Bioinspired Design Provides High-Strength Benzoxazine Structural Adhesives.

A synthetic strategy to incorporate catechol functional groups into benzoxazine thermoset monomers was developed, leading to a family of bioinspired small-molecule resins and main-chain polybenzoxazines derived from biologically available phenols. Lap-shear adhesive testing revealed a polybenzoxazine derivative with greater than 5 times improved shear strength on aluminum substrates compared to a widely studied commercial benzoxazine resin. Derivative synthesis identified the catechol moiety as an important design feature in the adhesive performance and curing behavior of this bioinspired thermoset. Favorable mechanical properties comparable to commercial resin were maintained, and glass transition temperature and char yield under nitrogen were improved. Blending of monomers with bioinspired main-chain polybenzoxazine derivatives provided formulations with enhanced shear adhesive strengths up to 16 MPa, while alloying with commercial core-shell particle-toughened epoxy resins led to shear strengths exceeding 20 MPa. These results highlight the utility of bioinspired design and the use of biomolecules in the preparation of high-performance thermoset resins and adhesives with potential utility in transportation and aerospace industries and applications in advanced composites synthesis.

Untemplated Resveratrol-Mediated Polydopamine Nanocapsule Formation.

Nanocapsules can be designed for applications including drug delivery, catalysis, and biological imaging. The mussel-inspired material polydopamine is a promising shell layer for nanocapsules because of its free radical scavenging capacity, ability to react with a broad range of functional molecules, lack of toxicity, and biodegradability. Previous reports of polydopamine nanocapsule formation have relied on a templating approach. Herein, we report a template-free approach to polydopamine nanocapsule formation in the presence of resveratrol, a naturally occurring anti-inflammatory and antioxidant compound found in red wine and grapes. Synthesis of nanocapsules occurs spontaneously in an ethanolic resveratrol/dopamine·HCl solution at pH 8.5. UV-vis absorbance spectroscopy and X-ray photoelectron spectroscopy indicate that resveratrol is incorporated into the nanocapsules. We also observed the formation of a soluble fluorescent dopamine-resveratrol adduct during synthesis, which was identified by high-performance liquid chromatography, UV-vis spectroscopy, and electrospray ionization mass spectrometry. Using transmission electron microscopy and dynamic light scattering, we studied the influence of solvent composition, dopamine concentration, and resveratrol/dopamine ratio on the nanocapsule diameter and shell thickness. The resulting nanocapsules have excellent free radical scavenging activity as measured by a 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay. Our work provides a convenient pathway by which resveratrol, and possibly other hydrophobic bioactive compounds, may be encapsulated within polydopamine nanocapsules.

Traceless Release of Alcohols Using Thiol-Sensitive Oxanorbornadiene Linkers.

A class of ester-amide oxanorbornadiene (EA-OND) molecules was developed to release alcohol cargos by succinimide formation upon addition of a thiol reagent. The resulting ring-closed adducts undergo further fragmentation by retro-Diels-Alder reaction to release a furan moiety in a manner similar to oxanorbornadiene diesters. The rates of each of these fragmentation pathways in the same medium were found to be sensitive to the steric nature of the amide substituent. Alcohol release was much faster in protic solvents than in aprotic ones, suggesting that this system may be useful for rapid response to thiols in biological environments. Accordingly, the attachment and thiol-dependent release of cholesterol was characterized as an example of the manipulation of a drug-like cargo.

Theoretical Analysis of the Retro-Diels-Alder Reactivity of Oxanorbornadiene Thiol and Amine Adducts.

Additions of amines or thiols to 7-oxanorbornadienes promote retro-[4 + 2] reactions to yield furans. Substitution at the bridgehead position also greatly influences the stability of the oxanorbornene adducts. Activation and reaction energies were computed with the M06-2X density functional, the origins of amine and thiol promoted fragmentation, and how substituent effects control fragmentation rates and reaction energetics are reported.

Albumin-Oxanorbornadiene Conjugates Formed ex Vivo for the Extended Circulation of Hydrophilic Cargo.

Oxanorbornadiene dicarboxylate (OND) reagents were explored for the purpose of binding and releasing chemical cargos from endogenous circulating serum albumins. ONDs bearing gadolinium chelates as model cargos exhibited variable conjugation efficiencies with albumin in rat subjects that are consistent with the observed reactivity of each linker and their observed stability toward serum hydrolases in vitro. The terminal elimination rate from circulation was dependent on the identity of the OND used, and increased circulation time of gadolinium cargo was achieved for linkers bearing electrophilic fragments designed to react with cysteine-34 of circulating serum albumin. This binding of and release from endogenous albumin highlights the potential of OND linkers in the context of optimizing the pharmacokinetic parameters of drugs or diagnostic agents.

Modular degradable hydrogels based on thiol-reactive oxanorbornadiene linkers.

Oxanorbornadiene dicarboxylate (OND) reagents are potent Michael acceptors, the adducts of which undergo fragmentation by retro-Diels-Alder reaction at rates that vary with the substitution pattern on the OND moiety. Rapid conjugate addition between thiol-terminated tetravalent PEG and multivalent ONDs yielded self-supporting hydrogels within 1 min at physiological temperature and pH. Erosion of representative hydrogel formulations occurred with predictable and pH-independent rates on the order of minutes to weeks. These materials could be made non-degradable by epoxidation of the OND linkers without slowing gelation. Hydrogels prepared with OND linkers of equal valence had comparable physical properties, as determined by equilibrium swelling behavior, indicating similar internal network structure. Diffusion and release of entrained cargo varied with both the rate of degradation of PEG-OND hydrogels and the hydrodynamic radius of the entrained species. These results highlight the utility of OND linkers in the preparation of degradable network materials with potential applications in sustained release.

Encapsidated atom-transfer radical polymerization in Qß virus-like nanoparticles.

Virus-like particles (VLPs) are unique macromolecular structures that hold great promise in biomedical and biomaterial applications. The interior of the 30 nm-diameter Qß VLP was functionalized by a three-step process: (1) hydrolytic removal of endogenously packaged RNA, (2) covalent attachment of initiator molecules to unnatural amino acid residues located on the interior capsid surface, and (3) atom-transfer radical polymerization of tertiary amine-bearing methacrylate monomers. The resulting polymer-containing particles were moderately expanded in size; however, biotin-derivatized polymer strands were only very weakly accessible to avidin, suggesting that most of the polymer was confined within the protein shell. The polymer-containing particles were also found to exhibit physical and chemical properties characteristic of positively charged nanostructures, including the ability to easily enter mammalian cells and deliver functional small interfering RNA.

Degradable conjugates from oxanorbornadiene reagents.

Oxanorbornadienedicarboxylate (OND) reagents were explored for purposes of binding and releasing drugs from serum albumins as representative macromolecular carriers. Being highly reactive Michael acceptors, ONDs form adducts with thiols and amines, which then undergo retro-Diels-Alder fragmentation. A study of more than 30 model adducts revealed a number of modifications that can be used to influence adduct stability. For the most reactive OND linkers, the labeling of the single available bovine serum albumin (BSA) cysteine residue was complete within minutes at a mid-micromolar concentration of reactants. While a selectivity of greater than 1000-fold for thiol over amine was observed with model amino acids, the labeling of protein amines with ONDs is fast enough to be practical, as demonstrated by the reaction with thiol-depleted BSA. The OND-amine adducts were found to be up to 15 times more stable than OND-thiol adducts, and to be sensitive to acid by virtue of a stereochemically dependent acceleration of cycloreversion. The release rate of fluorescent cargo from serum albumins was tuned by selecting the coupling partners: the available half-lives ranged from 40 min to 7 days at 37 °C. Such versatility of release profiles from protein carriers, controlled by the nature of the OND linkage, is a useful addition to the drug delivery toolbox.

Aqueous-phase deactivation and intramolecular [2 + 2 + 2] cycloaddition of oxanorbornadiene esters.

Both inter- and intramolecular degradation pathways were identified for the aqueous phase deactivation of oxanorbornadiene (OND) electrophiles, and propargylic OND esters were found to undergo facile intramolecular [2 + 2 + 2] homo-Diels-Alder cycloaddition in polar media.

1,3-Diazepanes of natural product-like complexity from cyanamide-induced rearrangement of epoxy-delta-lactams.

A synthetic procedure toward 1,3-diazepane scaffolds of natural product-like complexity was developed for the construction of RNA-directed ligand libraries. A molecular building block was designed that combines the characteristics of RNA-binding natural products, including a high density of hydrogen bond donors and acceptors around a rigid, nonplanar scaffold with straightforward total-synthetic accessibility that permits extensive control over the chemical space. The synthesis of the 1,3-diazepane scaffold was achieved via an unprecedented cyanamide-induced rearrangement of epoxy-delta-lactams.