Benzyl Carbamate Research Articles

Transfer Hydrogenolysis of O‐ and N‐Benzyl Groups in Water with Tetrahydroxydiboron by Using an Amphiphilic Polymer‐Supported Nano‐Palladium Catalyst

AbstractDebenzylation of O‐ and N‐benzyl groups was achieved under safe and mild conditions by using B2(OH)4 as an alternative to gaseous hydrogen in the presence of an amphiphilic polystyrene‐poly(ethylene glycol) resin‐supported nano‐palladium catalyst (ARP−Pd) in water. Benzyl groups of a variety of benzylic ethers, esters, carbamates, and amines, including benzyl‐protected carbohydrates and amino acids, were reductively removed in high yields. ARP−Pd was recovered by simple filtration and reused seven times without a significant loss of its catalytic activity.

Self-Immolative Polymers: From Synthesis to Applications

Polymers undergoing controlled degradation are of significant current interest. Among the classes of degradable polymers, self-immolative polymers (SIPs) are attracting increasing attention due to their ability to completely depolymerize from end to end following the cleavage of their endcap or backbone. Their amplified responses to stimuli, along with their ability to readily tune the stimulus to which they respond by changing only their endcap, are useful features for a variety of applications. This review covers the major classes of SIPs, including poly(benzyl carbamate)s, poly(benzyl ether)s, polyphthalaldehydes, polyglyoxylates, polydisulfides, polythioesters, and their related derivatives along with their endcaps. Distinctive features of their syntheses and depolymerizations are discussed. Applications of SIPs including imaging and sensing, therapeutics, gels, micro- and nanopatterning, transient or recyclable materials, and adhesives are described. We conclude with some challenges and future perspectives for the field.

Anti-cancer Potential of Bioactive Compounds from Moringa oleifera against PARK2 in Oral Cancer protein: In silico Approach

Background: Globally, oral cancer (OC) is one of the most common cancers and it is the second highest incidence in India. Medicinal plants are well known anticancer therapeutic agents since ages and considered alternative treatment of cancer diseases. Moringa oleifera, the most crucial medicinal plant contains a vast number of potential anti-cancer bioactive compounds. Objective: The aim of the current study is to investigate the therapeutic potential of five bioactive compounds kaempferol, niazimicin, niazinin, O-ethyl-4-(alpha-l-rhamnosyloxy) benzyl carbamate and quercetin of Moringa oleifera target PARK2 against OC proliferation via in silico study. Methodology: In silico approach via ADME/ProTox-II tools and molecular docking analysis have assessed to find binding affinity between PARK2 and Moringa oleifera selected compounds. Results: Our finding revealed that Kaempferol, bioactive compounds of Moringa oleifera shows Lipinski's Five Rules and is non-toxic to the liver. Besides, it also displays higher binding affinity -7.2kcal/mol and a lower binding energy followed by five selected compounds and also from 5-Flurouracil with the PARK2 interaction. Conclusion: The study provided insight into Kaempferol's possibilities of success as drug discovery candidates in the face of PARK2-related OC regulation. Thus, future in vitro, in vivo, and clinical studies are required to corroborate our findings.

A new quinoxaline-based fluorescent probe capable of naked eye recognition and cell imaging for biothiols

Maintaining biothiols homeostasis is extremely important for the health of organisms. In this work, a pair of fluorescent probes (Acr-QX8A and Acr-QX9A) was designed and synthesized to monitor biothiols. The two probes applied the same fused four ring quinoxaline as the skeleton, benzyl carbamate as the linker and acryloyl group as the recognition site, whose only difference was the amino group’s position on the skeleton. By comparing the optical properties, Acr-QX9A exhibited superior performances than Acr-QX8A and chosen for further studies. Probe Acr-QX9A displayed 180-fold, 135-fold and 69-fold fluorescence intensity enhancements upon interactions with Cys, Hcy and GSH respectively, owing to the release of fluorophore QX9A and the restoration of intramolecular charge transfer (ICT) process. Acr-QX9A showed good selectivity and excellent anti-interference, which could be served as the naked-eye colorimetric probe for biothiols detection. More importantly, the probe exhibited high sensitivity towards biothiols with outstanding detection of limits (75.2 nM for Cys, 92.7 nM for Hcy and 370 nM for GSH). Encouraged by the appreciable results in solutions, probe Acr-QX9A was then successfully applied as a promising tool for monitoring both endogenous and exogenous biothiols in living cells.

Condensation of Benzyl Carbamate with Glyoxal in Polar Protic and Aprotic Solvents.

The synthesis of substituted 2,4,6,8,10,12-hexaazaisowurtzitane via direct condensation is challenging. The selection of starting ammonia derivatives is very limited. The important step in developing alternative synthetic routes to these compounds is to investigate their formation process in detail. Here, we examined an acid-catalyzed condensation between benzyl carbamate and glyoxal in a ratio of 2:1 in a range of polar protic and aprotic solvents, and discovered a new process occurring during the cascade condensation of glyoxal with ammonia derivatives as well as discovered several processes hindering the formation of caged compounds. More specifically, a cyclic compound, N,N'-bis(carbobenzoxy)-3,6-diamino-1,4-dioxane-2,5-diol, was found to form at the early stage of condensation under low acidity conditions. The formation of this compound is governed by an easier condensation of alcohol groups compared to the amide ones. The condensation intermediates, N,N'-bis(carbobenzoxy)ethan-1,2-diol, N,N',N″-tris(carbobenzoxy)ethanol, and N,N',N″,N‴-tetrakis(carbobenzoxy)ethan, were obtained at a higher acidity. A range of solvents were identified: those that react with benzyl carbamate, those that promote the progress of side processes, and those that promote precipitation of condensation intermediates. A few byproducts were isolated and identified. It was found that DMSO exhibits a strong deactivating ability, while CH3CN exhibits a strong activating ability towards the acid-catalyzed condensation process of benzyl carbamate with glyoxal.

ROS-Responsive Self-Degradable DNA Nanogels for Targeted Anticancer Drug Delivery.

Here, a reactive oxygen species (ROS)-responsive targeted anticancer drug delivery system was developed by embedding a nitrophenyl tetramethyl-dioxaborolanyl benzyl carbamate (NBC)-modified deoxyribonuclease I (DNase I) in a DNase-degradable aptamer-based DNA nanogel. The DNA nanogel was formed by hybridization of three types of building blocks, namely, Y-shaped monomer 1 with three sticky ends, Y-shaped monomer 2 with two sticky ends and an aptamer end, and a DNA linker with two sticky ends. Single doxorubicin (DOX) or ribonuclease A (RNase A) as well as the combination of DOX and RNase A were effectively loaded into the nanogels, wherein DOX was embedded into DNA skeleton, while RNase A was encapsulated into nanogel matrix. The blocked enzymatic activity of DNase I due to NBC modification could be restored upon intracellular ROS-triggered NBC deprotection, resulting in self-degradation of the nanogels to release both DOX and RNase A. Consequently, the DOX and RNase A coloaded nanogels significantly inhibited the proliferation of MCF-7 cells through a synergistic effect. To sum up, this DNA-based drug delivery system with ROS-responsive self-degradation properties should be promising for application in targeted and synergistic cancer therapy.

Low Pressure Carbonylation of Benzyl Carbonates and Carbamates for Applications in13C Isotope Labeling and Catalytic CO2Reduction

AbstractHerein, we report a methodology to access isotopically labeled esters and amides from carbonates and carbamates employing an oxygen deletion strategy. This methodology utilizes a decarboxylative carbonylation approach for isotope labeling with near stoichiometric, ex situ generated12C, or13C carbon monoxide. This reaction is characterized by its broad scope, functional group tolerance, and high yields, which is showcased with the synthesis of structurally complex molecules. A complementary method that operates by the catalytic in situ generation of CO via the reduction of CO2liberated during decarboxylation has also been developed as a proof‐of‐concept approach that CO2‐derived compounds can be converted to CO‐containing frameworks. Mechanistic studies provide insight into the catalytic steps which highlight the impact of ligand choice to overcome challenges associated with low‐pressure carbonylation methodologies, along with rational for the development of future methodologies.

Low Pressure Carbonylation of Benzyl Carbonates and Carbamates for Applications in 13 C Isotope Labeling and Catalytic CO2 Reduction.

Herein, we report a methodology to access isotopically labeled esters and amides from carbonates and carbamates employing an oxygen deletion strategy. This methodology utilizes a decarboxylative carbonylation approach for isotope labeling with near stoichiometric, ex situ generated 12 C, or 13 C carbon monoxide. This reaction is characterized by its broad scope, functional group tolerance, and high yields, which is showcased with the synthesis of structurally complex molecules. A complementary method that operates by the catalytic in situ generation of CO via the reduction of CO2 liberated during decarboxylation has also been developed as a proof-of-concept approach that CO2 -derived compounds can be converted to CO-containing frameworks. Mechanistic studies provide insight into the catalytic steps which highlight the impact of ligand choice to overcome challenges associated with low-pressure carbonylation methodologies, along with rational for the development of future methodologies.

A Self-Immolative Linker for the pH-Responsive Release of Amides.

The administration of therapeutics using bioconjugation has been mainly limited to drugs containing amine, alcohol, or thiol functional groups. Here, we report a general procedure for the preparation of benzylic N-acyl carbamates suitable for masking the amide group in important drugs such as Linezolid, Enzalutamide, or Tasimelteon in good to acceptable yields. These N-acyl carbamates appear to be stable in plasma, while a qualitative analysis of further drug uncage demonstrates that, at pH values of 5.5, a classical 1,6-benzyl elimination mechanism takes place, releasing more than 80% of the drug in 24 h.

Design, synthesis, and metabolite identification of Tamoxifen esterase-activatable prodrugs

Tamoxifen (TAM) is used in treatment of hormonal dependent breast cancer, both in premenopausal and postmenopausal women. TAM is intrinsically metabolized by CYP450 enzymes to more active metabolites. Recent reports identified CYP2D6, an enzyme involved in the conversion of TAM to the more potent 4-OH-TAM, is encoded by theCYP2D6gene, which is highly polymorphic. Women with inactive alleles are poor metabolizers; in many cases they suffer acquired TAM resistance. Herein we report synthesis and biological evaluation of novel TAM analogues. The novel analogues are designed to elude CYP2D6 metabolism. Hydrolysis of the carbamate moiety on ring C is mediated via carboxylesterases. Compound 3d [E/Z Benzyl-carbamic acid4-{2-benzyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-but-1-enyl}-phenyl ester] showed GI50 = 0.09 µM on MCF-7 and GI50 = 1.84 µM on MDA-MB231 cell lines. To further validate our hypothesis, metabolites of selected novel analogues were determined in vitro under different incubation conditions. The hydroxylated analogues were obtained under non CYP2D6 dependent conditions. Compound 8d, a benzyl carbamate derivative, was the least-stable analog and showed the highest rate of metabolism among all tested analogues. Our in silico model showed the novel flexible analogues can still adopt an antiestrogenic binding profile occupying the same pocket as 4-OH-TAM.

Synthesis and evaluation of carbamate derivatives as fatty acid amide hydrolase and monoacylglycerol lipase inhibitors.

Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are the primary catabolic enzymes for endocannabinoids, anandamide (AEA), and 2-arachidonoyl glycerol. Numerous studies have shown that FAAH and MAGL play an important role in modulating various central nervous system activities; hence, the development of small molecule FAAH/MAGL inhibitors is an active area of research. Several small molecules possessing the carbamate scaffold are documented as potential FAAH/MAGL inhibitors. Here, we designed and synthesized a series of open chain and cyclic carbamates and evaluated their dual FAAH-MAGL inhibition properties. Phenyl [4-(piperidin-1-ylmethyl)phenyl]carbamate (2e) emerged as the most potent MAGL inhibitor (IC50 = 19 nM), benzyl (1H-benzo[d]imidazol-2-yl)carbamate (3h) was the most potent FAAH inhibitor (IC50 = 55 nM), and phenyl (6-fluorobenzo[d]thiazol-2-yl)carbamate (2i) egressed as a nonselective dual FAAH-MAGL inhibitor (FAAH: 82 nM, MAGL: 72 nM). The enzyme kinetics experiments revealed that the compounds inhibit FAAH/MAGL in a covalent-reversible manner, with a mixed binding mode of action. Moreover, the lead compounds were found suitable for blood-brain permeation in the parallel artificial membrane permeation assay. Furthermore, docking simulation experiments suggested that the potency of the lead compounds was governed by hydrogen bonds and hydrophobic interactions with the enzyme active sites. In silico drug-likeness and ADMETox prediction studies provided useful information on the compounds' oral absorption, metabolism, and toxicity profiles. In summary, this study afforded potent multifunctional carbamates with appreciable pharmacokinetic profiles meriting further investigation.

Development of an automated screen for Kv7.2 potassium channels and discovery of a new agonist chemotype

To identify pore domain ligands on Kv7.2 potassium ion channels, we compared wild-type (WT) and W236L mutant Kv7.2 channels in a series of assays with previously validated and novel agonist chemotypes. Positive controls were retigabine, flupirtine, and RL-81; i.e. Kv7.2 channel activators that significantly shift voltage-dependent activation to more negative potentials (ΔV50) at 5 µM. We identified 6 new compounds that exhibited differential enhancing activity between WT and W236L mutant channels. Whole cell patch-clamp electrophysiology studies were conducted to identify Kv7.2. Kv7.2/3, Kv7.4, and Kv7.5 selectivity. Our results validate the SyncroPatch platform and establish new structure activity relationships (SAR). Specifically, in addition to selective Kv7.2, Kv7.2/3, Kv7.4. and Kv7.5 agonists, we identified a novel chemotype, ZK-21, a 4-aminotetrahydroquinoline that is distinct from any of the previously described Kv7 channel modifiers. Using flexible receptor docking, ZK-21 was predicted to be stabilized by W236 and bind perpendicular to retigabine, burying the benzyl carbamate group into a tunnel reaching the core of the pore domain.

Hybrid imidazo[1,2-a]pyridine analogs as potent ATX inhibitors with concrete in vivo antifibrosis effect.

In recent years, small-molecule inhibitors targeting the autotaxin (ATX)/lysophosphatidic acid axis gradually brought excellent disease management benefits. Herein, a series of imidazo[1,2-a]pyridine compounds (1-11) were designed as ATX inhibitors through a hybrid strategy by combining the imidazo[1,2-a]pyridine skeleton in GLPG1690 and the benzyl carbamate moiety in PF-8380. As indicated by FS-3-based enzymatic assay, the carbamate derivatives revealed moderate to satisfying ATX inhibitory potency (IC50 = 23-343 nM). Subsequently, the carbamate linker was altered to a urea moiety (12-19) with the aim of retaining ATX inhibition and improving the druglikeness profile. The binding mode analysis all over the modification process well rationalized the leading activity of urea derivatives in an enzymatic assay. Following further structural optimization, the diethanolamine derivative 19 exerted an amazing inhibitory activity (IC50 = 3.98 nM) similar to the positive control GLPG1690 (IC50 = 3.72 nM) and PF-8380 (IC50 = 4.23 nM). Accordingly, 19 was tested directly for in vivo antifibrotic effects through a bleomycin model (H&E staining), in which 19 effectively alleviated lung structural damage and fibrosis at an oral dose of 20 and 60 mg/kg. Collectively, 19qualified as a promising ATX inhibitor for potential application in fibrosis-relevant disease treatment.

Design, synthesis and docking study of Vortioxetine derivatives as a SARS-CoV-2 main protease inhibitor.

PurposeVortioxetine an anti-depressant FDA-drug recently reported showing better in vitro efficacy against SARS-CoV-2.MethodsIn this study, we have synthesized ten new derivatives having alkenes, alkynes, benzyl, aryl, and mixed carbamate at the N-terminal of vortioxetine. Then the binding energy and interactions with the crucial amino acid residues in the binding pocket of main protease (Mpro) of SARS-CoV-2, of reported and ten newly synthesized vortioxetine derivatives (total thirty-one) in comparison with remdesivir are analyzed and presented in this paper.ResultsBased on the docking scores predicted by ADV and AD, most vortioxetine derivatives showed better binding efficiency towards Mpro of SARS-CoV-2 in comparison with remdesivir (an EUA approved drug against SARS-CoV-2 Mpro) and vortioxetine.ConclusionThis study shows that some vortioxetine derivatives can be developed into promising drugs for COVID-19 treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40199-022-00441-z.

Design, synthesis and promising anti-tumor efficacy of novel imidazo[1,2-a]pyridine derivatives as potent autotaxin allosteric inhibitors

Aiming to track the potential antitumor effect of novel allosteric autotaxin (ATX) inhibitors, a hybrid strategy was utilized by merging ATX inhibitors PF-8380 and GLPG1690, while the piperazinyl group in GLPG1690 was replaced with benzene ring to furnish imidazo[1,2-a]pyridine derivatives 10ã10k. Based on ATX enzymatic assay, we further changed the substituents within benzyl carbamate moiety and tuned the carbamate linker to urea group. Delightfully, compound 10c bearing a N-hydroxyethyl piperazinyl group was identified as the optimal ATX inhibitor with an IC50 value of 3.4 nM 10c exerted the most impressive antitumor effects, especially on Hep3B (0.58 μM) and RAW264.7 (0.63 μM) cell lines highly expressing ATX mRNA. Moreover, 10c could dose-dependently suppress the RAW264.7 cell migration rate in wound healing assay and significantly inhibit RAW264.7 cell colony formation. Meanwhile, 10c was capable of inducing weak to moderate apoptosis and achieved notable G2 phase arrest on RAW264.7 cells. Taken together, 10c may serve as a novel lead to probe possible role of ATX allosteric inhibitors in tumor diseases.

Rapid Access to γ-Amino-α-aryl Alcohol Scaffolds via an Enamine-Based Heck Coupling.

The γ-amino-α-aryl alcohol is a key functional group for the design of inhibitors directed toward a critical family of metabolic enzymes. Here we report the transformation of simple aryl halides to a highly functionalized benzyl (3-oxo-3-arylpropyl)carbamate intermediate that can rapidly be converted to a high value γ-amino-α-aryl alcohol. This chemistry is realized through a two-step process involving an enamine-based Heck coupling (EBHC) followed by a one-pot catalytic Cbz-deprotection and ketone reduction of EBHC products.

Novel imidazo[1,2-a]pyridine derivatives as potent ATX allosteric inhibitors: Design, synthesis and promising in vivo anti-fibrotic efficacy in mice lung model

Aiming to develop novel allosteric autotaxin (ATX) inhibitors, hybrid strategy was utilized by assembling the benzyl carbamate fragment in PF-8380 onto the imidazo[1,2-a]pyridine skeleton of GLPG-1690. The piperazine moiety in GLPG-1690 was replaced with phenyl ring to enhance the π-π interactions with adjacent residues. In the light of FS-3 based ATX enzymatic assay, further structure-guided optimizations were implemented by exploring the substituents within the carbamate aromatic moiety and examining the effect of the 2-ethyl. Eventually, 13c bearing 1,3-benzodioxole and 2-hydroxyethyl piperazine group was identified as a powerful ATX inhibitor with an IC50 value of 2.7 nM. Subsequently, 13c was forwarded into an in vivo bleomycin-induced mice lung fibrosis model. In histopathological and immunohistochemical assays, 13c could typically alleviate the severity of fibrosis tissues and effectively reduce the deposition of fibrotic biomarker α-SMA. At a dose of 60 mg/kg, 13c was observed equivalent or even better potency than GLPG-1690 with a significant inhibition of the in vivo ATX activity. Except for the fundamental H-bond and π-π interactions, an extra H-bond between the 1,3-benzodioxole (O atom) and Phe306 offered great rationale in constraining the binding conformation of 13c. Finally, binding free energy calculation was conducted to assist in the efficient identification of allosteric ATX inhibitors.

Antitumor properties of novel sesquiterpene lactone analogs as NFκB inhibitors that bind to the IKKβ ubiquitin-like domain (ULD).

Melampomagnolide B (MMB, 3) is a parthenolide (PTL, 1) based sesquiterpene lactone that has been used as a template for the synthesis of a plethora of lead anticancer agents owing to its reactive C-10 primary hydroxyl group. Such compounds have been shown to inhibit the IKKβ subunit, preventing phosphorylation of the cytoplasmic IκB inhibitory complex. The present study focuses on the synthesis and invitro antitumor properties of novel benzyl and phenethyl carbamates of MMB (7a-7k). Screening of these MMB carbamates identified analogs with potent growth inhibition properties against a panel of 60 human cancer cell lines (71% of the molecules screened had GI50 values<2μM). Two analogs, the benzyl carbamate 7b and the phenethyl carbamate7k, were the most active compounds. Lead compound 7b inhibited cell proliferation in M9 ENL AML cells, and in TMD-231, OV-MD-231 and SUM149 breast cancer cell lines. Interestingly, mechanistic studies showed that 7b did not inhibit p65 phosphorylation in M9 ENL AML and OV-MD-231cells, but did inhibit phophorylation of both p65 and IκBα in SUM149cells. 7b also reduced NFκB binding to DNA in both OV-MD-231 and SUM149cells. Molecular docking studies indicated that 7b and 7k are both predicted to interact with the ubiquitin-like domain (ULD) of the IKKβ subunit. These data suggest that in SUM149cells, 7b is likely acting as an allosteric inhibitor of IKKβ, whereas in M9 ENL AML and OV-MD-231cells 7b is able to inhibit an event after IκB/p65/p50 phosphorylation by IKKβ that leads to inhibition of NFκB activation and reduction in NFκB-DNA binding. Analog 7b was by far the most potent compound in either carbamate series, and was considered an important lead compound for further optimization and development as an anticancer agent.

Self‐Regenerating of Functional Polymer Surfaces by Triggered Layer Shedding Using a Stimulus‐Responsive Poly(urethane)

AbstractRegeneration of functional surfaces after damage or contamination could extend the life time of devices. Such regeneration can be achieved by layer shedding (like a lizard shedding its skin). In this work, triggered self‐regeneration of functional surfaces by an external stimulus is presented. Polymer multilayer stacks are assembled alternatingly from discrete 20–300 nm thick functional layers and depolymerizable interlayers, which are used as sacrificial layers. The sacrificial layers are depolymerizable poly(benzyl carbamates) end‐capped with 4‐hydroxy‐2‐butanone. Their depolymerization is triggered by alkaline pH, at which the end‐cap is cleaved. This initiates a 1,6‐elimination cascade of the polymer backbone, during which CO2 is released. Thus, the layer shedding is driven synergistically by mass transport and buoyancy forces. Proof‐of‐concept is achieved using poly(styrene) as a model functional layer, and also studied for hydrophilic, antimicrobially active poly(oxanorbornene) layers. The multilayer assembly and disassembly process is monitored by ellipsometry, Fourier transform infrared spectroscopy (FTIR), optical microscopy, and atomic force microscopy. FTIR spectra taken after degradation are confirmed the regeneration of the surface functionality.

Nickel Nanoparticles Immobilized over Mesoporous SBA-15 for Efficient Carbonylative Coupling Reactions Utilizing CO2: A Spotlight.

Ecofriendly routes for the synthesis of carbamates and carbonylative coupling products such as benzyl formate derivatives are very demanding for both academia and industries. Foreseeing a sustainable green future, we systematically analyzed the synthesis history of both these chemicals, mentioning their pros and cons. As a step towards green chemistry, here we have optimized the reaction conditions for the synthesis of various benzyl formates from corresponding benzyl halides and carbamates from substituted anilines and alkyl halides catalyzed by Ni(0) nanoparticles (NPs) immobilized over amine-functionalized ordered mesoporous SBA-15 material in the presence of CO2 as C1 source. This spotlight on applications is aimed to provide a clear outlook to date regarding the gradual progress in the synthesis of both these aforementioned chemicals and finally addresses further efforts for overcoming the current challenges.