Self-Assembled Tamoxifen-Selective Fluorescent Nanomaterials Driven by Molecular Structural Similarity

Most supramolecular systems were discovered by using a trial-and-error approach, leading to numerous synthetic efforts to obtain optimal supramolecular building blocks for selective guest encapsulation. Here, we report a simple coassembly strategy for preparing tamoxifen-selective supramolecular nanomaterials in an aqueous solution. The synthetic amphiphile molecule, 1,1,2,2-tetraphenylethylene (TPE), promotes large tamoxifen aggregate disassembly into smaller, discrete aggregates such as ribbon-like and micellar assemblies in coassembled solutions, enhancing the solubility and dispersion. The TPE moiety exhibits enhanced emission upon tamoxifen interaction, enabling the observation of the coassembled species in an aqueous solution for cell imaging. The tamoxifen-selective fluorescent micelles in the presence of a 1:1 molar ratio of TPE derivative with tamoxifen show enhanced tamoxifen absorption and anticancer effects against MCF-7 breast cancer cells. These supramolecular approaches, based on the coassembly of building blocks with molecular structural similarity, can provide a novel strategy for the efficient development of selective molecular carriers with enhanced biological activities

Directional Assembly of α‑Helical Peptides Induced by Cyclization

Effective stabilization of short peptide chains into a helical structure has been a challenge in the fields of chemistry and biology. Here we report a novel method for α-helix stabilization of short peptides through their confinement in a cyclic architecture. We synthesized block peptides based on a short peptide and a flexible linker as linear precursors. Subsequent cyclization of the peptide precursors resulted in a conformational change of the peptide unit from a random coil to an α-helix. The incorporation of hydrophobic residues into the peptide unit led to a facially amphiphilic conformation of the molecular cycle. The resulting amphiphilic peptide self-assembled into undulated nanofibers through the directional assembly of small oblate micelles

Reversible, Short α‑Peptide Assembly for Controlled Capture and Selective Release of Enantiomers

Although significant progress has been achieved with short peptide nanostructures, the construction of switchable membrane assemblies remains a great challenge. Here we report short α-peptide assemblies that undergo thermo-reversible switching between assembly and disassembly states, triggered by the conformational change of laterally grafted short peptides from a folded α-helix to a random coil conformation. The α-helical peptide based on two oligoether dendron side groups forms flat disks, while the peptide helix based on three dendron side groups forms hollow vesicles. The vesicular membrane can spontaneously capture a racemic mixture through the self-formation of vesicular containers upon heating and enantio­selectively release the chiral guest molecule through preferential diffusion across the vesicular walls

Guest-Driven Inflation of Self-Assembled Nanofibers through Hollow Channel Formation

The highlight of self-assembly is the reversibility of various types of noncovalent interactions which leads to construct smart nanostructures with switchable pores. Here, we report the spontaneous formation of inflatable nanofibers through the formation of hollow internal channels triggered by guest encapsulation. The molecules that form this unique nanofibers consist of a bent-shaped aromatic segment connected by a <i>m</i>-pyridine unit and a hydrophilic dendron at its apex. The aromatic segments self-assemble into paired dimers which stack on top of one another to form thin nanofibers with pyridine-functionalized aromatic cores. Notably, the nanofibers reversibly inflate into helical tubules through the formation of hollow cavities triggered by <i>p</i>-phenylphenol, a hydrogen-bonding guest. The reversible inflation of the nanofibers arises from the packing rearrangements in the aromatic cores from transoid dimers to cisoid macrocycles driven by the reversible hydrogen-bonding interactions between the pyridine units of the aromatic cores and the <i>p</i>-phenylphenol guest molecules

Synthesis and Biological Evaluation of α‑Galactosylceramide Analogues with Heteroaromatic Rings and Varying Positions of a Phenyl Group in the Sphingosine Backbone

We designed and synthesized seven α-GalCer analogues with a pyrazole moiety and varying positions of a phenyl group in the sphingosine backbone to polarize cytokine secretion. On the basis of in vitro and in vivo biological evaluations, we found that analogue <b>5</b> induced greater polarization toward Th2 and greater secretion of the immunomodulatory cytokine, IL-4, over secretion of pro-inflammatory cytokines, IFN-γ and IL-17. Treatment of a single dose of analogue <b>5</b> markedly ameliorated disease pathogenesis in an animal model of an inflammatory demyelinating disease of the central nervous system, compared to that of KRN7000 (<b>1</b>). Therefore, this new α-GalCer analogue <b>5</b> is a novel iNKT ligand that stimulates the selective secretion of anti-inflammatory cytokines and regulates autoimmune diseases by reducing Th1 and Th17 responses

Supramolecular Switching between Flat Sheets and Helical Tubules Triggered by Coordination Interaction

Here we report the spontaneous formation of switchable sheets in aqueous solution, which is based on bent-shaped aromatic amphiphiles containing <i>m</i>-pyridine units at the terminals and a hydrophilic dendron at the apex. The aromatic segments self-assemble into flat sheets consisting of a zigzag conformation through π–π stacking interactions. Notably, the sheets reversibly transform into helical tubules at higher concentration and into discrete dimeric macrocycles at a lower concentration in response to Ag­(I) ions through reversible coordination interactions between the pyridine units of the aromatic segments and the Ag­(I) ions. While maintaining the coordination bonding interactions, the helical tubules reversibly transform into the dimeric macrocycles in response to the variation in concentration

Inhibitory effects of 4d and 4e on NO and TNF-α production in LTA- or Poly I∶C-stimulated BV2 microglial cells.

<p>Cells were incubated for 16 h with LTA (10 µg/mL) (A) or Poly I∶C (10 µg/mL) (B) in the absence or presence of α-GalCer analogs <b>4d</b> and <b>4e</b> (5 µM), and the amounts of released NO and TNF-α were measured in supernatants. Treatment with α-GalCer analogs alone did not affect NO or TNF-α production. Bars indicate the mean ± S.E.M. of three independent experiments. *<i>P</i><0.05; significantly different from stimulated microglial cells.</p

Anti-Inflammatory Effects of α-Galactosylceramide Analogs in Activated Microglia: Involvement of the p38 MAPK Signaling Pathway

<div><p>Microglial activation plays a pivotal role in the development and progression of neurodegenerative diseases. Thus, anti-inflammatory agents that control microglial activation can serve as potential therapeutic agents for neurodegenerative diseases. Here, we designed and synthesized α-galactosylceramide (α-GalCer) analogs to exert anti-inflammatory effects in activated microglia. We performed biological evaluations of 25 α-GalCer analogs and observed an interesting preliminary structure-activity relationship in their inhibitory influence on NO release and TNF-α production in LPS-stimulated BV2 microglial cells. After identification of <b>4d</b> and <b>4e</b> as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis. We confirmed that <b>4d</b> and <b>4e</b> regulate the expression of iNOS, COX-2, IL-1β, and IL-6 at the mRNA level and the expression of TNF-α at the post-transcriptional level. In addition, both <b>4d</b> and <b>4e</b> inhibited LPS-induced DNA binding activities of NF-κB and AP-1 and phosphorylation of p38 MAPK without affecting other MAP kinases. When we examined the anti-inflammatory effect of a p38 MAPK-specific inhibitor, SB203580, on microglial activation, we observed an identical inhibitory pattern as that of <b>4d</b> and <b>4e</b>, not only on NO and TNF-α production but also on the DNA binding activities of NF-κB and AP-1. Taken together, these results suggest that p38 MAPK plays an important role in the anti-inflammatory effects of <b>4d</b> and <b>4e</b> via the modulation of NF-κB and AP-1 activities.</p></div

DNA sequences of primers used in real-time PCR reactions, and expected product sizes.

<p>DNA sequences of primers used in real-time PCR reactions, and expected product sizes.</p

Synthetic scheme of final modifications of the acyl chain resulting in 25 unique α-GalCer analogs.

<p>Synthetic scheme of final modifications of the acyl chain resulting in 25 unique α-GalCer analogs.</p