Engineering a drug eluting ocular patch for delivery and sustained release of anti-inflammatory therapeutics.

Ocular inflammation is commonly associated with eye disease or injury. Effective and sustained ocular delivery of therapeutics remains a challenge due to the eye physiology and structural barriers. Herein, we engineered a photocrosslinkable adhesive patch (GelPatch) incorporated with micelles (MCs) loaded with Loteprednol etabonate (LE) for delivery and sustained release of drug. The engineered drug loaded adhesive hydrogel, with controlled physical properties, provided a matrix with high adhesion to the ocular surfaces. The incorporation of MCs within the GelPatch enabled solubilization of LE and its sustained release within 15 days. In vitro studies showed that MC loaded GelPatch supported cell viability and growth. In addition, subcutaneous implantation of the MC loaded GelPatch in rats confirmed its in vivo biocompatibility and stability within 28 days. This non-invasive, adhesive, and biocompatible drug eluting patch can be used as a matrix for the delivery and sustained release of hydrophobic drugs.

Slip/Stick Viscosity Models of Nanoconfined Liquids: Solvent-Dependent Rotation in Metal-Organic Frameworks.

Artificial molecular machines are expected to operate in environments where viscous forces impact molecules significantly. With that, it is well-known that solvent behaviors dramatically change upon confinement into limited spaces as compared to bulk solvents. In this study, we demonstrate the utility of an amphidynamic metal-organic framework with pillars consisting of 2H-labeled dialkynyltriptycene and dialkynylphenylene barrierless rotators that operate as NMR sensors for solvent viscosity. Using line-shape analysis of quadrupolar spin echo spectra we showed that solvents such as dimethylformamide, diethylformamide, 2-octanone, bromobenzene, o-dichlorobenzene, and benzonitrile slow down their Brownian rotational motion (103-106 s-1) to values consistent with confined viscosity values (ca. 100-103 pa s) that are up to 10000 greater than those in the bulk. Magic angle spinning assisted 1H T2 measurements of included solvents revealed relaxation times of approximately 100-1000 ms over the explored temperature ranges, and MAS-assisted 1H T1 measurements of included solvents suggested a much lower activation energy for rotational dynamics as compared to those measured by the rotating pillars using 2H measurements. Finally, translational diffusion measurements of DMF using pulsed-field gradient methods revealed intermediate dynamics for the translational motion of the solvent molecules in MOFs.

Enhanced Gearing Fidelity Achieved Through Macrocyclization of a Solvated Molecular Spur Gear.

Molecular spur gear dynamics with high gearing fidelity can be achieved through a careful selection of constituent molecular components that favorably position and maintain the two gears in a meshed configuration. Here, we report the synthesis of a new macrocyclic molecular spur gear with a bibenzimidazole stator combined with a second naphthyl bis-gold-phosphine gold complex stator to place two 3-fold symmetric 9,10-diethynyl triptycene cogs at the optimal distance of 8.1 Å for gearing. Micro electron diffraction (µED) analysis confirmed the formation of the macrocyclic structure and the proper alignment of the triptycene cogs. Gearing dynamics in solution are predicted to be extremely fast and, in fact, were too fast to be observed with variable-temperature 1H NMR using CD2Cl2 as the solvent. A combination of molecular dynamics and metadynamics simulations predict that the barriers for gearing and slippage are ca. 4 kcal mol-1 and ca. 9 kcal mol-1, respectively. This system is characterized by enhanced gearing fidelity compared to the acyclic analog. This is achieved by rigidification of the structure, locking the two triptycenes in the preferred gearing distance and orientation.

Encapsulating N-Heterocyclic Carbene Binuclear Transition-Metal Complexes as a New Platform for Molecular Rotation in Crystalline Solid-State.

In crystalline solids, molecules generally have limited mobility due to their densely packed environment. However, structural information at the molecular level may be used to design amphidynamic crystals with rotating elements linked to rigid, lattice-forming parts, which may lead to molecular rotary motions and changes in conformation that determine the physical properties of the solid-state materials. Here, we report a novel design of emissive crystalline molecular rotors with a central pyrazine rotator connected by implanted transition metals (Cu or Au) to a readily accessible enclosure formed by two N-heterocyclic carbenes (NHC) in discrete binuclear complexes. The activation energies for the rotation could be tuned by changing the implanted metal. Exchanging Cu to Au resulted in an ∼4.0 kcal/mol reduction in the rotational energy barrier as a result of lower steric demand by elongation of the axle with the noble metal, and a stronger electronic stabilization in the rotational transition state by enhancement of the d-π* interactions between the metal centers and the pyrazine rotator. The Cu(I) rotor complex showed a greater electronic delocalization than the Au(I) rotor complex, causing a red-shifted solid-state emission. Molecular rotation-induced emission quenching was observed in both crystals. The enclosing NHC rotors are easy to prepare, and their rotational motion should be less dependent on packing structures, which are often crucial for many previously documented amphidynamic molecular crystals. The platform from the encapsulating NHC cationic metal complexes and the metal-centered rotation-axis provide a promising scaffold for a novel design of crystalline molecular rotors, including manipulation of rotary dynamics and solid-state emission.

2D Arrays of Organic Qubit Candidates Embedded into a Pillared-Paddlewheel Metal-Organic Framework.

The creation of ordered arrays of qubits that can be interfaced from the macroscopic world is an essential challenge for the development of quantum information science (QIS) currently being explored by chemists and physicists. Recently, porous metal-organic frameworks (MOFs) have arisen as a promising solution to this challenge as they allow for atomic-level spatial control of the molecular subunits that comprise their structures. To date, no organic qubit candidates have been installed in MOFs despite their structural variability and promise for creating systems with adjustable properties. With this in mind, we report the development of a pillared-paddlewheel-type MOF structure that contains 4,7-bis(2-(4-pyridyl)-ethynyl) isoindoline N-oxide and 1,4-bis(2-(4-pyridyl)-ethynyl)-benzene pillars that connect 2D sheets of 9,10-dicarboxytriptycene struts and Zn2(CO2)4 secondary binding units. The design allows for the formation of ordered arrays of reorienting isoindoline nitroxide spin centers with variable concentrations through the use of mixed crystals containing the secondary 1,4-phenylene pillar. While solvent removal causes decomposition of the MOF, magnetometry measurements of the MOF containing only N-oxide pillars demonstrated magnetic interactions with changes in magnetic moment as a function of temperature between 150 and 5 K. Variable-temperature electron paramagnetic resonance (EPR) experiments show that the nitroxides couple to one another at distances as long as 2 nm, but act independently at distances of 10 nm or more. We also use a specially designed resonance microwave cavity to measure the face-dependent EPR spectra of the crystal, demonstrating that it has anisotropic interactions with impingent electromagnetic radiation.

Molecular Spur Gears with Triptycene Rotators and a Norbornane-Based Stator.

We report efforts to prepare a molecular spur gear utilizing a convenient synthesis of a norbornane stator that positions two interdigitated diyne-linked triptycenes in parallel alignment. While gearing was not observed by 19F NMR for a -CF3-labeled analog at temperatures as low as 213 K, we used molecular dynamics simulation and 2D metadynamics calculations to understand the gearing/slippage energetic profile for various molecular spur gears to guide future designs of these systems.

Hydrogen-Bonded Crystalline Molecular Machines with Ultrafast Rotation and Displacive Phase Transitions.

Two new crystalline rotors 1 and 2 assembled through N-H⋅⋅⋅N hydrogen bonds by using halogenated carbazole as stators and 1,4-diaza[2.2.2]bicyclooctane (DABCO) as the rotator, are described. The dynamic characterization through 1 H T1 relaxometry experiments indicate very low rotational activation barriers (Ea ) of 0.67 kcal mol-1 for 1 and 0.26 kcal mol-1 for 2, indicating that DABCO can reach a THz frequency at room temperature in the latter. These Ea values are supported by solid-state density functional theory computations. Interestingly, both supramolecular rotors show a phase transition between 298 and 250 K, revealed by differential scanning calorimetry and single-crystal X-ray diffraction. The subtle changes in the crystalline environment of these rotors that can alter the motion of an almost barrierless DABCO are discussed here.

Correlated motion and mechanical gearing in amphidynamic crystalline molecular machines.

In this review we highlight the recent efforts towards the development of molecular gears with an emphasis on building molecular gears in the solid state and the role that molecular gearing and correlated motions may play in the function of crystalline molecular machines. We discuss current molecular and crystal engineering strategies, challenges associated with engineering correlated motion in crystals, and outline experimental and theoretical tools to explore gearing dynamics while highlighting key advances made to date.

Tailoring the cavities of hydrogen-bonded amphidynamic crystals using weak contacts: towards faster molecular machines.

This work describes the use of C-H⋯F-C contacts in the solid-state from the stator towards the rotator to fine-tune their internal motion, by constructing a set of interactions that generate close-fitting cavities in three supramolecular rotors 1-3I. The crystal structures of these rotors, determined by synchrotron radiation experiments at different temperatures, show the presence of such C-H⋯F-C contacts between extended carbazole stators featuring fluorinated phenyl rings and the 1,4-diazabicyclo[2.2.2]octane (DABCO) rotator. According to the 2H NMR results, using deuterated samples, and periodic density functional theory computations, the rotators experience fast angular displacements (preferentially 120° jumps) due to their low rotational activation energies (E a = 0.8-2.0 kcal mol-1). The higher rotational barrier for 1 (2.0 kcal mol-1) is associated with a larger number of weak C-H⋯F-C contacts generated by the stators. This strategy offers the possibility to explore the correlation among weak intermolecular forces, cavity shape, and internal dynamics, which has strong implications in the design of future fine-tuned amphidynamic crystals.

Triggering the dynamics of a carbazole-p-[phenylene-diethynyl]-xylene rotor through a mechanically induced phase transition.

A new rotor exhibits rich solvatomorphism behavior with eight X-ray structures obtained. A heterogeneous solid obtained by mechanical stress exhibited a dominant isotropic 2H line shape at high temperatures. The motion occurs only in the amorphous component of this solid, with an Ea of 7.4 kcal mol-1 and a low pre-exponential factor A of 6.22 × 1010 s-1, which indicates that the motion requires the distortion of the molecular axis.

Thermally Activated Transient Dipoles and Rotational Dynamics of Hydrogen-Bonded and Charge-Transferred Diazabicyclo [2.2.2]Octane Molecular Rotors.

We present here dielectric properties and rotational dynamics of cocrystals formed with either triphenylacetic acid (cocrystal I) or 9,10-triptycene dicarboxylic acid (cocrystal II), as hydrogen-bonding donors, and diazabicyclo[2.2.2]octane (DABCO), as a ditopic hydrogen-bond acceptor. While cocrystal I forms discrete 2:1 complexes with one nitrogen of DABCO hydrogen bonded and the other fully proton transferred, cocrystal II consists of 1:1 complexes forming infinite 1-D hydrogen-bonded chains capable of exhibiting a thermally activated response in the form of a broad asymmetric peak at ca. 298 K that extends from ca. 200 to 375 K in both the real and imaginary parts of its complex dielectric. The state of protonation in cocrystal II at 298 and 386 K was established by CPMAS 15N NMR, which showed signals typical of a neutral hydrogen-bonded complex. Taken together, these observations suggest a dielectric response that results from a small population of transient dipoles thermally generated when acidic protons are transiently transferred to either side of the DABCO base. A potential order-disorder transition further explored by taking advantage of the highly sensitive rotational dynamics of the DABCO group using line-shape analysis of solid-state spin echo 2H NMR and 1H NMR T1 spin-lattice relaxation showed no breaks in the Arrhenius plot or Kubo-Tomita 1H T1 fittings, indicating the absence of large structural changes. This was confirmed by variable-temperature single-crystal X-ray diffraction analysis, which showed a fairly symmetric hydrogen bond in cocrystal II at all temperatures, suggesting that both nitrogen atoms may be able to adopt a protonated state.

Origin of the isotropic motion in crystalline molecular rotors with carbazole stators.

Herein we report two crystalline molecular rotors 1 and 4 that show extremely narrow signals in deuterium solid-state NMR spectroscopy. Although this line shape is typically associated with fast-moving molecular components, our VT 2H NMR experiments, along with X-ray diffraction analyses and periodic DFT computations show that this spectroscopic feature can also be originated from low-frequency intramolecular rotations of the central phenylene with a cone angle of 54.7° that is attained by the cooperative motion of the entire structure that distorts the molecular axis to rotation. In contrast, two isomeric structures (2 and 3) do not show a noticeable intramolecular rotation, because their crystallographic arrays showed very restricting close contacts. Our findings clearly indicate that the multiple components and phase transitions in crystalline molecular machines can work in concert to achieve the desired motion.

A Concise Synthesis of Potential COX Inhibitor BRL-37959 and Analogs Involving Bismuth(III) Catalyzed Friedel-Crafts Acylation.

We report the development of a concise method of synthesizing possible cyclooxygenase (COX) inhibitor BRL-37959, which is believed to be a potent nonsteroidal anti-inflammatory drug (NSAID). The four-step synthesis greatly increased the efficiency of compound production from commercially available salicylaldehydes. The synthesis involved an optimized, bismuth(III) trifluoromethanesulfonate catalyzed benzoylation of a benzofuran ring.