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 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

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.

•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.

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.

•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.

•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.

•Three tetrakis(acetato)dirhodium(II) adducts have been synthesized and characterized.•The C–H⋯O interactions play the main role in the structural stacking of 1–3.•Their catalytic activity was evaluated in the C–H insertion reactions.Three complexes were synthesized in high yields by reaction of Rh2(O2CCH3)4 with 2-picoline (1), 3-picoline (2) and 4-picoline (3), respectively, and characterized by elemental analysis, ESI+-MS, FT-IR and 1H NMR along with single-crystal X-ray structural analysis. All picoline ligands coordinate to the axial sites of Rh2(O2CCH3)4 via the pyridine nitrogen atoms, and interestingly, the coordination of 2-picoline in 1 is assisted by two intramolecular C–H⋯O hydrogen bonds formed between the methyl of 2-picoline and the oxygen atoms of Rh2(O2CCH3)4. Moreover, the intermolecular C–H⋯O interactions play the main role in the structural stacking of 1–3. Their catalytic activity was evaluated in the C–H insertion reactions for the preparation of 4-nitrobenzyl-(4R,5R,6S)-6-((R)-1-hydroxyethyl)-4-methyl-3,7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylate, a key intermediate of Meropenem. The isolated yields for 1, 2 and 3 are 44%, 16% and 22%, respectively, significantly lower than the value of Rh2(O2CCH3)4 (73%), indicating that the axial ligands have negative but different influence on the catalytic activity. The activities of 1–3 are related to the displacement rate of the axial ligands, and essentially related to the Rh–N bond lengths which strong affect the displacement rate. Therefore, it is possible to tune the catalytic activity of Rh2(O2CCH3)4 by changing its axial ligands.Three complexes were synthesized by reaction of Rh2(O2CCH3)4 with 2-picoline, 3-picoline and 4-picoline, respectively. Their catalytic activity was significantly lower than the value of Rh2(O2CCH3)4. But the results suggest that it is possible to tune the catalytic activity of Rh2(O2CCH3)4 by changing its axial ligands.

•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.

•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.

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 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.

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.