A pillar[5]arene with an amino-terminated arm stabilizes the formation of aliphatic hemiaminals and imines.

We report a new mono-armed pillar[5]arene with the amino-substituent self-included in the pillarene cavity, which can stabilize the hemiaminals and imines formed from the reaction of aliphatic amines and aldehydes as monitored by mass spectroscopy.

Multifunctional Gold Nanoparticles Overcome MicroRNA Regulatory Network Mediated-Multidrug Resistant Leukemia.

Resistance to chemotherapy and molecularly targeted therapies is a major problem in current leukemia treatments. Here, we investigated cross-talk between the miR-221 network and P-glycoprotein (P-gp) in doxorubicin-induced drug resistance of leukemia cells. Multifunctional gold nanoparticles were designed and synthesized to co-deliver three anticancer agents, AS1411, doxorubicin and anti-221, for improving leukemia treatment efficacy. These nanoparticles significantly inhibited the proliferation and clonogenic potential, and induced apoptosis of drug-resistant leukemia cells. The decreased growth of drug-resistant cells induced by these nanoparticles was associated with marked downregulation of miR-221 and DNMT1, leading to restored p27kip1 and p15ink4b tumor suppressor expression, as well as miR-221-mediated reduction of P-gp expression. Finally, primary blasts derived from leukemia patients experiencing chemoresistant relapse that were exposed to these nanoparticles were sensitized to doxorubicin, as evidenced by suppression of leukemic cell growth and a significant reduction of the doxorubicin IC50 value. Our findings provide proof of concept that this novel drug delivery system can precisely reverse the multidrug resistant leukemia phenotype based on preclinical models of leukemia, providing the framework for future clinical trials aimed at overcoming drug resistance and improving patient outcome.

Facile surface functionalization of upconversion nanoparticles with phosphoryl pillar[5]arenes for controlled cargo release and cell imaging.

Upon surface functionalization and stabilization of ß-NaYF4:Yb/Er upconversion nanoparticles (UCNPs) with phosphoryl pillar[5]arenes (PP5) via a facile ligand exchange method, we constructed a new hybrid material (PP5-UCNPs) with good water dispersibility especially in a physiological environment and superior capability of controlled cargo release and cell imaging.

Targeting epigenetic pathway with gold nanoparticles for acute myeloid leukemia therapy.

Leukemia remains a fatal disease for most patients and novel therapeutic strategies are urgently needed. Aberrant DNA methylation is an epigenetic modification that is important in the initiation and progression of leukemia. Here, we demonstrated NCL/miR-221/NFκB/DNMT1 axis as a new molecular pathway promoting aggressive acute myeloid leukemia (AML) leukemogenesis and successfully designed and prepared a nuclear localization signal (NLS) peptide-targeted gold nanoparticles with co-loaded anti-221 and AS1411 (NPsN-AS1411/a221), which can specifically target NCL/miR-221/NFκB/DNMT1 signaling pathway in AML. NPsN-AS1411/a221 synergistically abrogate endogenous miR-221 promoting cancerous growth by inhibiting the expression of p27Kip1 suppressor gene, as well as effectively deregulate the DNMT1 expression through NFκB signaling which led to a reduction of global DNA methylation and the restoration of tumor suppressor p15INK4B via its promoter DNA hypomethylation. Functionally, NPsN-AS1411/a221 remarkably blockage leukemia proliferation and clonogenic potential in NCL/miR-221/NFκB/DNMT1 positive AML cell lines. More importantly, NPsN-AS1411/a221 cooperatively extend the overall survival, lower the white blood cells, reverse splenomegaly, inhibit blasts in bone marrow and metastatic to lung in a preclinical AML animal model. Altogether, our studies provide a proof of concept for multiple-functional drug delivery system that based on the specific gene network involved in tumor growth, and highlight the clinical potential of NCL/miR-221/NFκB/DNMT1-targeted AML nanotherapy.

Pillar[5]arene-based [1]rotaxane: high-yield synthesis, characterization and application in Knoevenagel reaction.

We report a quantitative synthetic strategy of a [1]rotaxane from a representative pseudo[1]rotaxane. The structure of the [1]rotaxane was characterized by 1H NMR, 13C NMR, 2D NMR, mass spectroscopy, and melting point, and its optimized geometry in CHCl3 by theoretical calculation at the B3LYP/6-31G(D) level using the PCM model matched well with 2D NOESY. This [1]rotaxane proves to be a good catalyst for the Knoevenagel reaction in CHCl3, which follows second order kinetics.

Biological and related applications of pillar[n]arenes.

Pillar[n]arenes are a new class of synthetic supramolecular macrocycles streamlined by their particular pillar-shaped architecture which consists of an electron-rich cavity and two fine-tuneable rims. The ease and diversity of the functionalization of the two rims open possibilities for the design of new architectures, topological isomers, and scaffolds. Significantly, this emerging class of macrocyclic receptors offers a unique platform for biological purposes. This review article covers the most recent contributions from the pillar[n]arene field in terms of artificial membrane transport systems, controlled drug delivery systems, biomedical imaging, biosensors, cell adhesion, fluorescent sensing, and pesticide detection based on host-guest interactions. The review also uniquely describes the properties of sub-units that make pillar[n]arenes suitable for biological applications and it provides a detailed outline for the design of new innovative pillar-like structures with specific properties to open up a new avenue for pillar[n]arene chemistry.

Enhanced chemical synthesis at soft interfaces: a universal reaction-adsorption mechanism in microcompartments.

A bimolecular synthetic reaction (imine synthesis) was performed compartmentalized in micrometer-diameter emulsion droplets. The apparent equilibrium constant (Keq) and apparent forward rate constant (k1) were both inversely proportional to the droplet radius. The results are explained by a noncatalytic reaction-adsorption model in which reactants adsorb to the droplet interface with relatively low binding energies of a few kBT, react and diffuse back to the bulk. Reaction thermodynamics is therefore modified by compartmentalization at the mesoscale--without confinement on the molecular scale--leading to a universal mechanism for improving unfavorable reactions.

Enhanced imine synthesis in water: from surfactant-mediated catalysis to host-guest mechanisms.

An environment-responsive and fluorogenic reaction is reported and used as a model system to demonstrate experimentally three mechanisms of enhanced imine synthesis in water using either surfactants (below and above their CMC) or double-stranded DNA (acting as a reaction host).

Reversible covalent chemistries compatible with the principles of constitutional dynamic chemistry: new reactions to create more diversity.

An approach to make chemical diversity space more manageable is to search for smaller molecules, or fragments, and then combine or elaborate these fragments. Dynamic Combinatorial Chemistry (DCC) is a powerful approach whereby a number of molecular elements each with binding potential can be reversibly combined via covalent or noncovalent linkages to generate a dynamic library of products under thermodynamic equilibrium. Once a target molecule has been added, the distribution of products can be shifted to favor products that bind to the target. Thus the approach can be employed to identify products that selectively recognize the target. Although the size of the repertoire of reversible covalent reactions suitable for DCC has increased significantly over the past 5-10 years, the discovery of new reactions that satisfy all the criteria of reversibility and biocompatibility remains an exciting challenge for chemists. Increasing the number of chemical reactions will enable the engineering of larger and more diverse DCLs, which remains a key step toward a broader use of DCC. In this review, we aim to provide a nonexhaustive list of reversible covalent reactions that are compatible with the concept of DCC, focusing mainly on the most recent examples that were reported in the literature in the past 5 years.

Dual sensing of hairpin and quadruplex DNA structures using multicolored peptide nucleic acid fluorescent probes.

Synthesis of water-soluble 5-mer peptide nucleic acids (PNAs) functionalized at their 5'- and 3'-ends with two original precursors of pentamethine cyanine dye synthesis is reported. The successful use of these PNA probes for sensing DNA hairpin structures in vitro was also demonstrated where specific hairpin formation was associated with the appearance of a characteristic fluorescence signal at 660 nm. A comparative study between three different strategies where PNAs were targeting either the stem or the loop of the hairpin was carried out. Best sensitivity was obtained using PNA sequences complementary to the loop sequence and directing both functional moieties toward the base of loop. Unprecedented proof-of-concept for the simultaneous sensing of hairpin and quadruplex DNAs with a nonoverlapping two-color system (C3 and C5) is also demonstrated.

Synthesis, spectroscopic and DNA alkylating properties of malondialdehyde (MDA) bis-imine fluorescent adducts.

The synthesis of a series of malondialdehyde (MDA) fluorescent adducts that mimic the well-known pentamethine cyanine dyes is reported. This new subclass of bis-imino dyes shares some common spectroscopic properties with their polymethine analogues although absorbing at significantly shorter wavelengths. A small library of trimethine and pentamethine cyanine dye bis-imino analogues have been synthesised and characterised that cover a spectral range from blue to orange. Of particular interest is their capacity to act as mono- and bis-alkylating agents of nucleosides in general and of cytidine (and 2'-deoxycytidine) in particular.

Reversible synthesis and characterization of dynamic imino analogues of trimethine and pentamethine cyanine dyes.

A new family of unsymmetrical imine-based trimethine and pentamethine cyanine dye analogues is reported that can form under reversible and thermodynamically controlled conditions from non- or weakly emissive amine and aldehyde building blocks. These dynamic fluorophores show spectroscopic properties comparable to those of their parent cyanine dyes and are responsive to external effectors.