A concise and efficient route for the synthesis of quinone methide substituted neonicotinoid derivatives (4–5) via the one-pot Cs2CO3-catalyzed 1,6-conjugate addition of N-benzyl nitro ketene amines (2) or 1,1-enediamines (3) with para-quinone methides (1) in acetone and an oxidation reaction using atmospheric oxygen has been developed. This protocol represents a route to obtain a novel class of quinone methide substituted neonicotinoid derivatives in a concise, rapid, and practical manner. This reaction is particularly attractive because of the following features: low-cost and biocompatible solvent, mild temperature, atomic economy, high yields, and potential biological activity of the product.Keywords: 1,6-Conjugate addition; Environmentally friendly; Neonicotinoids; Oxidation; para-Quinone methides;

Self-labeled inhibitors (SLIs) are promising for creating links, ranging from cancer therapy and metastatic pathways to mechanistic elucidation. In this study, a new category of “two-in-one” fluorescent xanthone inhibitors was developed for the systematic evaluation of anticancer activity and the selective imaging of cytoplasm in vitro. These xanthone inhibitors presented high fluorescent brightness, working over a wide pH range enabled by a “switchable reaction” of the heterocyclic backbone. The strength and nature of fluorescence were probed via spectroscopic methods and density functional theory calculations on the molecular level, respectively. Along with the potent anticancer activity, which was demonstrated using MTT and clonogenic assays with high fluorescent brightness in the cytoplasm, SLI 3fd could be established as a modeled self-monitoring drug in cancer therapy.

Self-labeled inhibitors (SLIs) are promising for creating links, ranging from cancer therapy and metastatic pathways to mechanistic elucidation. In this study, a new category of “two-in-one” fluorescent xanthone inhibitors was developed for the systematic evaluation of anticancer activity and the selective imaging of cytoplasm in vitro. These xanthone inhibitors presented high fluorescent brightness, working over a wide pH range enabled by a “switchable reaction” of the heterocyclic backbone. The strength and nature of fluorescence were probed via spectroscopic methods and density functional theory calculations on the molecular level, respectively. Along with the potent anticancer activity, which was demonstrated using MTT and clonogenic assays with high fluorescent brightness in the cytoplasm, SLI 3fd could be established as a modeled self-monitoring drug in cancer therapy.

A concise, metal-free, and gram-scale strategy to convert indoline-2,3-diones to 1,2,4-oxadiazole[4,5-a]indolones through an improved [3 + 2] cycloaddition of α-ketone-lactam with nitrile oxides has been developed. The lactim form of the resonance structure of isatin in protic solvents is the key active dipolarophile that shows chemo- and regioselectivity under experimental and theoretical conditions. This strategy conveniently enabled the assembly of several 1,2,4-oxadiazole[4,5-a]indolines with a broad range of functional groups. Compounds 3a and 4b exhibit cytotoxicity in the NCI/ADR-RES, SKOV3, and OVCAR8 cell lines.Topics: Carbonyl compounds (organic); Chemoselectivity; Cycloaddition reaction; Drug discovery and Drug delivery systems; Electronic structure; Equilibrium; Equilibrium; Green chemistry; Heterocyclic compounds; Molecular structure; Nucleic acids; Physical and chemical processes; Potential energy; Reaction mechanism; Solvation;

A concise and eco-friendly route for the synthesis of highly functionalized bicyclic pyridinium derivatives (3) via a one-pot reaction of chromone-3-carboxaldehydes (1) and N-benzyl nitro ketene aminals (NBNKAs) (2) under reflux in ethanol media has been developed. The targeted compound was efficiently obtained by filtration without further post-treatment. In the one-pot two step reaction, C—C and C═N bonds were constructed, while at the same time one C—O bond was cleaved. This protocol represents a valuable route to obtain highly functional bicyclic pyridinium derivatives in a concise, rapid, and practical manner. The reaction is particularly attractive due to features such as low cost, mild conditions, atom economy, high yield, using biocompatible solvent, and potential biological activity of the product.Keywords: Atom economy; Environment friendly; Imidazopyridine; Neonicotinoids; Pyridinium;

The methods for the synthesis of two novel types of compounds, including pyridin-2-ones 3 and pyrimidin-4-ones 4 were developed. Pyridin-2-ones 3 were synthesised via the regioselective reaction of N,N′-disubstituted 1,1-ene diamines 1a–1w with mercaptals 2a–2c in acetonitrile promoted by Cs2CO3 under refluxing conditions. Fortunately, pyrimidin-4-ones 4 were obtained when the N-monosubstituted 1,1-ene diamines 1x–1b′, used as substrate, by accident, reacted with mercaptals 2 under similar conditions. As a result, two kinds of novel heterocycles were synthesised by this protocol. The reactions have some advantages, such as excellent yield, inexpensive raw materials and convenient final treatment. The antitumor bioactivity screening showed that certain compounds had potent antitumor activity. Especially, compounds 3r, which showed the most potent activity with IC50 values lower than 12.3 μmol L−1 against four human tumor cell lines, making it more active than cisplatin (DDP). In addition, a preliminary assessment of the structure–selectivity relationship of the compounds was also performed.

A efficient and concise one-pot procedure has been developed for the synthesis of highly functional morphan derivatives 3 based on diastereoselective double Michael addition reactions of various quinone monoketals 1 with a variety of heterocyclic ketene aminals (HKAs) 2 in the green solvent water at 60 °C. This protocol is especially suitable for efficient and rapid parallel syntheses of N-containing bridged heterocycles possessing pharmacological activities. As a result, a library of highly functional morphan derivatives was easily synthesized using this reported environmentally benign, mild, and catalyst-free one-pot reaction.

A first asymmetric synthesis of the lycorine-type Amaryllidaceae alkaloid (−)-δ-lycorane by using a chiral bifunctional squaramide-catalysed cascade reaction as a powerful tool to construct the skeleton of the alkaloid on the basis of unsaturated β-ketoester and nitroalkene is reported. The sequence afforded a highly functionalized intermediate with three stereogenic centres with high diastereoselectivity (>20 : 1 dr) and high enantioselectivity (92% ee) in one step, which was converted into (−)-δ-lycorane in eight steps.

A novel series of 2-phenylquinoline-4-carboxamide derivatives was synthesized, characterized and evaluated for its antiproliferative activity against five cancer cell lines, Hela, SK-OV-3, HCT116, A549 and MDA-MB-468, and a normal human fetal lung fibroblastic cell line, MRC-5. Among them, compound 7b displayed potent cytotoxic activity in vitro against SK-OV-3 and HCT116 cell lines with IC50 values of 0.5 and 0.2 μM, respectively. In general, the antiproliferative activity was correlated with the binding property of the colchicine binding site and inhibitory effect on tubulin polymerization. In addition, immunofluorescence and flow cytometry analysis revealed that selected compounds caused disruption of the mitotic spindle assembly and G2/M phase arrest of the cell cycle, which correlated with proliferation inhibitory activity. Molecular docking analysis demonstrated the interaction of 7b at the colchicine binding site of tubulin. These results indicate these compounds are promising inhibitors of tubulin polymerization for the potent treatment of cancer.Download high-res image (228KB)Download full-size image

An efficient method of synthesizing bicyclic fused [1,2,4]oxadiazolo[4,5-c]pyrimidine-5,7(6H)-dione derivatives was developed through a [3 + 2] cycloaddition of uracil derivatives and nitrile oxides. In the one step reaction, CN and CO bonds were constructed, the target compounds were efficiently obtained in good yields. The method represents a valuable way to obtain highly functional fused bicyclic heterocycle derivatives in a simple, rapid and practical manner. The method fusing bicyclic heterocycles can be applied for modification of uracil analogues that may have potential biological activities.Download high-res image (133KB)Download full-size image

This study investigated inclusion formation and the physicochemical properties of naringin/cyclodextrin through a combined computational and experimental approach. Molecular dynamics simulations were applied to investigate the thermodynamics and geometry of naringin/cyclodextrin cavity docking. The complexes were investigated by UV, FT-IR, DSC, XRD, SEM, 2D-NOSEY and 1H-NMR analyses. Clearly visible protons belonging to naringin and chemical shift displacements of the H3 and H5 protons in cyclodextrin were anticipated in the formation of an inclusion complex. Naringin solubility increased linearly with increasing cyclodextrin concentration (displaying an AL profile). The simulations indicated that the phenyl group of naringin was located deep within the cyclodextrin cavity, while the glycoside group of naringin was on the plane of the wider rim of cyclodextrin. The simulation and molecular modeling results indicate that (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) provided the more stable inclusion complex. This result was also in good concordance with the stability constants that had been determined by the phase solubility method. The consistency of the computational and experimental results indicates their reliability.

AbstractA concise and efficient synthesis of imidazo[1,2,4]oxadiazole derivatives that proceeds through the [3+2] cycloaddition of 2-chloro-1H-benzo[d]imidazole with nitrile oxides has been developed. This strategy can conveniently construct tricyclic imidazole heterocyclic derivatives that contain a broad range of functional groups. Compound 3 p showed excellent cytotoxic activity against the KYSE410 cell line (IC50=0.26 μm). These tricyclic imidazole heterocyclic derivatives are promising candidates for drug discovery.

A novel water-soluble oral satraplatin/β-cyclodextrin inclusion complex was prepared and characterized with a variety of techniques. Molecular dynamics simulations were performed to clarify its inclusion mechanism. Enabled by encapsulation with cyclodextrin, the water solubility of satraplatin was successfully increased to 7.4 mg mL−1 and significantly improved by phase solubility studies. Meanwhile, the stability of satraplatin in acidic and weak alkaline aqueous solution was also effectively enhanced by forming the inclusion complex. Importantly, in an in vitro cytotoxicity test, the satraplatin encapsulated complex displayed superior cytotoxicity compared to free satraplatin against A549 and MCF-7 cells but was almost non-toxic to Caco-2 cells. In an in vivo antitumor test, this satraplatin encapsulated complex has shown much better activity in repressing lung cancer than free satraplatin but nearly no damage to intestinal mucosa by oral administration evaluated in xenograft mice models. Overall, the development of the current satraplatin/β-cyclodextrin inclusion complex has significantly improved the bioavailability of satraplatin and could benefit further applications in related pharmaceutical formulations.

Two novel water-soluble morin hydrate (MH) complexes, composed of a hydrophobic MH core and hydrophilic cyclodextrin shell, were prepared and systematically investigated in both aqueous solution and the solid state by means of UV–Vis spectroscopy, 1H NMR, 2D NMR (ROESY), SEM, FT-IR, DSC, TGA, and XRD analysis. The characterization information resulting from these investigations revealed that the MH/cyclodextrin inclusion complexes formed by the MH with CD in 1:1 stoichiometry, and demonstrated satisfactory water solubility. The MH/cyclodextrin complexes still maintained antibacterial activity in vitro test against Staphylococcus aureus bacteria.

A facile synthesis of highly functionized indanone fused multicyclic pyrrolines using the heterocyclic ketene aminal and ninhydrin is described. Derivative alkoxyl or amine substituted analogues were also directly achieved upon adding alcohols or amines as corresponding starting materials. The reaction conditions are environment friendly and have a good tolerance towards a variety of heterocyclic ketene aminals. A library including three series of molecularly diverse indanone fused pyrrolines with potential bioactivities was demonstrated to be rapidly constructed with good to excellent yields.

•Oxaliplatin complexes with β-CD, γ-CD and HP-β-CD were prepared and characterized.•The oxaliplatin/β-CD complex is more stable than free oxaliplatin, oxaliplatin/HP-β-CD and oxaliplatin/γ-CD.•By complexation with cyclodextrins, the water solubility of oxaliplatin was improved.•The complexes enhanced antitumor activities in vivo against HCT116 and MCF-7 cells.Three water-soluble oxaliplatin complexes were prepared by inclusion complexation with β-cyclodextrin (β-CD), γ-CD and HP-β-CD. The structures of oxaliplatin/CDs were confirmed by NMR, FTIR, TGA, XRD as well as SEM analysis. The results show that the water solubility of oxaliplatin was increased in the complex with CDs in 1:1 stoichiometry inclusion modes, and the cyclohexane ring of oxaliplatin molecule was deeply inserted into the cavity of CDs. Moreover, the stoichiometry was established by a Job plot and the water stability constant (Kc) of oxaliplatin/CDs was calculated by phase solubility studies, all results show that the oxaliplatin/β-CD complex is more stable than free oxaliplatin, oxaliplatin/HP-β-CD and oxaliplatin/γ-CD. Meanwhile, the inclusion complexes displayed almost twice as high cytotoxicity compared to free oxaliplatin against HCT116 and MCF-7 cells. This satisfactory water solubility and higher cytotoxic activity of the oxaliplatin/CD complexes will potentially be useful for their application in anti-tumour therapy.

A concise and efficient synthesis of pyrrolo[1,2-a]imidazoles and imidazo[1,2-a]-pyridines was developed by regioselective aza-ene additions and regioselective cyclic–condensation reactions of heterocyclic ketene aminals with ethyl 3-benzoylacrylate or methyl acetylacrylate derivatives under catalyst-free conditions. This method has some advantages including high regioselectivity, good yields and simple work-up procedures.

A series of adamantoyl L-prolinamides have been synthesized. These compounds have been found to be highly efficient organocatalysts for the Michael addition of aldehydes and ketones to nitroalkenes. Under the optimized reaction conditions, the corresponding Michael adducts were obtained in good yields (up to 95%), excellent enantioselectivities (up to 99% ee) and moderate diastereoselectivities.

•The cordycepin/α-CD complex is more stable than others.•Purine ring of the cordycepin is included in the CD cavities.•ESI-MS examinations gave direct evidence for the 1:1 binding model.•Electrostatic force and hydrogen bond are the main interaction between CDs with cordycepin.The inclusion complexes of cordycepin with cyclodextrins (CDs) were prepared, the resultant complexes were characterised by UV–vis, FTIR, DSC, SEM, XRD, ESI-MS and proton nuclear magnetic resonance spectroscopy (1H NMR). The stoichiometry was established using a Job plot and the inclusion mechanism was clarified using molecular dynamic simulations. Molecular modelling calculations have been carried out to rationalise the experimental findings and predict the stable molecular structure of the inclusion complex. The stability of the inclusion complexes were confirmed by energetic and thermodynamic properties (ΔE, ΔH, ΔG and ΔS) and HOMO, LUMO orbital. The 1:1 binding model of complexes were visually proved by ESI-MS experiment. Our results showed that the purine group of cordycepin molecule was deeply inserted into the cavity of CDs.

•FIT/CDs complexes have been characterized by apparatuses and experimental approaches.•By complexation with cyclodextrins, the water solubility of FIT was improved.•The complexes enhanced antitumor activities in vivo against Hela and MCF-7 cells.•The binding mode and free energy of satraplatin nanoencapsulation were calculated.Novel water-soluble inclusion complexes for fisetin (FIT) were developed by introducing β-cyclodextrin (β-CD) and γ-CD. Properties of the obtained complexes, as well as the interactions between each component, were systematically investigated in both solution and solid states by means of ESI-MS, NMR, FT-IR, XRD, DSC, SEM etc. All characterization information demonstrated that FIT/CDs inclusion complexes were formed, and exhibited different spectroscopic features and properties from FIT. A complex with 1:1 stoichiometry of FIT and CDs was confirmed with Job's method. Meanwhile, as supported by molecular modeling calculations, we suggested that phenyl group (C ring) of FIT molecule was included in the CDs cavity from the wide side. Moreover, the water solubility of FIT/CDs was successfully improved from 2.8 mg/mL (in ethanol aqueous solution) to 4.5 mg/mL (FIT/β-CD complex) and 7.8 mg/mL (FIT/γ-CD complex), and higher thermal stability results were shown by thermal analysis for those complexes. Notably, the inclusion complexes displayed almost two times higher cytotoxicity compared to free FIT against Hela and MCF-7 cells. These results suggested that FIT/CDs complexes could be potentially useful in food industry and healthcare area.

A three-component domino [3+2] cyclization for the synthesis of new multi-functional fused pyrroles has been developed via reaction of heterocyclic ketene aminals (HKAs) 1 with arylglyoxal monohydrates 2 and 1,3-diphenylpropane-1,3-dione 3 under catalyst-free conditions in ethanol. In the one-step domino reaction, one C–N bond and two C–C bonds were formed and one C–C bond was cleaved. The established protocol is advantageous in providing excellent regioselectivity and concise one-pot methodology with the use of environmentally friendly solvents and readily available starting materials.

A series of novel fused polyhalogeno-7a-hydroxy-[1,2-a]indol-5-one derivatives has been synthesized with good yields based on the Nenitzescu reaction of heterocyclic ketene aminals (HKAs) with halogenated quinones without catalyst in acetone under room temperature. The highly efficient, catalyst-free and one pot synthesis serves as a nice addition to group-assisted-purification (GAP) chemistry, and the pure products were obtained simply by washing the crude products with 95% ethanol.

A concise and efficient one-pot three-component synthesis of structurally diverse fluorine substituted bicyclic pyridines was constructed by simply refluxing a mixture of different types of heterocyclic ketene aminals, triethoxymethane, and fluorine-containing methylene compounds under solvent-free and catalyst-free conditions. These bicyclic pyridines are promising candidates for drug discovery; consequently, a library of fluorine substituted bicyclic pyridines was rapidly constructed in 79%–93% yields.

A novel C–N cleavage strategy for the regioselective synthesis of 2-nitroso heterocyclic ketene aminals (HKAs) has been established. In this procedure, the C–N bond of nitrobenzenyl nitroethene is cleaved by the oxidation reaction and selective nitroso reaction of the α-carbon in HKAs. The presented synthetic route features excellent selectivity, straightforward purification and simple starting materials.

As a classical and well-established named reaction, the Nenitzescu reaction is of special value for the construction of biologically meaningful 5-hydroxyindole derivatives. However, to date, its sister, the anti-Nenitzescu reaction and the corresponding synthetic methodology for 3a-hydroxy-indol-6-one derivatives, has remained an unexplored area. We discovered herein an environmentally benign, mild, and catalyst-free reaction in ethanol for the site-selective construction of rarely fused [1,2-a]indolone derivatives (3) from quinones (1) and heterocyclic ketene aminals (HKAs) (2) via an unexpected anti-Nenitzescu strategy. This unconventional methodology suggests that it will be suitable for the site-selective synthesis of 3a-hydroxy-indol-6-one derivatives from a green perspective. On the other hand, the developed target compounds 3 have a promising future for the further synthesis of aromatic 6-hydroxyindoles or dehydroxylated indol-6-ones in situ. In order to systematically elucidate the mechanistic details and controlling factors of the two Nenitzescu reactions, density functional theory (DFT) calculations were also performed. According to the computational results, the origin of site-selectivity can be explained by the following reasons: all energy barriers for the anti-Nenitzescu reaction can be overcome at room temperature, yet the extremely high energy barrier of imine–enamine tautomerization for the Nenitzescu reaction indicates its failure under the same conditions. The reduced density gradient (RDG) analysis hinted that the greater thermodynamic stability of the Nenitzescu product 3h′ mainly depends on the release of the strong steric effect.

A three-component catalyst-free protocol for the regioselective synthesis of dual highly functionalized fused pyrroles has been developed from a cascade [3 + 2] cyclization of heterocyclic ketene aminals (HKAs) 1 with arylglyoxal monohydrates 2 and cyclohexane-1,3-diones 3 in water–ethanol media. The kinetically controlled products 4 could be synthesized within 1 h but would irreversibly transform to thermodynamically controlled products 5 over an additional 5 h. At the same time, the transformative synthesis of 5a from 4a by controlling the oxygen or nitrogen proved the proposed mechanism. Furthermore, the DFT calculation also corroborated that the stability of products 5 are a 100,000 times more thermodynamically stable than products 4. Finally, the origin of the greater stability of 5 could be explained by the reduced density gradient (RDG) analysis, which hinted that the crucial factors are the formation of a new intramolecular hydrogen bond and the release of the steric effect of the crowded rings. In conclusion, this novel synthetic strategy offers an alternative method using thermodynamic or kinetic control for regioselective construction of biologically meaningful fused pyrrole architectures from a concise, rapid, and environmentally friendly vision.Keywords: Catalyst-free; Fused pyrroles; Green and sustainable chemistry; Heterocyclic ketene aminals; Kinetic; Multicomponent reactions; Regioselective synthesis; Thermodynamic; Water−ethanol media

A three-component strategy for the efficient and diastereoselective synthesis of unprecedented polycyclic pyrroles (4) bearing four consecutive quaternary stereocenters has been developed. The reaction was performed with three readily available starting materials: heterocyclic ketene aminals (HKAs) (1), acenaphthylene-1,2-dione (2), and ethyl trifluoroacetylacetate (3). In the one-step cascade reaction, two C–C bonds, two C–Hetero bonds, four consecutive quaternary stereocenters, and two heterocycles were constructed. The established protocol presented outstanding diastereoselectivity (up to 99:1) and provided a valuable route to access highly functionalized polycyclic pyrroles with conciseness, rapidness, and practicability. The reaction is particularly attractive due to the following advantages: atom economy, optimum convergence, high bond-forming efficiency, and operational simplicity.Keywords: Cascade reaction; C−C bonds; C−Hetero bonds; Diastereoselective; Heterocyclic ketene aminals; Multicomponent reaction; Pyrrole; Quaternary stereocenters;

•GA-13316/β-CD had determined by apparatuses and experimental approaches.•The water solubility and stability of GA-13316 were significantly enhanced by wrapped.•The stronger binding ability was obtained by phase solubility and molecular modeling.•The antitumor activity against HCT116 and H460 cells was retained.•The GA-13316/β-CD complex should be regarded as a promising anticancer therapy.The inclusion complex of GA-13316 with β-cyclodextrin (β-CD) is one of a unique series of gibberellin derivatives possessed of potential anticancer activities. The complex with β-CD was characterized by means of UV, XRD, DSC, TG, 1H, and 2D NMR spectroscopy. In addition, we investigated the main aspects of the interaction between GA-13316 and β-CD using both experimental and molecular modeling approaches. The complex still maintained its anticancer activity, as shown by in vitro cell survival assay on the human colon carcinoma cell line (HCT116) and the human lung cancer cell line (H460). The results showed that the use of β-CD could be obviously improved the water solubility and stability of GA-13316, implying that the inclusion complex could be a promising future therapeutic agent.

•Epothilone A complexes with β-CD, γ-CD and HPβCD were prepared and characterized.•By complexation with cyclodextrins, the water solubility of Epothilone A was improved.•By complexation with cyclodextrins, the stability of Epothilone A was improved.•The complexes still maintain good antitumor activities in vivo.The inclusion complexation of Epothilone A with native cyclodextrin (β- or γ-CD) and its derivative hydroxypropyl-β-cyclodextrin (HPβCD) were prepared. Their behavior, characterization, and binding ability were investigated in both solution and the solid state by means of UV–vis, NMR, XRD, DSC and SEM. The results show that the water solubility and solution stability obviously increased in the inclusion complex with cyclodextrins. Meanwhile, the inclusion complexes still retained anticancer activity against A549 and MCF-7 cells, similar to free Epothilone A. This satisfactory water solubility, high solution stability, and high anticancer activity of the Epothilone A/CD complexes will be potentially useful as an anticancer therapy.

An efficient synthesis of highly substituted bicyclic pyrrolidinone derivatives via a cascade reaction of heterocyclic ketene aminals (HKAs) and N-substituted maleimide in an environmentally friendly medium under catalyst-free conditions is described. This protocol uses group-assisted purification (GAP) chemistry in which purification via chromatography and recrystallization can be avoided, and the pure products were obtained simply by washing the crude products with 95% ethanol. The library of bicyclic pyrrolidinone derivatives has been constructed with moderate to excellent yields.

An eco-benign and highly efficient aza–ene reaction for preparing imidazo[1,2-a]pyrrolo[3,4-e]pyridine derivatives from heterocyclic ketene aminals (HKAs) and 2,3-dioxopyrrolidines has been developed in environmentally benign solvent systems, as well as in the absence of any catalyst. The procedures feature excellent yields, short reaction times, a convenient one-pot method, and simple purification that not only minimise the generation of waste but also simplify the work-up procedure.

Epiandrosterone derivatives-organocatalyzed asymmetric Michael addition of aldehydes to nitroalkenes was investigated. Among the various catalysts, a novel type of epiandrosterone-derived L-prolineamide catalyst was synthesized and exhibited better performance in both catalytic activity and stereoselectivity, providing the products with high yields (up to 98%), excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99:1 dr), and low catalyst loading (5 mol%).

A novel silver(I)-mediated direct coupling reaction using heterocyclic ketene aminals (HKAs) and diaryl dichalcogenides for the construction of C(sp2)–S and C(sp2)–Se bonds was reported. The transformation involves a variety of functionalized substrates, leading to α-arylthio and α-phenylselanyl HKAs in a mild, facile and efficient way with high regioselectivity and excellent yields. The broad scope of the starting materials enhanced the chemo-diversity of the target materials, thus affording a number of potential applications in the synthesis of heterocycles and its relevant medicinal chemistry.

A method for regioselective synthesis of 9,10-dihydro-6H-chromeno[4,3-d]imidazo[1,2-a]pyridin-6-one derivatives has been developed. The reaction was readily performed by reacting inexpensive materials, 4-chloro-3-formylcoumarin and HKAs, in EtOH catalyzed by Et3N. This protocol has many advantages including convenient operation, short reaction times, green solvent, and simple purification by washing the crude products with 95% EtOH, defined as GAP (Group-Assistant-Purification) chemistry. The library of 9,10-dihydro-6H-chromeno[4,3-d]imidazo[1,2-a]pyridin-6-one derivatives has been constructed with excellent yields.

•Catalytic asymmetric formal total synthesis of (+)-dichroanone and (+)-taiwaniaquinone H has been achieved.•Key reaction features an arylboronic acid addition to cyclohexenone and subsequent one-pot aldol-type condensation.•Conversion of ketone into germinal dimethyl group provides new synthetic method of abietane skeleton.Catalytic asymmetric formal total synthesis of (+)-dichroanone and (+)-taiwaniaquinone H has been achieved. Key step involved construction of all-carbon quaternary carbon by palladium-catalyzed conjugate addition of arylboronic acid to 3-methyl cyclohexenone. Furthermore, a new approach to build [6-5-6] tricyclic backbone via formyl introduction and subsequent aldol-type condensation was also explored.

•Picoplatin/γ-CD has been characterised by apparatuses and experimental approaches.•The water solubility of picoplatin complex was obviously improved by complexation.•The complex still maintains good antitumor activities against A549 and MCF-7 cells.•The binding free energy of picoplatin complex was calculated.The inclusion complex of picoplatin with γ-cyclodextrin (γ-CD) was prepared and characterised by different analytical methods, including NMR, FTIR, TGA, phase solubility as well as SEM. All of these approaches indicated that picoplatin was able to form an inclusion complex with γ-CD, and that the picoplatin/γ-CD inclusion compounds exhibited different spectroscopic features and properties from free picoplatin. The stoichiometry of the complex was 1:1; the pyridine group of picoplatin was deeply inserted into the cavity of γ-CD and the amine platinum group of picoplatin was near the narrower rim of γ-CD. The calculated apparent stability constant of the complex was 10,318 M−1. Moreover, the water solubility of picoplatin was significantly improved, according to phase-solubility studies. The complex maintained its anticancer activity, as shown by an in vitro cell-survival assay on A549 and MCF-7 cancer cell lines. All of these results showed that inclusion complexation may be a promising strategy to design a novel formulation of picoplatin as an anticancer therapy.

Two chiral aromatic l-prolinamides were synthesized in high overall yield (95%) from N-Boc-l-proline and served as organocatalysts in asymmetric Michael reactions of aldehydes to nitroalkenes. Under the optimized reaction conditions, (S)-N-tritylpyrrolidine-2-carboxamide 4 was found to be a highly efficient organocatalyst for the Michael addition, and the corresponding Michael adducts were obtained in good yields (up to 94%), with excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99:1 dr).tert-Butyl (S)-2-(benzhydrylcarbamoyl)pyrrolidine-1-carboxylateC24H34N2O4[α]D20 = −78.6 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (S)(S)-N-Benzhydrylpyrrolidine-2-carboxamideC18H20N2O[α]D20 = −59.1 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (S)tert-Butyl (S)-2-(tritylcarbamoyl)pyrrolidine-1-carboxylateC29H32N2O3[α]D20 = −38.4 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (S)(S)-N-Tritylpyrrolidine-2-carboxamideC24H24N2O[α]D20 = −27.0 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (S)(2R,3S)-2-Methyl-4-nitro-3-phenylbutanalC11H13NO3[α]D20 = +8.3 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)(2R,3S)-2-Ethyl-4-nitro-3-phenylbutanalC12H15NO3[α]D20 = +8.8 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)(R)-2-((S)-2-Nitro-1-phenylethyl)pentanalC13H17NO3[α]D20 = +6.8 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)(2R,3S)-2-Isopropyl-4-nitro-3-phenylbutanalC13H17NO3[α]D20 = +25.5 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)(2R,3S)-3-(4-Bromophenyl)-2-ethyl-4-nitrobutanalC12H14BrNO3[α]D20 = +7.6 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)(2R,3S)-3-(4-Bromophenyl)-2-ethyl-4-nitrobutanalC12H14ClNO3[α]D20 = +9.5 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)(2R,3S)-3-(2-Chlorophenyl)-2-ethyl-4-nitrobutanalC12H14ClNO3[α]D20 = +11.8 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)(2R,3S)-2-Ethyl-3-(4-methoxyphenyl)-4-nitrobutanalC13H17NO4[α]D20 = +10.4 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)(2R,3S)-2-Ethyl-4-nitro-3-(p-tolyl)butanalC13H17NO3[α]D20 = +13.1 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)(2R,3S)-2-Ethyl-4-nitro-3-(4-(trifluoromethyl)phenyl)butanalC13H14F3NO3[α]D20 = +9.8 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)(2R,3R)-2-Ethyl-3-(furan-2-yl)-4-nitrobutanalC10H13NO4[α]D20 = +17.2 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)(2R,3S)-2-Isopropyl-4-nitro-3-(p-tolyl)butanalC14H19NO3[α]D20 = +66.1 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)(2R,3S)-3-(4-Bromophenyl)-2-isopropyl-4-nitrobutanalC13H16BrNO3[α]D20 = +92.5 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)(2R,3S)-2-Isopropyl-4-nitro-3-(p-tolyl)butanalC14H19NO3[α]D20 = +78.3 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)(2R,3S)-3-(2-Chlorophenyl)-2-isopropyl-4-nitrobutanalC13H16ClNO3[α]D20 = +107.1 (c 1.0, CHCl3)Source of chirality: newAbsolute configuration: (2R,3S)(2R,3R)-2-Isopropyl-4-nitro-3-(thiophen-2-yl)butanalC11H15NO3S[α]D20 = +29.3 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2R,3S)

A concise and efficient one-pot regio- and stereoselective synthesis of structurally diverse spirooxindoles was constructed by simply refluxing a mixture of different types of heterocyclic ketene aminals, isatins and ethyl trifluoroacetate using catalytic piperidine. The advantages of this method include high efficiency, mild reaction conditions and environmentally benign reagents. These spirooxindoles are promising candidates for drug discovery; consequently, a library of diverse spirooxindoles was rapidly constructed using the present protocol.

Vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibition is a well-established strategy to promptly tackle tumor growth by suppression of angiogenesis. We report herein a series of 5-anilinoquinazoline derivatives substituted by 1,3-disubstituted urea. All the newly synthesized compounds described were evaluated for VEGFR-2 kinase inhibition and antiproliferative activity against various cancer cells. The novel 1-aryl, 3-aryl-disubstituted urea quinazolines were effective VEGFR-2 kinase inhibitors with in vitro IC50 values in the submicromolar range (compound 6f, IC50 12.0 nM), but showed a weak to moderate inhibitory activity on cancer cells. Molecular interactions of the compounds were studied using molecular docking studies.

A one-step, transition-metal-free protocol, involving facile post-treatment, for the regioselective synthesis of 1,3-diazaheterocycle fused [1,2-a][1,8]naphthyridine derivatives (3) from 2-chloroquinoline-3-carbaldehydes (ClQuAlds) (1) and heterocyclic ketene aminals (HKAs) (2) was developed via a joint experimental–computational approach. The computational prediction of the reactivity of two series of synthons was applied in the process of optimizing the reaction conditions, which relied on density functional theory (DFT) calculations together with concepts of frontier molecular orbital (FMO) theory and quantitative structure–reactivity relationship (QSRR) presumptions. The combined results enabled the proposal of a pre-synthetic prediction of global reactivity. The fully consistent results of the synthetic experiments with the in silico evaluation confirmed the rationality, effectiveness, and practicability of the new strategy. Notably, the joint method is not limited to the laboratory, but has applications ranging from routine to industry. This approach is likely to yield numerous insights to accelerate HKA-related synthetic chemistry that can be extended to numerous heterocycles. It thus opens up a novel entry towards rapidly investigating the reactivity of novel synthons with unique properties, a further step towards exploiting cascade reactions by avoiding the futile waste of time and resources.

A series of polyhalo 2-aryl-4-aminoquinazolines 3a–3n were prepared by reacting polyhalo isophthalonitriles 1a–1c with amidine hydrochlorides under basic conditions with good yields (70–93%). Also, through the reaction of polyhalo isophthalonitriles 1a–1c with hydrazines to give novel polyhalo 3-aminoindazoles 5 and 7 with moderate yield (70–87%). The anticancer activities of compounds 3, 5 and 7 were evaluated in vitro against human cell lines SKOV-3, HeLa, U2-OS, A549, and MCF-7. Some compounds showed excellent growth inhibitory activities and 3a was found to be the most potent derivative, with an IC50 value lower than 3.86 μg mL−1 against the five tumor cell lines. The mechanism of action of representative compound 5b was investigated in the HCT116 colorectal cancer cell line. It was shown that 5b reduced cell viability of cancer cells in a time and concentration dependent manner. Cells treated with 5b accumulate in the G2/M phase of the cell cycle and finally go into apoptosis.

An efficient one-pot three-component synthesis of novel 1H-pyrazol-5(4H)-one-based heterocyclic ketene aminal libraries was performed by simply refluxing a mixture of heterocyclic ketene aminals (HKAs), 1-phenyl-1H-pyrazol-5(4H)-ones and triethoxymethane under solvent-free and catalyst-free conditions. The protocol has the advantages of being highly efficient and environmentally benign, with excellent yields and easy work-up, making it suitable for large-scale and parallel combination synthesis. These compounds are promising candidates for drug discovery. Consequently, a library of diverse 1H-pyrazol-5(4H)-one-based HKAs was rapidly constructed using this method.

A series of polyhalo isophthalonitrile derivatives (3 and 4) that incorporate a variety of substituents at the 2-, 4-, 5- and/or 6-positions of the isophthalonitrile moieties have been designed and synthesized. These derivatives were evaluated for their antimicrobial activity against Staphylococcus aureus, Bacillus cereus (Gram-positive bacteria), Escherichia coli, Pseudomonas aeruginosa (Gram-negative bacteria); and Candida albicans (Fungi). Compounds 3 and 4 showed stronger inhibition of Gram-positive bacteria and fungi growth, and the antimicrobial ability of compound 3j (a 4-(benzylamino)-5-chloro-2,6-difluoro analog, MIC[SA] = 0.5 μg/mL; MIC[BC] = 0.4 μg/mL; MIC[CA] = 0.5 μg/mL) were close to nofloxacin and fluconazole and identified as the most potent antimicrobial agents in the series. The preliminary analysis of structure–activity relationships is also discussed.

A novel series of polyhalobenzonitrile quinazolin-4(3H)-one derivatives were synthesized and characterized by NMR, IR, MS, and HRMS spectra. All of the newly prepared compounds were screened for antimicrobial activities against four strains of bacteria (Gram-positive bacterial: Staphylococcus aureus and Bacillus cereus; Gram-negative bacterial: Escherichia coli and Pseudomonas aeruginosa) and one strain of fungi (Candida albicans). Among the synthesized compounds, 5-(dimethylamino)-8-(2,4,5-trichloro-isophthalonitrile) quinazolin-4(3H)-one (7k) exhibited significant activity towards Gram-positive bacterial, Gram-negative bacterial, and the fungi strains. The MIC (0.8–3.3 μg/mL) and MBC (2.6–7.8 μg/mL) for this compound were close to those of nofloxacin, chlorothalonil, and fluconazole, making it the most potent antimicrobial agents in the series.

GA-13315 (13-chlorine-3,15-dioxy-gibberllic acid methyl ester) was semi-synthesized by GA3 (gibberellic acid) as a potential anticancer drug. To pursue its promising application, cyclodextrin was used for forming complexes to overcome its drawbacks such as poor water solubility and stability. So, GA-13315/CD complexes were prepared with native β-cyclodextrin and its derivatives (hydroxypropyl-β-cyclodextrin (HPβCD)) and their inclusion complexation behavior, characterization and binding ability in both solution and the solid state was studied by means of UV, XRD, DSC, SEM, 1H and 2D NMR spectroscopy. Furthermore, preliminary in vitro cytotoxicity assay showed that the complexes still maintain antitumor activities, compared with GA-13315 or adriamycin (ADM, positive control) as the positive control. The results showed that the water solubility and stability of GA-13315 were obviously improved in the inclusion complex with cyclodextrins, suggesting the inclusion complexes as promising future therapeutic agents.Highlights► GA-13315 complexes with β-CD and HPβCD were prepared and characterized. ► By complexation with cyclodextrins, the water solubility of GA-13315 was improved. ► By complexation with cyclodextrins, the stability of GA-13315 was improved. ► The complexes still maintain good antitumor activities in vivo.

A concise and efficient route for the synthesis of highly substituted imidazopyrroloquinoline derivatives by simply refluxing a reaction mixture of different types of isatins and heterocyclic ketene aminals (HKAs) by acetic acid was developed. This method is suitable for combinatorial and parallel syntheses in drug discovery; consequently, a library of highly substituted imidazopyrroloquinoline derivatives was rapidly constructed using the present protocol.

The inclusion complexation behavior, characterization and binding ability of taxifolin with native cyclodextrin (α-, β-, or γ-CD) and its derivative hydroxypropyl-β-cyclodextrin (HPβCD) were investigated in both solution and the solid state by means of XRD, DSC, SEM, 1H and 2D NMR and UV–vis spectroscopy. The results showed that the water solubility and thermal stability of taxifolin were obviously increased in the inclusion complex with cyclodextrins. This satisfactory water solubility and high thermal stability of the taxifolin/CD complexes will be potentially useful for their application as herbal medicines or healthcare products.

A series of polyhalo 1,3-diazaheterocycle fused isoquinolin-1(2H)-imines were evaluated in vitro against human tumour cell lines including A431, K562, HL60, HepG2 and Skov-3. As a result, some of the target compounds such as 5b, 5c, 5i, 5o, 6c, 6h and 7f showed stronger cytotoxicity against K562, H562 and Skov-3 cells in comparison with cisplatin, and the others displayed moderate cytotoxicity to A431 and HepG2. Biological investigations using the representative compounds 5c, 6c and 6h were also performed in mice bearing S180 and H22 tumours. The results indicated that these three compounds inhibit S180 and H22 growth. In addition, compounds 6c and 6h have very low acute toxicities. The preliminary analysis of structure–activity relationships is also discussed.A series of polyhalo 1,3-diazaheterocycle fused isoquinolin-1(2H)-imines were evaluated for their anti-tumour activities in vitro and in vivo. Some representative compounds showed good anti-tumour activity and low toxicity.Research highlights► Polyhalo isoquinolin-1(2H)-imines show excellent cytotoxicity. ► The fluorine atom and intramolecular hydrogen bond can enhance biological activity. ► Polyhalo isoquinolin-1(2H)-imines show good anti-tumour activity in vivo. ► Polyhalo isoquinolin-1(2H)-imines exhibit better levels of safety.

The inclusion complexation behavior, characterization and binding ability of crassicauline A (CLA) with β-cyclodextrin (β-CD) has been investigated in both solution and the solid state by means of UV–vis spectroscopy, FT-IR, 1H and 2D NMR, XRD, SEM and DSC. The results showed that the water solubility and thermal stability of CLA were obviously increased in the inclusion complex with β-CD. This satisfactory water solubility and high stability of the CLA/β-CD complex will be potentially useful for its application as herbal medicine or healthcare products.

An efficient and green method has been developed for the synthesis of tetrahydroimidazo[1,2-a]pyridines by three-component reactions of heterocyclic ketene aminals (HKAs), triethoxymethane and nitroalkenes in one pot in the absence of catalyst and solvent. This protocol has advantages of environmental friendliness, high yields (73–93%), short reaction time and convenient operation.

A facile synthesis of tetracyclo-isocoumarins based on the AcOH-catalyzed cyclocondensation and rearrangement reaction between heterocyclic ketene aminals and 2,2-dihydroxy-2H-indene-1,3-dione is described. This method provides direct access to tetacyclo-isocoumarins, a class of compounds with potential broad spectrum biological activities.

An efficient one-pot, three-component synthesis of highly substituted bicyclic pyridines containing a ring-junction nitrogen, starting from simple and readily available materials, is described. Cyclocondensation of heterocyclic ketene aminals (HKAs), triethoxymethane, and active methylene compounds by refluxing under solvent-free and catalyst-free conditions, provided bicyclic pyridines in excellent yields.

The substitution-cyclization reaction of heterocyclic ketene aminals with polyhalo isophthalonitrile in the presence of t-BuOK to form 1,3-diazaheterocycle fused [1,2-b]isoquinolin-1(2H)-imines, followed by hydrolysis with 1 N HCl, provides a concise and efficient route for the synthesis of highly functional polyhalo 1,3-diazaheterocycle fused [1,2-b]isoquinolin-1(2H)-ones.

The inclusion complexation behavior, characterization, and binding ability of nimbin with β-cyclodextrin (β-CD) and its derivatives were investigated in both solution and the solid state by means of XRD, DSC, 1H and 2D NMR, and UV−vis spectroscopy. The results showed that the water solubility and thermal stability of nimbin were obviously increased in the inclusion complex with cyclodextrins. This satisfactory water solubility and high thermal stability of the nimbin/CD complexes will be potentially useful for their application as herbal medicines or healthcare products.

Polyhalo isophthalonitriles were reacted with substituted anilines and subsequently cyclocondensed in the presence of sulfuric acid to give polyhalo acridones. These polyhalo acridones were proven to be useful as pH-sensitive fluorescent probes for a wide range of acidic and basic conditions.Polyhalo isophthalonitriles were reacted with substituted anilines and subsequently cyclocondensed in the presence of sulfuric acid to give polyhalo acridones. These polyhalo acridones were proven to be useful as pH-sensitive fluorescent probes for a wide range of acidic and basic conditions.

Novel polyhalo 2,4-diaminoquinazolines 3a–3d were prepared by reacting polyhaloisophthalonitriles with guanidine carbonate under solvent-free conditions and in the absence of a catalyst with good yields (74–95%). A series of highly functionalized 2,4-diaminoquinazolines 4–5 were then synthesized based on 3a–3c. The anticancer activities of compounds 3–5 were evaluated in vitro against human cell lines such as Skov-3, HL-60, A431, A549, and HepG-2. Some of the compounds showed excellent cytotoxic activity and 5a was found to be the most potent derivative, with an IC50 value lower than 2.5 μg/mL against the five tumor cell lines, making it more active than cisplatin. Representative compounds were also preliminarily evaluated as HIV-1 inhibitors in vitro, and 3c showed the most potent anti-HIV-1 activity with EC50 values of 0.6 and 1.6 μg/mL, and TI values of >59.6 and 66.6, respectively.The novel 2,4-diaminoquinazolines 3–5 were easily prepared based on the reaction of polyhaloisophthalonitriles with guanidine carbonate. The anticancer and anti-HIV activities of 3–5 were evaluated in vitro. Compound 5a was the most potent derivative against the five tumor cell lines with an IC50 value lower than 2.5 μg/mL, and 3c showed the most potent anti-HIV-1 activity with EC50 values of 0.6 and 1.6 μg/mL, and TI values of >59.6 and 66.6, respectively.

A series of heterocycle-fused 1,2,3-triazoles were easily prepared by the 1,3-dipolar cycloaddition of heterocyclic ketene aminals or N,O-acetals with sodium azide and polyhalo isophthalonitriles in a one-pot reaction at room temperature without a catalyst and evaluated in vitro against a panel of human tumour cell lines. 1,3-Oxazoheterocycle fused 1,2,3-triazoles were more potent against the tumour cell lines Skov-3, HL-60, A431, A549 and HepG-2 than 1,3-diazoheterocycle fused 1,2,3-triazoles. 4-Methoxyphenyl substituted 1,3-oxazoheterocycle fused 1,2,3-triazole 6j was found to be the most potent derivative with IC50 values lower than 1.9 μg/mL against A431 and K562 human tumour cell lines.A series of heterocycle-fused 1,2,3-triazoles were easily prepared by the 1,3-dipolar cycloaddition in a one-pot reaction and evaluated in vitro against a panel of human tumor cell lines. 1,3-Oxazoheterocycle fused 1,2,3-triazoles were more potent against the tumor cell lines. 4-Methoxyphenyl substituted 1,3-oxazoheterocycle fused 1,2,3-triazole 6j was found to be the most potent derivative with IC50 values lower than 1.9 μg/mL against A431 cell line.

A series of polyhalo heterocyclic ketene aminals (polyhalo-HKAs) were synthesized under solvent-free conditions and evaluated in vitro against a panel of human tumor cell lines. Trifluoro-HKAs were the most cytotoxic compounds, followed by difluoro-HKAs and trichloro-HKAs. Trichloro-HKAs were more potent against the tumor cell lines Skov-3, Hep-2, K562, and A431 than difluoro-HKAs. An ethoxycarbonyl at the 2-position of the polyhalo HKAs gave the highest activity. Ethoxycarbonyl substituted 5o, bearing three fluorine atoms on the isophthalonitrile ring, was found to be the most potent derivative with IC50 values lower than 3.7 μg/mL against five human tumor cell lines making it more active than cisplatin (DDP).A series of polyhalo heterocyclic ketene aminals (HKAs) were synthesized under solvent-free conditions and evaluated in vitro against a panel of human tumor cell lines. Trifluoro-HKAs were the most cytotoxic compounds, then difluoro-HKAs and trichloro-HKAs. Ethoxycarbonyl substituted 5o was found to be the most potent derivative with IC50 values lower than 3.7 μg/mL against 5 human tumor cell lines making it more active than cisplatin (DDP).

An inclusion complex of the antimalarial artemether (ATM) in hydroxypropyl-β-cyclodextrin (HPβCD) was prepared and characterized. The phase-solubility diagram for the drug showed an increase in water solubility and gave an apparent binding constant of 220 M−1. According to 1H NMR and 2D NMR spectroscopy (ROESY), the inclusion mode involves two CH3 from the drug orientated in the HPβCD cavity. The complex was characterized by Powder X-ray diffraction and thermal analysis. In addition, the complex produces a 1.81-fold enhancement in apparent bioavailability compared to artemether.

A series of cyclodextrin/scutellarin inclusion complexes were prepared from α-cyclodextrin, β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin with scutellarin (SCU), and their inclusion complexation behaviors, such as stoichiometry, complex stability constants and inclusion mode, were investigated by means of UV/Vis spectroscopy, 1H NMR and 2D NMR. The results showed that the SCU could be efficiently encapsulated in the cyclodextrin cavity in aqueous solution to produce complexes that were more soluble than free SCU. The enhanced binding ability of cyclodextrins towards SCU was discussed from the viewpoint of the size/shape-fit and multiple recognition mechanism between host and guest.

A one-step, transition-metal-free protocol, involving facile post-treatment, for the regioselective synthesis of 1,3-diazaheterocycle fused [1,2-a][1,8]naphthyridine derivatives (3) from 2-chloroquinoline-3-carbaldehydes (ClQuAlds) (1) and heterocyclic ketene aminals (HKAs) (2) was developed via a joint experimental–computational approach. The computational prediction of the reactivity of two series of synthons was applied in the process of optimizing the reaction conditions, which relied on density functional theory (DFT) calculations together with concepts of frontier molecular orbital (FMO) theory and quantitative structure–reactivity relationship (QSRR) presumptions. The combined results enabled the proposal of a pre-synthetic prediction of global reactivity. The fully consistent results of the synthetic experiments with the in silico evaluation confirmed the rationality, effectiveness, and practicability of the new strategy. Notably, the joint method is not limited to the laboratory, but has applications ranging from routine to industry. This approach is likely to yield numerous insights to accelerate HKA-related synthetic chemistry that can be extended to numerous heterocycles. It thus opens up a novel entry towards rapidly investigating the reactivity of novel synthons with unique properties, a further step towards exploiting cascade reactions by avoiding the futile waste of time and resources.

A first asymmetric synthesis of the lycorine-type Amaryllidaceae alkaloid (−)-δ-lycorane by using a chiral bifunctional squaramide-catalysed cascade reaction as a powerful tool to construct the skeleton of the alkaloid on the basis of unsaturated β-ketoester and nitroalkene is reported. The sequence afforded a highly functionalized intermediate with three stereogenic centres with high diastereoselectivity (>20:1 dr) and high enantioselectivity (92% ee) in one step, which was converted into (−)-δ-lycorane in eight steps.

Vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibition is a well-established strategy to promptly tackle tumor growth by suppression of angiogenesis. We report herein a series of 5-anilinoquinazoline derivatives substituted by 1,3-disubstituted urea. All the newly synthesized compounds described were evaluated for VEGFR-2 kinase inhibition and antiproliferative activity against various cancer cells. The novel 1-aryl, 3-aryl-disubstituted urea quinazolines were effective VEGFR-2 kinase inhibitors with in vitro IC50 values in the submicromolar range (compound 6f, IC50 12.0 nM), but showed a weak to moderate inhibitory activity on cancer cells. Molecular interactions of the compounds were studied using molecular docking studies.