold nanoparticles of about 30 nm as the shell. The exposure of high-index facets improves the catalytic activity of MF-Au. MF-Au/MGA was used for the construction of an aptasensor for electrochemical detection of carbendazim. The aptamer hybridizes with assistant strand DNA to form duplex DNA. Carbendazim binds with the formed duplex DNA to release assistant strand DNA, triggering one three-cascade DNA cycle. The utilization of a DNA cycle allows one carbendazim molecule to bring many methylene blue-labeled DNA fragments to the electrode surface. This promotes significant signal amplification due to the redox reaction of methylene blue. The detection signal is further enhanced by the catalysis of MF-Au and MGA towards the redox of methylene blue. A differential pulse voltammetric signal, best measured at - 0.32 V vs. Ag/AgCl, increases linearly with the carbendazim concentration ranging from 1.0 × 10-16 to 1.0 × 10-11 M with a detection limit of 4.4 × 10-17 M. The method provides ultrahigh sensitivity and selectivity and was successfully applied to the electrochemical detection of carbendazim in cucumber. This study reports on an ultrasensitive aptasensor for electrochemical detection of carbendazim in cucumber based on mulberry fruit-like gold nanocrystal-multiple graphene aerogel and DNA cycle double amplification.

A Validated LC-MS/MS Assay for the Simultaneous Quantification of the FDA-Approved Anticancer Mixture (Encorafenib and Binimetinib): Metabolic Stability Estimation.

The concurrent use of oral encorafenib (Braftovi, ENF) and binimetinib (Mektovi, BNB) is a combination anticancer therapy approved by the United States Food and Drug Administration (USFDA) for patients with BRAFV600E/V600K mutations suffering from metastatic or unresectable melanoma. Metabolism is considered one of the main pathways of drug elimination from the body (responsible for elimination of about 75% of known drugs), it is important to understand and study drug metabolic stability. Metabolically unstable compounds are not good as they required repetitive dosages during therapy, while very stable drugs may result in increasing the risk of adverse drug reactions. Metabolic stability of compounds could be examined using in vitro or in silico experiments. First, in silico metabolic vulnerability for ENF and BNB was investigated using the StarDrop WhichP450 module to confirm the lability of the drugs under study to liver metabolism. Second, we established an LC-MS/MS method for the simultaneous quantification of ENF and BNB applied to metabolic stability assessment. Third, in silico toxicity assessment of ENF and BNB was performed using the StarDrop DEREK module. Chromatographic separation of ENF, BNB, and avitinib (an internal standard) was achieved using an isocratic mobile phase on a Hypersil BDS C18 column. The linear range for ENF and BNB in the human liver microsome (HLM) matrix was 5-500 ng/mL (R2 ≥ 0.999). The metabolic stabilities were calculated using intrinsic clearance and in vitro half-life. Furthermore, ENF and BNB did not significantly influence each other's metabolic stability or metabolic disposition when used concurrently. These results indicate that ENF and BNB will slowly bioaccumulate after multiple doses.

Santacruzamate A Compositions, Analogs and Methods of Use: A Patent Evaluation of WO 2014/018913 (A2).

BACKGROUND: Santacruzamate A (SCA) is a natural product isolated from a marine cyanobacterium. Activity test results revealed that SCA is a highly potent HDAC2 inhibitor with an IC50 value of 0.112 nM. The IC50 of SCA in inhibiting cancer cell proliferation is 28.3 µM and 1.3µM on HCT116 and HuT-78 cells, respectively. OBJECTIVE: To develop HDAC inhibitors with improved activity, SCA analogs were synthesized for the Structure-Activity Relationship (SAR) studies. METHODS: Various substituted groups were introduced into the zinc binging group, linker, and cap regions of SCA by various chemical synthetic methods. RESULTS: Compared with SCA, the derivatives of SCA did not exhibit improved HDAC2 inhibitory activity. Nevertheless, several molecules such as III-32, III-33, IV-4b, and IV-11 showed improved activity in inhibiting cell proliferation on HCT116 and HuT-78 cells. CONCLUSION: Collectively, a potent HDAC2 inhibitor SCA was discovered as a lead compound for further development of selective HDAC inhibitors.

The Pharmacology and Clinical Efficacy of Antiseizure Medications: From Bromide Salts to Cenobamate and Beyond.

Epilepsy is one of the most common and disabling chronic neurological disorders. Antiseizure medications (ASMs), previously referred to as anticonvulsant or antiepileptic drugs, are the mainstay of symptomatic epilepsy treatment. Epilepsy is a multifaceted complex disease and so is its treatment. Currently, about 30 ASMs are available for epilepsy therapy. Furthermore, several ASMs are approved therapies in nonepileptic conditions, including neuropathic pain, migraine, bipolar disorder, and generalized anxiety disorder. Because of this wide spectrum of therapeutic activity, ASMs are among the most often prescribed centrally active agents. Most ASMs act by modulation of voltage-gated ion channels; by enhancement of gamma aminobutyric acid-mediated inhibition; through interactions with elements of the synaptic release machinery; by blockade of ionotropic glutamate receptors; or by combinations of these mechanisms. Because of differences in their mechanisms of action, most ASMs do not suppress all types of seizures, so appropriate treatment choices are important. The goal of epilepsy therapy is the complete elimination of seizures; however, this is not achievable in about one-third of patients. Both in vivo and in vitro models of seizures and epilepsy are used to discover ASMs that are more effective in patients with continued drug-resistant seizures. Furthermore, therapies that are specific to epilepsy etiology are being developed. Currently, ~ 30 new compounds with diverse antiseizure mechanisms are in the preclinical or clinical drug development pipeline. Moreover, therapies with potential antiepileptogenic or disease-modifying effects are in preclinical and clinical development. Overall, the world of epilepsy therapy development is changing and evolving in many exciting and important ways. However, while new epilepsy therapies are developed, knowledge of the pharmacokinetics, antiseizure efficacy and spectrum, and adverse effect profiles of currently used ASMs is an essential component of treating epilepsy successfully and maintaining a high quality of life for every patient, particularly those receiving polypharmacy for drug-resistant seizures.

Coordination compounds with heterocyclic ester derivatives. Structural characterization and anti-proliferative activity.

A series of new coordination compounds of cobalt(II), copper(II) and zinc(II) with heterocyclic ester derivatives (ethyl 4-methyl-5-imidazole-carboxylate (emizco), 1-(2-(phenylsulphonyl)ethyl)-4-imidazole carboxylate (semizco)) and methyl 5-(propylthio)-2-benzimidazolecarbamate (albendazole, abz) were synthesized. They were fully characterized by different techniques such as IR, UV-Vis-NIR, elemental analysis, molar conductivity and magnetic susceptibility. Additionally, X-ray crystal structures of semizco and its [Co(semizco)2Cl2]·2CH3CN 10, [Co(smmizco)2Br2]·2CH3CN 11 and [Cu(semizco)2Br2] 15 coordination compounds are analyzed. These compounds present lone pair SO⋯π interactions between the sulfone and the imidazolic ring. These ligands showed three coordination modes: monodentate, through an imidazolic nitrogen atom, or a bidentate chelating mode by a nitrogen and an oxygen atom from the ester group. The different coordination modes and the number of coordinated ligands gave rise to tetrahedral and octahedral compounds, or for [Cu(semizco)(µ-Br)Br]n·0.5H2O 7 a square base pyramidal geometry. A cytotoxic study was carried out with the free ligands and their copper(II) and zinc(II) halide coordination compounds on HeLa (cervix-uterine), MCF-7 (breast), HCT-15 (colon), PC3 (prostate) human carcinoma cell lines and L929 mouse fibroblast (healthy cells). A TUNEL assay (terminal deoxynucleotidyl transferase dUTP nick end labeling) was performed with the most active copper(II) compounds to determine if cell death was by apoptosis.

Norcyanine-Carbamates Are Versatile Near-Infrared Fluorogenic Probes.

Fluorogenic probes in the near-infrared (NIR) region have the potential to provide stimuli-dependent information in living organisms. Here, we describe a new class of fluorogenic probes based on the heptamethine cyanine scaffold, the most broadly used NIR chromophore. These compounds result from modification of heptamethine norcyanines with stimuli-responsive carbamate linkers. The resulting cyanine carbamates (CyBams) exhibit exceptional turn-ON ratios (∼170×) due to dual requirements for NIR emission: carbamate cleavage through 1,6-elimination and chromophore protonation. Illustrating their utility in complex in vivo settings, a γ-glutamate substituted CyBam was applied to imaging γ-glutamyl transpeptidase (GGT) activity in a metastatic model of ovarian cancer. Overall, CyBams have significant potential to extend the reach of fluorogenic strategies to intact tissue and live animal imaging applications.

Synthesis and Initial Characterization of a Selective, Pseudo-irreversible Inhibitor of Human Butyrylcholinesterase as PET Tracer.

The enzyme butyrylcholinesterase (BChE) represents a promising target for imaging probes to potentially enable early diagnosis of neurodegenerative diseases like Alzheimer's disease (AD) and to monitor disease progression in some forms of cancer. In this study, we present the design, facile synthesis, in vitro and preliminary ex vivo and in vivo evaluation of a morpholine-based, selective inhibitor of human BChE as a positron emission tomography (PET) tracer with a pseudo-irreversible binding mode. We demonstrate a novel protecting group strategy for 18 F radiolabeling of carbamate precursors and show that the inhibitory potency as well as kinetic properties of our unlabeled reference compound were retained in comparison to the parent compound. In particular, the prolonged duration of enzyme inhibition of such a morpholinocarbamate motivated us to design a PET tracer, possibly enabling a precise mapping of BChE distribution.

Quinoline-sulfamoyl carbamates/sulfamide derivatives: Synthesis, cytotoxicity, carbonic anhydrase activity, and molecular modelling studies.

Carbonic anhydrase (CA) IX, and XII isoforms are known to be highly expressed in various human tissues and malignancies. CA IX is a prominent target for some cancers because it is overexpressed in hypoxic tumors and this overexpression leads to poor prognosis. Novel twenty-seven compounds in two series (sulfamoylcarbamate-based quinoline (2a-2o) and sulfamide-based quinoline (3a-3l)) were synthesized and characterized by means of IR, NMR, and mass spectra. Their inhibitory activities were evaluated against CA I, CA II, CA IX, and CA XII isoforms. 2-Phenylpropyl (N-(quinolin-8-yl)sulfamoyl)carbamate (2m) exhibited the highest hCA IX inhibition with the Ki of 0.5 µM. In addition, cytotoxic effects of the synthesized compounds on human colorectal adenocarcinoma (HT-29; HTB-38), human breast adenocarcinoma (MCF7; HTB-22), human prostate adenocarcinoma (PC3; CRL-1435) and human healthy skin fibroblast (CCD-986Sk; CRL-1947) cell lines were examined. The cytotoxicity results showed that 2j, 3a, 3e, 3f are most active compounds in all cell lines (HT-29, MCF7, PC3, and CCD-986Sk).

Design and synthesis of new carbamates as inhibitors for fatty acid amide hydrolase and cholinesterases: Molecular dynamic, in vitro and in vivo studies.

As anandamide (N-arachidonoylethanolamine, AEA) shows neuroprotective effects, the inhibition of its degradative enzyme, fatty acid amide hydrolase (FAAH) has been considered as a hopeful avenue for the treatment of neurodegenerative diseases, like Alzheimer's disease (AD). Memory loss, cognitive impairment and diminution of the cholinergic tone, due to the dying cholinergic neurons in the basal forebrain, are common hallmarks in patients with AD. By taking advantage of cholinesterase inhibitors (ChEIs), the degradation of acetylcholine (ACh) is decreased leading to enhanced cholinergic neurotransmission in the aforementioned region and ultimately improves the clinical condition of AD patients. In this work, new carbamates were designed as inhibitors of FAAH and cholinestrases (ChEs) (acetylcholinestrase (AChE), butyrylcholinestrase (BuChE)) inspired by the structure of the native substrates, structure of active sites and the SARs of the well-known inhibitors of these enzymes. All the designed compounds were synthesized using different reactions. All the target compounds were tested for their inhibitory activity against FAAH and ChEs by employing the Cayman assay kit and Elman method respectively. Generally, compounds possessing aminomethyl phenyl linker was more potent compared to their corresponding compounds possessing piperazinyl ethyl linker. The inhibitory potential of the compounds 3a-q extended from 0.83 ± 0.03 µM (3i) to ˃100 µM (3a) for FAAH, 0.39 ± 0.02 µM (3i) to 24% inhibition in 113 ± 4.8 µM (3b) for AChE, and 1.8 ± 3.2 µM (3i) to 23.2 ± 0.2 µM (3b) for BuChE. Compound 3i a heptyl carbamate analog possessing 2-oxo-1,2-dihydroquinolin ring and aminomethyl phenyl linker showed the most inhibitory activity against three enzymes. Also, compound 3i was investigated for memory improvement using the Morris water maze test in which the compound showed better memory improvement at 10 mg/kg compared to reference drug rivastigmine at 2.5 mg/kg. Molecular docking and molecular dynamic studies of compound 3i into the enzymes displayed the possible interactions of key residues of the active sites with compound 3i. Finally, kinetic study indicated that 3i inhibits AChE through the mixed- mode mechanism and non-competitive inhibition mechanism was revealed for BuChE.

Nucleoside and Non-Nucleoside DOT1L Inhibitors: Dawn of MLLrearranged Leukemia.

Herein, the underlying role of disruptor of telomeric silencing 1-like (DOT1L) as a therapeutic target for mixed-lineage leukemia (MLL)-rearranged is comprehensively clarified. DOT1L can be aberrantly recruited by an MLL fusion partner, thereby causing the over-expression, of several leukemia relevant genes and eventually leading to leukemia. As the unique histone methyltransferase (HMT), DOT1L possesses the function to specifically methylate H3K79, which was identified as a hallmark of active transcription. Accordingly, blockading of DOT1L has been recognized as an effective approach for cancer treatment. Currently, nucleoside DOT1L inhibitors have been developed successfully with the only EPZ5676 entering phase I clinical trial in 2013, which was validated as 'orphan drug' toward MLL-rearranged leukemia by FDA. In order to find compounds with better pharmacokinetic properties as DOT1L inhibitors, other types of non-nucleoside skeletons have also been reported successively.