Alkyl Bond Research Articles

Iodine catalyzed oxidative C(CO)–C(methyl) bond cleavage in methyl ketones: Application to the synthesis of β-Carboline-3-esters

A novel synthesis of substituted β-carboline-3-esters was achieved by the molecular iodine catalyzed reaction of tryptophan methyl ester hydrochlorides with methyl ketones through oxidative C(CO) − C(methyl) bond cleavage. The products in these reactions are similar to those produced in regular Pictet-Spengler reactions of tryptophan methyl esters with analogous aldehyde substrates. Studies revealed that, reaction involves iminium formation, cyclization and followed by iodine catalyzed C(CO) − C(alkyl) bond cleavage of methyl group of ketone substrate to the final compound.

Targeting H3N2 influenza virus RNA dependent RNA polymerase dependent inhibitory activity by principal components from latex of Calotropis gigantean

The H3N2 influenza virus is spiking dramatically, which is a major concern worldwide and in India. The multifunctional hetero-trimer influenza virus RNA-dependent RNA polymerase (RdRP) is involved in the generation of viral mRNA and is crucial for viral infectivity, which is directly related to the virus’s ability to survive. The goal of the current work was to use molecular docking to determine how the RdRP protein might be affected by powerful bioactive chemicals found in Calotropis gigantia latex. By applying CB-dock 2 analysis and 2D interactions, an in-silico docking study was conducted using a GC-FID (gas chromatography with flame-ionization detection) based composition profile. Tocospiro A (15%), Amyrin (7%), and Gombasterol A were found by GC-FID to be the main phytocompounds in the latex of Calotropis gigantia. The docking result showed that ligands were effectively bound to RdRP. According to interaction studies, RdRP/ligand complexes create hydrogen bonds, van der Waals forces, pi-alkyl bonds, alkyl bonds, and pi-Sigma bonds. Therefore, it was suggested that Calotropis gigantia latex may represent a possible herbal remedy to attenuate H3N2 infections based on the above findings of the fragrance profile and docking.

Design anticancer potential of Zn(II)isoleucinedithiocarbamate complex on MCF-7 cell lines: synthesis, characterization, molecular docking, molecular dynamic, ADMET, and in-vitro studies.

Cisplatin is a cancer medication widely used today, but it still poses some problems due to its toxic properties in the body. To overcome this issue, a new complex has been developed as a potential anticancer drug prospect by minimizing its toxic consequences. A novel Zn(II)IleDTC complex containing isoleucine dithiocarbamate ligands has been produced and analyzed using a range of analytical and spectroscopic methods. The Zn(II) IleDTC complex were characterized using various methods, including UV-Vis spectroscopy, FT-IR, determination of melting point, conductivity, and HOMO-LUMO analysis. Furthermore, computational NMR spectrum analysis was conducted in this study. Molecular docking studies was conducted to evaluate the potential of Zn(II) isoleucine dithiocarbamate as an HIF1 inhibitor. The results showed that the Zn complex exhibited a good docking score of -6.6 and formed hydrogen bonds with ARG 17, VAL264, and GLU15, alkyl bonds with TRP27 and LEU32, and Pi-Alkyl bonds with PRO41 and ARG44. This suggests that the Zn(II) isoleucine dithiocarbamate complex could be a promising candidate for cancer treatment with potential HIF1 inhibition properties. To assess the dynamic stability and efficacy of protein-ligand interactions over time, molecular dynamics simulations was conducted for both individual proteins and protein complexes. The cytotoxicity evaluation of Zn(II) isoleucine dithiocarbamate against MCF-7 cells obtained an IC50 value of 362.70µg/mL indicating moderate cytotoxicity and morphological changes of cancer cells causing cancer cells to undergo apoptosis. The Zn(II) isoleucine dithiocarbamate complex may have promising potential as an anticancer compound due to its significant inhibitory effect on the breast cancer cell line (MCF7). According to the ADMET study, the complex exhibits drug-like characteristics with low toxicity, further supporting its potential as a viable drug candidate.

Radioprotective Effects of Carvacrol and/or Thymol against Gamma Irradiation-Induced Acute Nephropathy: In Silico and In Vivo Evidence of the Involvement of Insulin-like Growth Factor-1 (IGF-1) and Calcitonin Gene-Related Peptide.

Radiotherapy (RT) is an effective curative cancer treatment. However, RT can seriously damage kidney tissues resulting in radiotherapy nephropathy (RN) where oxidative stress, inflammation, and apoptosis are among the common pathomechanisms. Carvacrol and thymol are known for their antioxidative, anti-inflammatory, and radioprotective activities. Therefore, this study investigated the nephroprotective potentials of carvacrol and/or thymol against gamma (γ) irradiation-induced nephrotoxicity in rats along with the nephroprotection mechanisms, particularly the involvement of insulin-like growth factor-1 (IGF-1) and calcitonin gene-related peptide (CGRP). Methods: Male rats were injected with carvacrol and/or thymol (80 and 50 mg/kg BW in the vehicle, respectively) for five days and exposed to a single dose of irradiation (6 Gy). Then, nephrotoxicity indices, oxidative stress, inflammatory, apoptotic biomarkers, and the histopathological examination were assessed. Also, IGF-1 and CGRP renal expressions were measured. Results: Carvacrol and/or thymol protected kidneys against γ-irradiation-induced acute RN which might be attributed to their antioxidative, anti-inflammatory, and antiapoptotic activities. Moreover, both reserved the γ -irradiation-induced downregulation of CGRP- TNF-α loop in acute RN that might be involved in the pathomechanisms of acute RN. Additionally, in Silico molecular docking simulation of carvacrol and thymol demonstrated promising fitting and binding with CGRP, IGF-1, TNF-α and NF-κB through the formation of hydrogen, hydrophobic and alkyl bonds with binding sites of target proteins which supports the reno-protective properties of carvacrol and thymol. Collectively, our findings open a new avenue for using carvacrol and/or thymol to improve the therapeutic index of γ-irradiation.

Double alkyl–alkyl bond construction across alkenes enabled by nickel electron-shuttle catalysis

Double alkyl–alkyl bond construction across alkenes enabled by nickel electron-shuttle catalysis

Rapid identification of α-glucosidase inhibitors from Poria using spectrum-effect, component knock-out, and molecular docking technique.

Poria (Poria cocos) is known for its health-promoting effects and is consumed as a food due to its potential hypoglycemic activity. However, the composition of Poria is complex, and the bioactive compounds that inhibit α-glucosidase are not clear. In this study, the fingerprint of the Poria methanol extract characterized by high-performance liquid chromatography (HPLC) and the model of the corresponding spectrum-effect relationship for α-glucosidase was first established to screen the active compounds from Poria. Then, the predicted bioactive compounds were knocked out and identified using mass spectrometry. Finally, the potential binding sites and main bonds of each compound with α-glucosidase were studied using molecular docking. The results have shown that at least 11 compounds from Poria could inhibit α-glucosidase effectively. Moreover, eight individual compounds, i.e., poricoic acid B (P8), dehydrotumulosic acid (P9), poricoic acid A (P10), polyporenic acid C (P12), 3- epidehydrotumulosic acid (P13), dehydropachymic acid (P14), 3-O-acetyl-16α-hydroxytrametenolic acid (P21), and pachymic acid (P22), were identified, and they exhibited effective inhibitory activity against α-glucosidase. The possible inhibitory mechanism of them based on molecular docking showed that the binding sites are mainly found in the rings A, B, and C of these compounds, and C-3 C-16 and side chains of C-17, with the phenylalanine, arginine, tyrosine, histidine, and valine of α-glucosidase. The main interactions among them might be alkyl and hydrogen bonds, which theoretically verified the inhibitory activity of these compounds on α-glucosidase. The achievements of this study provided useful references for discovering bioactive compounds with hypoglycemic effects from Poria.

Nickel‐Catalyzed Selective C(sp2)−F Bond Alkylation of Industrially Relevant Hydrofluoroolefin HFO‐1234yf

AbstractThe selective transition‐metal catalyzed C−F bond functionalization of inexpensive industrial fluorochemicals represents one of the most attractive approaches to valuable fluorinated compounds. However, the selective C(sp2)−F bond carbofunctionalization of refrigerant hydrofluoroolefins (HFOs) remains challenging. Here, we report a nickel‐catalyzed selective C(sp2)−F bond alkylation of HFO‐1234yf with alkylzinc reagents. The resulting 2‐trifluoromethylalkenes can serve as a versatile synthon for diversified transformations, including the anti‐Markovnikov type hydroalkylation and the synthesis of bioactive molecule analogues. Mechanistic studies reveal that lithium salt is essential to promote the oxidative addition of Ni0(Ln) to the C−F bond; the less electron‐rich N‐based ligands, such as bipyridine and pyridine‐oxazoline, feature comparable or even higher oxidative addition rates than the electron‐rich phosphine ligands; the strong σ‐donating phosphine ligands, such as PMe3, are detrimental to transmetallation, but the less electron‐rich and bulky N‐based ligands, such as pyridine‐oxazoline, facilitate transmetallation and reductive elimination to form the final product.

Nickel-Catalyzed Selective C(sp2 )-F Bond Alkylation of Industrially Relevant Hydrofluoroolefin HFO-1234yf.

The selective transition-metal catalyzed C-F bond functionalization of inexpensive industrial fluorochemicals represents one of the most attractive approaches to valuable fluorinated compounds. However, the selective C(sp2 )-F bond carbofunctionalization of refrigerant hydrofluoroolefins (HFOs) remains challenging. Here, we report a nickel-catalyzed selective C(sp2 )-F bond alkylation of HFO-1234yf with alkylzinc reagents. The resulting 2-trifluoromethylalkenes can serve as a versatile synthon for diversified transformations, including the anti-Markovnikov type hydroalkylation and the synthesis of bioactive molecule analogues. Mechanistic studies reveal that lithium salt is essential to promote the oxidative addition of Ni0 (Ln ) to the C-F bond; the less electron-rich N-based ligands, such as bipyridine and pyridine-oxazoline, feature comparable or even higher oxidative addition rates than the electron-rich phosphine ligands; the strong σ-donating phosphine ligands, such as PMe3 , are detrimental to transmetallation, but the less electron-rich and bulky N-based ligands, such as pyridine-oxazoline, facilitate transmetallation and reductive elimination to form the final product.

A validated LC-MS/MS method for the quantification of bevacizumab in rat, cynomolgus monkey, and human serum

Bevacizumab is a humanized monoclonal antibody used in the treatment of advanced colorectal and non-small cell lung cancer. Our main aim was to establish a simple, economical, and high efficiency liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantifying the content of bevacizumab in various biological fluids (rat, cynomolgus monkey, and human serum). A surrogate peptide of bevacizumab, specifically FTFSLDTSK, was generated through trypsin hydrolysis, and quantified using an isotopically labeled peptide containing two amino acids, FTFSLDTSK[13C6, 15N2]ST, as an internal standard to correct for variations introduced during the enzymatic hydrolysis process and any mass spectrometry variabilities. The pre-treatment process included denaturation, disulfide bond reduction and alkylation, trypsin hydrolysis, and termination of the reaction, with a total duration of approximately 2.5–3 h. The results of the methodological validation showed that the linear range in three different biological matrices was 0.2 µg/mL to300 µg/mL, with an LLOQ of 0.2 µg/mL. The precision and accuracy of the measurements met the required standards. The validated LC-MS/MS method was used to conduct pharmacokinetic analysis in rats administered bevacizumab at a dose of 10 mg/kg intravenously.

Iron‐Catalyzed Reductive Cross‐Coupling of Alkyl Electrophiles with Olefins

AbstractIn terms of its abundance and its minimal toxicity, iron has advantages relative to other transition metals. Although alkyl–alkyl bond construction is central to organic synthesis, examples of iron‐catalyzed alkyl–alkyl couplings of alkyl electrophiles are relatively sparse. Herein we report an iron catalyst that achieves cross‐coupling reactions of alkyl electrophiles wherein olefins, in the presence of a hydrosilane, are used in place of alkylmetal reagents. Carbon–carbon bond formation proceeds at room temperature, and the method employs commercially available components (Fe(OAc)2, Xantphos, and Mg(OEt)2); interestingly, this set of reagents can be applied directly to a distinct hydrofunctionalization of olefins, hydroboration. Mechanistic studies are consistent with the generation of an alkyl radical from the alkyl electrophile, as well as with reversibility for elementary steps that precede carbon–carbon bond formation (olefin binding to iron and β‐migratory insertion).

Condition-Controlled Selective Synthesis of Pyranone-Tethered Indazoles or Carbazoles through the Cascade Reactions of N-Nitrosoanilines with Iodonium Ylides.

Presented herein is a condition-controlled selective synthesis of pyranone-tethered indazoles or carbazole derivatives via the cascade reactions of N-nitrosoanilines with iodonium ylides. Mechanistically, the formation of the former involves an unprecedented cascade process including nitroso group-directed C(sp2)-H bond alkylation of N-nitrosoaniline with iodonium ylide followed by intramolecular C-nucleophilic addition to the nitroso moiety, solvent-assisted cyclohexanedione ring opening, and intramolecular transesterification/annulation. On the contrary, the formation of the latter involves the initial alkylation followed by intramolecular annulation and denitrosation. These developed protocols feature easily controllable selectivity, mild reaction conditions, a clean and sustainable oxidant (air), and valuable products that are structurally diverse. In addition, the utility of the products was showcased by their facile and diverse transformations into synthetically and biologically interesting compounds.

Nickel-Catalyzed Remote Asymmetric Hydroalkylation of Alkenyl Ethers to Access Ethers of Chiral Dialkyl Carbinols.

Site- and enantio-selective alkyl-alkyl bond formation is privileged in the retrosynthetic analysis due to the universality of sp3-hybridized carbon atoms in organic molecules. Herein, we report a nickel-catalyzed remote asymmetric hydroalkylation of alkenyl ethers via synchronous implementation of alkene isomerization and enantioselective C(sp3)-C(sp3) bond formation. Regression analysis of catalyst structure-activity relationships accelerates the rational ligand modification through modular regulation. This reaction has several advantages for synthesizing chiral dialkyl carbinols and their ether derivatives, including the broad substrate scope, good functional group tolerance, excellent regioselectivity (>20:1 regioisomeric ratio), and high enantioselectivity (up to 95% enantiomeric excess).

Acylsilane Directed Rh-Catalyzed Arene C-H Alkylation with Maleimides and Visible-Light-Induced Siloxycarbene-Amide Cyclization: [3 + 2] Carbo-Annulation in Ru Catalysis.

We herein demonstrate the acylsilane-directed Rh-catalyzed arene C-H bond alkylation with maleimides. The resulting derivatives were utilized in visible-light-induced intramolecular siloxycarbene-amide cyclization for the synthesis of new tricyclic γ-lactams. In parallel, we also harnessed the same acylsilane and maleimide units through [3 + 2] carbo-annulation by using Ru-catalysis. A wide range of maleimides and aroylsilanes were used to establish the broadness of these transformations.

Exploration of Annona muricata (Annonaceae) in the Treatment of Hyperlipidemia through Network Pharmacology and Molecular Docking

Soursop (Annona muricata L.) is one of the plants that have antihyperlipidemic effects, but its underlying mechanism of action remains unknown. Previous investigations used TCMSP, KNApSAcK, ETCM, SwissTargetPrediction, SuperPred, CTD, and TTD to identify potential targets of soursop as antihyperlipidemic. Therefore, this study aims to explore soursop active compounds and demonstrate their mechanisms against hyperlipidemia through network pharmacology and molecular docking. OB and drug-likeness properties of the compounds from A. muricata were screened based on Lipinski’s Ro5 (Lipinski’s Rule of Five) parameters. Subsequently, the network of the compound–target–disease–pathways was constructed using Cytoscape. The target PPI (protein-protein interaction) network was built using STRING and the core targets were analyzed using GO with KEGG. The main active compounds against the targets were confirmed by molecular docking analysis. Based on the results, 158 compounds were identified in A. muricata, and the human body was found to absorb 56. It was discovered that 20 compounds were associated with cholesterol disease. The highest degree of the disease pathway of target compounds disease was annomuricin, XDH, myocardial ischemia, and metabolic pathways, respectively. The PPI showed GAPDH (glyceraldehyde-3-phosphate dehydrogenase) protein also has the highest degree. BP, CC, MF, and KEEG enrichments that play important roles are the response to drugs, plasma membranes, protein binding, and metabolic pathways. The molecular docking experiment confirmed the correlation between ligands and receptors (quercetin-XDH, coclaurine-ADRB3, fisetin, and robinetin-XDH) with binding energies of –9.3; –8.9; and –8.8 kcal mol–1, respectively. The interactions between ligands and receptors are hydrogen, alkyl, Pi-alkyl, Pi-sigma, and van der Waals bonds. It was discovered that A. muricata provided therapeutic effects, involving multi-compounds, multi-targets, multi-diseases, and multi-pathways as well as deep insight into the pathogenesis of hyperlipidemia. This can be used to design new drugs and develop novel therapies to treat hyperlipidemia.

Controllable C-H Alkylation of Polyethers via Iron Photocatalysis.

The efficient conversion of a C-H bond in the polyether chain to other functional groups provides great opportunities for development of novel applications in many research fields. However, this field is quite underdeveloped due to the key challenge on controlling the selectivity of the C-H bond functionalization over the chain cleavage. In this work, we report a controllable C-H bond alkylation of polyethers under mild conditions via photoinduced iron catalysis. The level of functionalization could be controlled by using different amounts of alkenes and various reaction times, while the molecular weight distributions were maintained narrow. A broad scope of electron-deficient alkenes containing nitrile, ester, epoxide, terminal alkynyl, 2,5-dioxotetrafuranyl, and 2,5-dioxopyrrolidinyl groups could be utilized to functionalize the different polyethers with great efficiencies. The potential applications of the modified polyethylene glycols and polyethylene oxides were explored by the preparation of novel hydrogels and solid-state electrolytes with enhancement of lithium ion conductivities. Moreover, the density functional theory calculation disclosed the plausible mechanism and explained the high selectivity for the C-H alkylation.

Recyclable bio‐based epoxy resins containing hybrid cross‐linking networks

AbstractBio‐based “thiol‐epoxides” thermosets containing dynamic cross‐linked network topologies, permanent cross‐linking and recyclability have been successfully utilized in coatings, adhesives and composites. However, these materials typically have a low glass transition temperature and limited mechanical strength. Combining excellent mechanical properties with thermal properties remains a significant challenge. In this study, we developed a recyclable itaconic acid‐based epoxy thermoset material with high glass transition temperature and tensile strength through thiol‐olefin/thiol‐epoxy click reaction and alkyl bond radical copolymerization to construct a hybrid cross‐linked network. The tensile strength reached up to (105.9 MPa) while maintaining a high Tg (93.3°C), which is the highest value reported in the literature so far. In addition, the itaconic acid‐based epoxy has excellent recyclable processing, self‐healing properties, high hardness, solvent resistance, and surface bond strength as an adhesive and coating. The results hold potential applications in achieving sustainable development in coatings and adhesives.

Molecular docking study of Zingiber officinale Roscoe compounds as a mumps virus nucleoprotein inhibitor

Background: Mumps virus (MuV) can trigger severe infections, such as parotitis, epididymo-orchitis, and meningitis. The effectiveness of MuV vaccine administration has been proven, but current outbreaks warrant the development of antivirals against MuV. Zingiber officinale var. Roscoe or ginger is often used as an alternative remedy. Currently, there are no known in vitro or in vivo studies that investigate ginger as an MuV antiviral. Purpose: This study aims to evaluate the antiviral potency of the bioactive compounds in Zingiber officinale var. Roscoe against MuV. Methods: Antiviral activity screening was conducted by druglikeness analysis, antiviral probability, molecular docking, and molecular dynamic simulation. Results: As an antiviral, 6-shogaol from Zingiber officinale var. Roscoe has potency against MuV. It has a good binding affinity and can establish interactions with the binding domain of the target protein by forming hydrogen, Van der Waals, and alkyl bonds. Conclusion: The complex of 6-shogaol_NP was predicted to be volatile but stable for triggering inhibitory activity. However, these results must be proved by in vivo and in vitro approaches to strengthen the scientific evidence.

Rhodium(i)-catalyzed cascade C(sp2)-H bond alkylation - amidation of anilines: phosphorus as traceless directing group.

We introduce a versatile Rh(i)-catalyzed cascade reaction, combining C(sp2)-H bond functionalization and amidation between N-arylphosphanamines and acrylates. This innovative approach enables the rapid synthesis of dihydroquinolinone scaffolds, a common heterocycle found in various pharmaceuticals. Notably, the presence of the phosphorus atom facilitates the aniline ortho-C(sp2)-H bond activation prior to N-P bond hydrolysis, streamlining one-pot intramolecular amidation. Moreover, we demonstrate the applicability of this reaction by synthesizing an antipsychotic drug. Detailed mechanistic investigations revealed the involvement of a Rh-H intermediate, with substrate inhibition through catalyst saturation.

Comparative study of CO2 insertion into pincer supported palladium alkyl and aryl complexes.

The insertion of CO2 into metal alkyl bonds is a crucial elementary step in transition metal-catalyzed processes for CO2 utilization. Here, we synthesize pincer-supported palladium complexes of the type (tBuPBP)Pd(alkyl) (tBuPBP = B(NCH2PtBu2)2C6H4-; alkyl = CH2CH3, CH2CH2CH3, CH2C6H5, and CH2-4-OMe-C6H4) and (tBuPBP)Pd(C6H5) and compare the rates of CO2 insertion into the palladium alkyl bonds to form metal carboxylate complexes. Although, the rate constant for CO2 insertion into (tBuPBP)Pd(CH2CH3) is more than double the rate constant we previously measured for insertion into the palladium methyl complex (tBuPBP)Pd(CH3), insertion into (tBuPBP)Pd(CH2CH2CH3) occurs approximately one order of magnitude slower than (tBuPBP)Pd(CH3). CO2 insertion into the benzyl complexes (tBuPBP)Pd(CH2C6H5) and (tBuPBP)Pd(CH2-4-OMe-C6H4) is significantly slower than any of the n-alkyl complexes, and CO2 does not insert into the palladium phenyl bond of (tBuPBP)Pd(C6H5). While (tBuPBP)Pd(CH2CH3) and (tBuPBP)Pd(CH2CH2CH3) are resistant to β-hydride elimination, we were unable to synthesize complexes with n-butyl, iso-propyl, and tert-butyl ligands due to β-hydride elimination and an unusual reductive coupling, which involves the formation of new C-B bonds. This reductive process also occurred for (tBuPBP)Pd(CH2C6H5) at elevated temperature and a related process involving the formation of a new H-B bond prevented the isolation of (tBuPBP)PdH. DFT calculations provide insight into the relative rates of CO2 insertion and indicate that steric factors are critical. Overall, this work is one of the first comparative studies of the rates of CO2 insertion into different metal alkyl bonds and provides fundamental information that may be important for the development of new catalysts for CO2 utilization.

Photoinduced iron-catalyzed C-H alkylation of polyolefins.

Chemically introducing diverse polar groups into polyolefins via carbon-hydrogen bond alkylation with polar olefins is of substantial value in the synthesis of next-generation lightweight thermoplastics, which is still underdeveloped. In this work, we report a new approach for efficient carbon-hydrogen bond alkylation in commodity polyolefins using photoinduced iron catalysis. Various polyolefins could be functionalized with broad scope. Polar groups could be incorporated in a single step. The controllable synthesis of multi-polar functional polyolefins could be achieved by a designed module-assembled process. Remarkably, even low levels of functionalization could upcycle the polyolefin materials to exhibit unusual physical properties, such as enhancement of the transparencies, strains, stresses at break of the materials, and hydrophilicity.