Peptide-lipid hybrid vesicles with stimuli-responsive phase separation for controlled membrane functions.

A disulfide-tethered peptide-lipid conjugate self-assembled into a homogeneously distributed peptide-lipid hybrid vesicle. Upon dithiothreitol treatment, the homogeneous peptide-lipid membrane spontaneously divided into lipid-rich and peptide-rich domains, while the vesicle retained its size and shape. Membrane phase separation enhanced temperature-dependent cargo release.

Solvent Effects on the Self-Assembly of an Amphiphilic Polypeptide Incorporating α-Helical Hydrophobic Blocks.

The self-assembly of biological molecules is an important pathway to understanding the molecular basis of complex metabolic events. The presence of a cosolvent in an aqueous solution during the self-assembly process can promote the formation of kinetically trapped metastable intermediates. In nature, a category of cosolvents termed osmolytes can work to strengthen the hydrogen-bond network of water such that the native states of certain proteins are favored, thus modulating their function and stability. However, identifying cosolvents that act as osmolytes in biomimetic applications, such as the self-assembly of soft materials, remains challenging. The present work examined the effects of ethanol (EtOH) and acetonitrile (ACN) as cosolvents on the self-assembly of the amphiphilic polypeptide PSar30-(l-Leu-Aib)6 (S30L12), which incorporates α-helical hydrophobic blocks, in aqueous solution. The results provided a direct observation of morphological behavior of S30L12 as a function of solvent composition. Morphological transitions were investigated using transmission electron microscopy, while the packing of peptide molecules was assessed using circular dichroism analyses and evaluations of membrane fluidity. In the EtOH/H2O mixtures, the EtOH strengthened the hydrogen-bond network of the water, thus limiting the hydrophobic hydration of S30L12 assemblies and enhancing hydrophobic interactions between assemblies. In contrast, ACN formed self-associated nanoclusters in water and at the hydrophobic cores of peptide assemblies to stabilize the edges exposed to bulk water and enhance the assembly kinetics. Fourier transform infrared (FT-IR) analysis indicated that both EtOH and ACN can modify the self-assembly of biomaterials in the same manner as osmolyte protectants or denaturants.

Synthesis of Photoreactive Poly(ethylene oxide)s for Surface Modification.

Photoreactive polymers that generate active species upon irradiation with light are very useful for modifying the surfaces of substrates. However, water solubility decreases as the number of photoreactive functional groups on the polymer increases because most photoreactive functional groups are hydrophobic. In order to improve the hydrophilicity of the photoreactive polymer, we synthesized polyethylene glycol-based photoreactive polymers bearing hydrophobic azidophenyl groups on their side chains. Because of the hydrophilicity of the ethylene glycol main chain, polymers with large numbers of azidophenyl groups were solubilized in protic solvents compared to hydrophobic alkylene chain-based polymers prepared by radical polymerization of methacrylate monomers. Polymers were immobilized on various substrates by irradiation with ultraviolet light and were shown to suppress nonspecific interactions between proteins and cells on the substrate. We conclude that such polymers are useful, highly water soluble antifouling agents.

Enhancement of Binding Affinity of Folate to Its Receptor by Peptide Conjugation.

(1) Background: The folate receptor (FR) is a target for cancer treatment and detection. Expression of the FR is restricted in normal cells but overexpressed in many types of tumors. Folate was conjugated with peptides for enhancing binding affinity to the FR. (2) Materials and Methods: For conjugation, folate was coupled with propargyl or dibenzocyclooctyne, and 4-azidophenylalanine was introduced in peptides for "click" reactions. We measured binding kinetics including the rate constants of association (ka) and dissociation (kd) of folate-peptide conjugates with purified FR by biolayer interferometry. After optimization of the conditions for the click reaction, we successfully conjugated folate with designed peptides. (3) Results: The binding affinity, indicated by the equilibrium dissociation constant (KD), of folate toward the FR was enhanced by peptide conjugation. The enhanced FR binding affinity by peptide conjugation is a result of an increase in the number of interaction sites. (4) Conclusion: Such peptide-ligand conjugates will be important in the design of ligands with higher affinity. These high affinity ligands can be useful for targeted drug delivery system.

Ni-Catalyzed α-Alkylation of Unactivated Amides and Esters with Alcohols by Hydrogen Auto-Transfer Strategy.

A transition-metal-catalyzed borrowing hydrogen/hydrogen auto-transfer strategy allows the utilization of feedstock alcohols as an alkylating partner, which avoids the formation of stoichiometric salt waste and enables a direct and benign approach for the construction of C-N and C-C bonds. In this study, a nickel-catalyzed α-alkylation of unactivated amides and ester (tert-butyl acetate) is carried out by using primary alcohols under mild conditions. This C-C bond-forming reaction is catalyzed by a new, molecularly defined nickel(II) NNN-pincer complex (0.1-1 mol %) and proceeds through hydrogen auto-transfer, thereby releasing water as the sole byproduct. In addition, N-alkylation of cyclic amides under Ni-catalytic conditions is demonstrated.

Pd(ii)-Catalyzed gamma-C(sp3)-H alkynylation of amides: selective functionalization of R chains of amides R1C(O)NHR.

The gamma C(sp3)-H bond alkynylation of R chains of amides R1C(O)NHR, a fundamental class of synthetic substrates, has not been accomplished to date. Here, the first example of palladium(ii)-catalyzed alkynylation of an unactivated gamma C(sp3)-H bond of alkyl amides (cyclic, linear, and amino acids) is reported. The kinetic experiment shows that the rate of the reaction depends on the coupling partners and the amides. Late-stage diversification of alkynylated amides was developed by utilizing amine and alkyne functionalities.

Manganese-Catalyzed Direct Conversion of Ester to Amide with Liberation of H2.

A simple and efficient Mn-catalyzed acylation of amines is achieved using both acyl and alkoxy functions of unactivated esters with the liberation of molecular hydrogen as a sole byproduct. The present protocol provides an atom-economical and sustainable route for the synthesis of amides from esters by employing an earth-abundant manganese salt and inexpensive phosphine-free tridentate ligand.

Transition-metal-catalyzed hydrogen-transfer annulations: access to heterocyclic scaffolds.

The ability of hydrogen-transfer transition-metal catalysts, which enable increasingly rapid access to important structural scaffolds from simple starting materials, has led to a plethora of research efforts on the construction of heterocyclic scaffolds. Transition-metal-catalyzed hydrogen-transfer annulations are environmentally benign and highly atom-economical as they release of water and hydrogen as by-product and utilize renewable feedstock alcohols as starting materials. Recent advances in this field with respect to the annulations of alcohols with various nucleophilic partners, thus leading to the formation of heterocyclic scaffolds, are highlighted herein.

Synthesis of pyrrolo-/indolo[1,2-a]quinolines and naphtho[2,1-b]thiophenes from gem-dibromovinyls and sulphonamides.

A highly efficient and simple route for the synthesis of pyrrolo-/indolo[1,2-a]quinolines and naphtho[2,1-b]thiophenes from gem-dibromovinyls and sulphonamides is reported. The noteworthy feature of this report is that the methodology involves a two-step protocol to synthesize tri- and tetracyclic heterocycles in a one-pot fashion through the Cu(I)-catalyzed formation of ynamide followed by a Ag(I)-assisted intramolecular hydroarylation. The photophysical properties of representative examples of pyrrolo- and indolo[1,2-a]quinolines in solid and solution states have also been studied.

Pd(0)-catalyzed regio- and stereoselective cyclization of alkynes: selective synthesis of (E)-4-(isobenzofuran-1(3H)-ylidene)-1,2,3,4-tetrahydroisoquinolines and aze/oxepinoindoles.

Palladium-catalyzed highly regio- and stereoselective 6-exo-dig and 7-endo-dig cyclization of functionalized propargylic compounds has been developed for the synthesis of (E)-4-(isobenzofuran-1(3H)-ylidene)-1,2,3,4-tetrahydroisoquinolines and aze/oxepinoindoles.

Tetrasubstituted olefinic xanthene dyes: synthesis via Pd-catalyzed 6-exo-dig cyclization/C-H activation of 2-bromobenzyl-N-propargylamines and solid state fluorescence properties.

Tetrasubstituted olefin based new xanthene derivatives have been synthesized via palladium-catalyzed carbopalladation/C-H activation of 2-bromobenzyl-N-propargylamine derivatives. The synthesized compounds display a pronounced solid state fluorescence due to their restricted internal rotation of a C-Ar bond in the solid or aggregation state.