Two-step Sequence Research Articles

Synthesis and Biological Evaluation of a Fused Structure of Indolizine and Pyrrolo[1,2-c]pyrimidine: Identification of Its Potent Anticancer Activity against Liver Cancer Cells

A highly efficient approach to a new indolizine scaffold fused with pyrrolo[1,2-c]pyrimidine was achieved via one-pot three-component coupling followed by an oxidative cyclization reaction. The simple two-step sequence allowed rapid access to various tetracyclic compounds from commercially available starting materials with the formation of five new bonds. Here, we observed the effects of these compounds on cell viability in HepG2, H1299, HT29, AGS, and A549 cancer cell lines. Interestingly, this fused scaffold had more potent anticancer activity in hepatocellular carcinoma HepG2 and Huh7 cells than other cancer cells. In particular, 5r strongly decreased cell viability in HepG2 and Huh7 cells with an IC50 value of 0.22 ± 0.08 and 0.10 ± 0.11 µM, respectively, but had a very weak inhibitory effect on the cell viability of other cancer cell lines. In addition, 5r significantly inhibited cell migration and induced apoptosis in HepG2 and Huh7 cells via the activation of caspase-3 and cleavage of PARP in a dose-dependent manner. Notably, the co-treatment of 5r with gemcitabine resulted in the significant additional inhibition of cell viability in HepG2 and Huh7 cells. Our results suggest that 5r could be used to develop new chemotype anticancer agents against liver cancers.

N-Trifluoropropylation of Azoles through N-Vinylation and Sequential Hydrogenation.

Installing a fluoroalkyl group onto the nitrogen atom of azoles represents a potential strategy for lead optimization in medicinal chemistry. Herein, we describe a method for the N-trifluoropropylation of azoles. This process is accomplished using a combination of regioselective N-vinylation and sequential hydrogenation. The two-step sequence is applicable to a diverse set of azoles and tolerates a wide range of functionalities. In addition, we showcase its practicability and utility through the gram-scale synthesis and the late-stage modification of a complex molecule.

Efficient synthesis of novel colchicine-magnolol hybrids and evaluation of their inhibitory activity on key proteases of 2019-nCoV replication and acute lung injury

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or 2019-nCoV), is a life-threatening infectious condition. Acute lung injury is a common complication in patients with COVID-19. 3-chymotrypsin-like protease (3CLpro) of 2019-nCoV and neutrophil elastase are critical targets of COVID-19 and acute lung injury, respectively. Colchicine and magnolol are reported to exert inhibitory effects on inflammatory response, the severe comorbidity in both COVID-19 and acute lung injury. We thus designed and synthesized a series of novel colchicine-magnolol hybrids based on a two-step synthetic sequence. It was found that these novel hybrids provided unexpected inhibition on 3CLpro and neutrophil elastase, a bioactivity that colchicine and magnolol did not possess. These findings not only provide perquisites for further in vitro and in vivo investigation to confirm the therapeutic potentiality of novel colchicine-magnolol hybrids, but also suggest that the concurrent inhibition of 3CLpro and neutrophil elastase may enable novel colchicine-magnolol hybrids as effective multi-target drug compounds.

Enantiospecific Syntheses of Congested Atropisomers through Chiral Bis(aryne) Synthetic Equivalents.

The synthetic equivalents of the enantiopure binaphthyl bis(aryne) atropisomers derived from BINOL (1,1'-bi-2,2'-naphtol) featuring a stereogenic axis vicinal to the two reactive triple bonds can be generated for the first time in solution in an enantiospecific manner. Using a two-step sequence based on the bidirectional [4+2] cycloaddition of furan derivatives followed by an aromatizative deoxygenation reaction, several 9,9'-bianthracenyl-based atropisomers could be prepared enantiospecifically in high enantiomeric purity. Alternatively, bidirectional reactions with anthracene, 2-bromostyrene, and perylene as the arynophiles afforded very congested bis(benzotriptycene), bis(tetraphene) and bis(anthra[1,2,3,4-ghi]perylene) nanocarbon atropisomers in equally high enantiomeric purity. In complement, cross reactions with two different arynophiles revealed possible. The unusual atropisomer prototypes described in this study open the way to enantiopure nanographene atropisomers designed for functions.

Synthesis of Optically Active syn- and anti-Chlorohydrins through a Bienzymatic Reductive Cascade.

A bienzymatic cascade has been designed and optimized to obtain enantiopure chlorohydrins starting from the corresponding 1-aryl-2-chlorobut-2-en-1-ones. For the synthesis of these α-chloroenones, a two-step sequence was developed consisting of the allylation of the corresponding aldehyde with 3-dichloroprop-1-ene, followed by oxidation and further isomerization. The selective cooperative catalytic system involving ene-reductases (EREDs) and alcohol dehydrogenases (ADHs) afforded the desired optically active chlorohydrins under mild reaction conditions in excellent conversions (up to >99%) and selectivities (up to >99:1 diastereomeric ratio (dr), >99% enantiomeric excess (ee)).

Allowable stresses related to crack growth stability and leak-before-break for circumferentially cracked pipes governed by limit loads: Part I, Pipes subjected to tensile loading

When cracks are found in high toughness ductile pipes governed by limit loads at in-service inspections, and the applied stresses at the cracked locations are less than the allowable stresses, the cracks are allowable. The allowable stresses are generally determined in combination with failure stresses and safety factors. Failure of pipes with circumferential part-through cracks subjected to tensile loading occurs in a two-step sequence: first there is the onset of crack penetration, and then there is the break after the crack penetration. The Local Approach of Limit Load Criteria, which is based on the net-section stress approach, can estimate both crack penetration and break stresses for high-toughness ductile pipes. Using the Local Approach of Limit Load Criteria, allowable tensile stresses based on crack penetration stresses are determined by means of safety factors for plant service level conditions. The allowable stresses decrease with increasing crack angles and depths. The characters of the allowable tensile stresses are found to vary with changing sizes of crack angles and depths. These different characters involve the presence/absence of two parameters: leak-before-break (LBB) and crack growth stability. The crack size boundary on LBB vs non-LBB can be expressed by appropriate equations containing crack depths and angles. In addition, the boundaries of crack growth stability/instability are also expressed by crack depths and angles. These boundaries are taken into consideration during non-destructive inspection and crack growth evaluation.

Visual priming of two-step motion sequences.

Perception of an ambiguous apparent motion is influenced by the immediately preceding motion. In positive priming, when an observer is primed with a slow-pace (1–3 Hz) sequence of motion frames depicting unidirectional drift (e.g., Right–Right–Right–Right), subsequent sequences of ambiguous frames are often perceived to continue moving in the primed direction (illusory Right–Right …). Furthermore, priming an observer with a slow-pace sequence of rebounding apparent motion frames that alternate between opponently coded motion directions (e.g., Right–Left–Right–Left) leads to an illusory continuation of the two-step rebounding sequence in subsequent random frames. Here, we show that even more arbitrary two-step motion sequences can be primed; in particular, two-step motion sequences that alternate between non-opponently coded directions (e.g., Up–Right–Up–Right; staircase motion) can be primed to be illusorily perceived in subsequent random frames. We found that staircase sequences, but not drifting or rebounding sequences, were primed more effectively with four priming frames compared with two priming frames, suggesting the importance of repeating the sequence element for priming arbitrary two-step motion sequences. Moreover, we compared the effectiveness of motion primes to that of symbolic primes (arrows) and found that motion primes were significantly more effective at producing prime-consistent responses. Although it has been proposed that excitatory and rivalry-like mechanisms account for drifting and rebounding motion priming, current motion processing models cannot account for our observed priming of staircase motion. We argue that higher order processes involving the recruitment and interaction of both attention and visual working memory are required to account for the type of two-step motion priming reported here.

Dearomative Ring Expansion of Polycyclic Arenes.

Benzocycloheptenes constitute a common structural motif embedded in many natural products and biologically active compounds. Herein, we report their concise preparation from non‐activated polycyclic arenes using a two‐step sequence involving dearomative [4+2]‐cycloaddition with arenophile in combination with palladium‐catalyzed cyclopropanation, followed by cycloreversion‐initiated ring expansion. The described strategy provides a working alternative to the Buchner reaction, which is limited to monocyclic arenes. Overall, this methylene‐insertion molecular editing approach enables rapid and direct conversion of simple (hetero)arenes into a range of substituted (aza)benzocycloheptatrienes, which can undergo a myriad of downstream functionalizations.

Kinetics of two-step catalytic sequence on nanoclusters with limited cluster occupancy

Two-step catalytic sequence was considered for cooperative kinetics of heterogeneous catalytic reactions on nanoclusters with a limited number of adsorbed species due to size restrictions allowing for derivation of the corresponding rate expressions. Dependence of the kinetic parameters on the number of adsorbed species was considered for different models of biographical (intrinsic) and induced non uniform surfaces. Explicit expressions were derived for the rates on evenly nonuniform surfaces exhibiting a linear decrease in the Gibbs energy with site occupancy. An expression for the apparent activation energy was obtained for the two step sequence with both irreversible steps. Simulations were performed for several expressions for the forward reaction rate in a two-step sequence with different number of maximal adsorbed species. The analysis illustrated that the reaction rates in the forward direction pass through maxima even without any competition of both reactants. Strong nonuniformity or lateral interactions make the rate maxima less prominent. Larger clusters, which can accommodate more adsorbed intermediates per cluster, exhibit rather wide maxima in the rates expanding over a broad range of concentrations.The experimental data on resazurin reduction with hydroxylamine over gold clusters bearing 15 to 25 gold atoms were used to illustrate applicability of the developed theoretical approach showing a dramatic switch in kinetic regularities between Au15 and Au18 clusters, which could be attributed to changes in the number of adsorbed species per cluster.

Selective palladium-catalyzed functionalization of α-methylene butanolides

We describe an efficient and selective functionalization of α-methylene-γ-butyrolactone. The two-step sequence involves the preparation of bromomethylene butyrolactone 2 in good yield prior to a palladium-catalyzed coupling process. The latter allowed the installation of aryl, alkenyl, and alkynyl groups under Suzuki-Miyaura, Heck, and Sonogashira cross-coupling conditions. The reaction sequences involving Pd(dppf)Cl2-CsF, Pd(OAc)2-PPh3-Ag2CO3, Pd(PPh4)4-CuI-Et3N as the corresponding catalytic systems allow the preparation of an unprecedented panel of α-unsaturated substituted butyrolactones 4–16 ranging from moderate to excellent yields. In all cases, the E-configuration of the exo-double bond is retained from the starting materials to the targets, regardless of the nature of the substituent introduced.

Synthesis of Hexa-Aminated Trinaphtho[3.3.3]propellane and Its Porous Polymer Solids with Alkane Adsorption Properties

Abstract Rigid three-dimensional π-skeletons are useful building blocks for organic porous materials but only a few types of compounds are available as compared with a variety of planar building blocks. Herein, we report that hexa-aminated trinaphtho[3.3.3]propellane was readily prepared by a two-step reaction sequence from a non-functionalized propellane in moderate yield and was active toward condensation with boronic acids and aldehydes. Solvothermal condensation with terephthalaldehyde gave an amorphous polymeric solid with moderate BET surface area, different from precursor molecules. The solid displayed good adsorption capacities for hydrocarbon gases and vapors. Because of multiple CH/π interactions, the adsorption was efficient even at low-pressure for n-butane and larger alkanes, providing good selectivity over smaller alkanes.

2,15-dibutoxy-6,11-dicyano[6]Helicene: Synthesis, electrochemical, photophysical properties and computational studies

2,15-Dibutoxy-6,11-dicyano[6]Helicene (CN-HEL) has been prepared through a two-step sequence under mild conditions, in an overall 78% yield, starting from 2,7-bis(cyanomethyl)naphthalene as a suitable material. The Helicene has been experimentally characterized and its absorption and photoluminescence (PL) properties have been evaluated showing a blue emission in the visible spectrum. A strong absorption is entirely in the UV region (λmax = 290 nm), yet fluorescence occurs at 400 nm. This equates to a Stokes shift of 1.17 eV (9482 cm−1) which is among the largest Stokes shifts reported for small molecules, making it a promising candidate for optoelectronic applications. Furthermore, the 1H NMR, FT-IR, UV-vis and PL spectra were computed by means of the very efficient time-dependent density functional theory (TD-DFT) approach. The computed spectra with two recommended density functional (PBEPBE and cam/B3LYP) and extended basis sets compare very well with the corresponding experimental data. HOMO and LUMO energy levels were also investigated experimentally, showing an electrochemical band gap of 2.54 eV. Results obtained throughout this work are of great importance and prove the relevance of the target Helicene to be used in a wide range of both existing and new applications such as fluorescence probes and molecular sensors.

Spontaneous Lithiation of Binary Oxides during Epitaxial Growth on LiCoO2.

Epitaxial growth is a powerful tool for synthesizing heterostructures and integrating multiple functionalities. However, interfacial mixing can readily occur and significantly modify the properties of layered structures, particularly for those containing energy storage materials with smaller cations. Here, we show a two-step sequence involving the growth of an epitaxial LiCoO2 cathode layer followed by the deposition of a binary transition metal oxide. Orientation-controlled epitaxial synthesis of the model solid-state-electrolyte Li2WO4 and anode material Li4Ti5O12 occurs as WO3 and TiO2 nucleate and react with Li ions from the underlying cathode. We demonstrate that this lithiation-assisted epitaxy approach can be used for energy materials discovery and exploring different combinations of epitaxial interfaces that can serve as well-defined model systems for mechanistic studies of energy storage and conversion processes.

Mengukur Keberkesanan Kelas Pendidikan Mualaf: Kemahiran Guru Dan Kesan Program Mentor Melalui Pendekatan Kaunseling Dan Motivasi

Mentoring programs have long been a concern among academics and industry as programs for professional development and excellent personal formation. The mentor is acting as chancellor, counselor, coach to every mentee. In empowering the religious education of new brothers, mentoring programmes are essential to be implemented to enable a new student to get the advice and assistance needed. The objective of this study was to measure the effectiveness of new sibling education classes through mentor-mentee programmes implemented by new brother mentors. Next study the psychosocial function of the mentor in providing chancellory support and motivation to the mentee. The study used quantitative research design and obtained data with purposeful sampling. This method of exploring factors is made through double linear regression. The data required for this study was collected from the State Islamic Religious Council (SIRC) in Kuala Lumpur, Malaysia. Surveys are conducted with questionnaires at the class session using survey design samples. The planned questionnaire was distributed throughout the target population of 244 respondents through self-management. The data were analyzed using Partial Least Squares-Structural Equation Modeling (PLS-SEM) through a survey instrument with a five-point Likert preferred question, with an analysis of the PLS two-step sequence. The results of the study found that teacher skills, mentor motivational approach and student satisfaction had a positive relationship and a sustainable mentoring atmosphere in the knowledge and learning of participants among the new sibling class. The study also found that the mentor’s motivational approach was a significant factor between teacher skills and student satisfaction in the classroom.

Fully lignocellulose-based PET analogues for the circular economy

Polyethylene terephthalate is one of the most abundantly used polymers, but also a significant pollutant in oceans. Due to growing environmental concerns, polyethylene terephthalate alternatives are highly sought after. Here we present readily recyclable polyethylene terephthalate analogues, made entirely from woody biomass. Central to the concept is a two-step noble metal free catalytic sequence (Cu20-PMO catalyzed reductive catalytic fractionation and Raney Ni mediated catalytic funneling) that allows for obtaining a single aliphatic diol 4-(3-hydroxypropyl) cyclohexan-1-ol in high isolated yield (11.7 wt% on lignin basis), as well as other product streams that are converted to fuels, achieving a total carbon yield of 29.5%. The diol 4-(3-hydroxypropyl) cyclohexan-1-ol is co-polymerized with methyl esters of terephthalic acid and furan dicarboxylic acid, both of which can be derived from the cellulose residues, to obtain polyesters with competitive Mw and thermal properties (Tg of 70–90 °C). The polymers show excellent chemical recyclability in methanol and are thus promising candidates for the circular economy.

Cover Feature: Chiral Hemilabile P,N‐Ligand‐Assisted Gold Redox Catalysis for Enantioselective Alkene Aminoarylation (Chem. Eur. J. 34/2022)

Enantioselective gold redox catalysis was achieved with newly designed chiral hemilabile P,N ligands (shown as a heavy load in the truck). We reveal a new strategy through a two-step sequence: A) Apply a chiral hemilabile P,N ligand at the AuI stage to promote AuI oxidative addition toward aryl iodide; B) nucleophilic addition to a chiral AuIII intermediate formed in situ as a stereodetermining step (SDS). This strategy presents a new opportunity to enrich the versatile reactivity of gold catalysis in an enantioselective fashion. More information can be found in the Research Article by M. Li, X. Shi and co-workers (DOI: 10.1002/chem.202201018).

Observation of Selectively Populated Monohalide Excited States from the Reactions of Group 3 Metal (Sc, Y, and La) Monomers and Dimers with Halogen-Containing Molecules.

The chemiluminescent reactions of the group 3 metals Sc and Y with F2, Cl2, Br2, ClF, ICl (Sc), IBr (Y), and SF6 and La with F2, SF6, Cl2, and ClF have been studied at low pressures (6 × 10-6 to 4 × 10-4 Torr) using a beam-gas arrangement and extended to the 10-3 Torr multiple collision pressure range. Contrary to previous reports, the observed chemiluminescent spectra are primarily attributed to emission from the metal monohalides. Extensive pressure and temperature dependence studies and high-level correlated molecular orbital theory calculations of the bond dissociation energies support this conclusion and the attribution of the chemiluminescence. Evidence for the "selective" production of a monohalide excited electronic state is obtained for several of the Sc and Y reactions. All reactions producing the metal monofluorides are first order with respect to the oxidant, while reactions producing the monochlorides and monobromides are found to be "faster than first order" with respect to the oxidant. This difference is associated with the metal halide bond dissociation energies and the metal halide product internal density of states. Analysis of the temperature dependence for six representative reactions indicates that the "selective" excited-state formation of the metal monohalides proceeds via a direct mechanism with negligible activation energy. We compare and contrast the present results with previous experiments and interpretations which have assigned the selective emission from these systems to the group 3 dihalides produced in a two-step reaction sequence analogous to an electron jump process. The current results suggest a distinctly different interpretation of the observed processes in these systems. The observed selectivity observed in these studies is remarkable given the significant number of known and potential excited states in the scandium and yttrium halides as well as their different electronic configurations.

Synthesis of a Diacetonide-Protected, Mannose-Based Oxepine: Configurational Control of Anomeric Acetate Activation.

Carbohydrate-based oxepines are seven-membered-ring oxacycles containing an enol ether moiety. These compounds have been used as intermediates in the preparation of septanose carbohydrates by functionalization through their double bond. Reported here is a new synthesis of a carbohydrate based oxepine that uses 2,3;4,6-di-O-acetonide mannose as a key starting material. The oxepine is an important precursor used in the synthesis of septanose glycomimetics of mannopyranosides. The central feature of the synthesis is a two-step sequence that converts a septanose 1,2-di-O-acetate to the septanosyl bromide and onward to the oxepine via a reductive elimination.

Two-step, sequential, efficient, artificial light-harvesting systems based on twisted cucurbit[14]uril for manufacturing white light emission materials

White-light-emitting (WLE) materials have promising and valuable applications in controllable lighting, screen displays and sensing. In this study, a two-step sequence of highly efficient artificial light-harvesting systems (ALHSs) with white light emission is successfully constructed in the aqueous phase through a non-covalent bond among imidazole derivatives (DIm), twisted cucurbit[14]uril (tQ[14]), eosin Y (ESY), and Nile red (NiR). The prepared linear supramolecular polymer (DIm@tQ[14]) constructed by DIm and tQ[14] through host–guest interaction is an ideal energy donor due to its superior aggregation-induced emission effect, which enables one-step energy transfer by loading ESY and two-step energy transfer by further loading NiR with a high efficiency of 91.47%. The emission color of the two-step sequential ALHSs changes from cyan to chartreuse then to orange-red, and bright white light emission can be achieved by controlling the donor/acceptor molar ratio. Moreover, the assemblies of the two-step sequential ALHSs can be applied to white LED materials. This research not only simulates the multi-step energy transfer process in nature but also has an attractive commercial value in the manufacturing of WLE materials.

The biosynthetic origin of ribofuranose in bacterial polysaccharides.

Bacterial surface polysaccharides are assembled by glycosyltransferase enzymes that typically use sugar nucleotide or polyprenyl-monophosphosugar activated donors. Characterized representatives exist for many monosaccharides but neither the donor nor the corresponding glycosyltransferases have been definitively identified for ribofuranose residues found in some polysaccharides. Klebsiella pneumoniae O-antigen polysaccharides provided prototypes to identify dual-domain ribofuranosyltransferase proteins catalyzing a two-step reaction sequence. Phosphoribosyl-5-phospho-D-ribosyl-α-1-diphosphate serves as the donor for a glycan acceptor-specific phosphoribosyl transferase (gPRT), and a more promiscuous phosphoribosyl-phosphatase (PRP) then removes the residual 5'-phosphate. The 2.5-Å resolution crystal structure of a dual-domain ribofuranosyltransferase ortholog from Thermobacillus composti revealed a PRP domain that conserves many features of the phosphatase members of the haloacid dehalogenase family, and a gPRT domain that diverges substantially from all previously characterized phosphoribosyl transferases. The gPRT represents a new glycosyltransferase fold conserved in the most abundant ribofuranosyltransferase family.