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Multimetallic architectures that combine chemically diverse materials to affect tandem reactions within a single scaffold drive future nanocatalyst development. Here, we show the unique, interlatti...

Fibrin plays a critical role in wound healing and hemostasis, yet it is also the main case of cardiovascular diseases and thrombosis. Here, we show the unique design of Au-Cu@PANI alloy core-shell rods for fibrin clot degradation. Microscopic (transmission electron microscopy (TEM), scanning transmission electron microscopy-energy-dispersive X-ray (STEM-EDX)) and structural characterizations (powder X-ray diffraction (PXRD), X-ray photoelectron spectroscopy (XPS)) of the Au-Cu@PANI hybrid material reveal the formation of Au-Cu heterogeneous alloy core rods (aspect ratio = 3.7) with thin Cu

Multi-metallic hybrid nancatalysts consisting of a porous metal oxide host and metal satellite guests serve as a scaffold for multi-step transformations of divergent and energy-challenging substrates. Here we have developed a 3D porous MgO framework (Lewis basic host) with Ag(0) nanoparticles (noble metal guest) for ambient pressure activation and insertion of CO(2) into unsaturated alkyne substrates. The hybrid MgO@Ag-x (x = 2, 5, 7, 8 at % Ag) catalysts are synthesized by impregnating Ag(+) ions in porous MgO cubes followed by reduction using NaBH(4). Morphological (SEM, TEM, EDX mapping) and structural (PXRD, XPS) characterization reveal that the micron-sized hybrid cubes derive from self-assembly of ~100 nm (edge length) MgO cubes decorated with ~ 5 to 25 nm Ag(0) NPs. Detailed XPS analysis illustrates Ag(0) is present in two forms

Environmental impacts of continued CO2 production have led to an increased need for new methods of CO2 removal and energy development. Nanomaterials are of special interest for these applications, because of their unique chemical and physical properties that allow for highly active surfaces. Here, we successfully synthesize AgPd nanodendrite-modified Au nanoprisms in various shapes (nanoprisms, hexagonal nanoplates, and octahedral nanoparticles) by selective metal deposition. This strategy involves coupling galvanic replacement between Ag layers in Au@Ag core–shell nanoprisms and H2PdCl4 with a coreduction process of silver and palladium ions. Synthesis of AgPd nanodendrite-tipped (4.14–11.47 wt % Pd) and -edged (25.25–31.01 wt % Pd) Au nanoparticles can be controlled simply by tuning the concentration of H2PdCl4. More importantly, these multicomponent AgPd nanodendrite-modified Au nanoparticles show exceptional electrocatalytic performance for CO2 reduction. AgPd nanodendrite-edged Au nanoprisms show mor...

A suite of lanthanoenediyne complexes of the form Ln(macrocycle)X(3) (Ln = La(3+), Ce(3+), Eu(3+), Gd(3+), Tb(3+), Lu(3+); X = NO(3)(−), Cl(−), OTf(−)) was prepared by utilizing an enediyne-containing [2 + 2] hexaaza-macrocycle (2). The solid-state Bergman cyclization temperatures, measured via DSC, decrease with the denticity of X (bidentate NO(3)(−), T = 267−292 °C; monodentate Cl(−), T = 238–262 °C; noncoordinating OTf(−), T = 170–183 °C). (13)C NMR characterization shows that the chemical shifts of the acetylenic carbon atoms also rely on the anion identity. The alkyne carbon closest to the metal binding site, C(A), exhibits a Δδ > 3 ppm downfield shift, while the more distal alkyne carbon, C(B), displays a concomitant Δδ ≤ 2.5 ppm upfield shift, reflecting a depolarization of the alkyne on metal inclusion. For all metals studied, the degree of perturbation follows the trend 2 < NO(3)(−) < Cl(−) < OTf(−). This belies a greater degree of electronic rearrangement in the coordinated macrocycle as the denticity of X and its accompanying shielding of the metal’s Lewis acidity decrease. Computationally modeled structures of LnX(3) show a systematic increase in the lanthanide–2 coordination number (CN(La-mc) = 2 (NO(3)(−)), 4 (Cl(−)), 5 (H(2)O, model for OTf(−))) and a decrease in the mean Ln−N bond length (La−N(average) = 2.91 Å (NO(3)(−)), 2.78 Å (Cl(−)), 2.68 Å (H(2)O)), further suggesting that a decrease in the anion coordination number correlates with an increase in the metal–macrocycle interaction. Taken together, these data illustrate a Bergman cyclization landscape that is influenced by the bonding of metal to an enediyne ligand but whose reaction barrier is ultimately dominated by the coordinating ability of the accompanying anion.

The predictable and controllable interaction of small organic or peptidic molecules with biological substrates is the primary reason most pharmaceuticals are narrowly decorated carbon frameworks. The inhibition or activation binding models are measurable and without side reactions that can cause pathological angst. Yet many diseases, especially those involving rapid proliferation of cells (i.e., cancer) or aggregation of peptides (e.g., heart disease, Alzheimer's disease) have not yet been cured by inhibition therapeutics. Additionally, interventional medicine is often required to alleviate such maladies by physical removal first, followed by molecular-level therapy as a second stage. Thus, there appears to be a niche for more aggressive therapeutics that may employ harsher chemical processes to realize clinical efficacy, albeit without causing catastrophic side effects. Molecules that may be considered for this challenge are not typically biomimetic, nor do they fit the traditional pharmaceutical paradigm. They may have unusual modes of action or undesired reactivity that can be lethal if not controlled. These are the outliers; potential pharmacophores that biology does not know how to manage or adapt to. This is why they may be an intriguing class of agents that needs continuous development. In this Account, we connect the under-developed enediyne family of compounds and our metalloenediyne derivatives to existing radical-based therapeutics such as bleomycin and doxorubicin to illustrate that controlled diradical reactivity, although an outlier mechanism, has a place in the therapeutic portfolio. This is self-evident in that of the 11 natural product enediynes known, 2 have clinical impact, a strong ratio. We expand on the chemical diversity of potential enediyne constructs and focus on the accessible trigger mechanisms to activate diradical formation as a method to control toxicity. Moreover, we further illustrate how electromagnetic fields can be employed to activate both molecular and larger nanomaterial constructs that carry highly concentrated payloads of reactive reagent. Finally, we describe how controlled diradical reactivity can reach beyond traditional therapeutic targets such as DNA, to peptide aggregates found in blood clots, neural fibrils, and membrane scaffolds. It is our belief that cleverly constructed frameworks with well-designed and controlled activation/reaction schemes can lead to novel therapeutics that can challenge evolving viral and bacterial invaders. From this evangelical perspective, our hope is that the conceptual framework, if not the specific designs in this Account, stimulate the readership to develop out-of-the-box therapeutic designs that may combat resistant disease targets.

Developing facile synthetic routes to multifunctional nanoparticles combining the magnetic properties of iron oxides with the optical and catalytic utility of noble metal particles remains an important goal in realizing the potential of hybrid nanomaterials. To this end, we have developed a single route to noble metal-decorated magnetic nanoparticles (Fe3O4@SiO2-M; M = Au, Pd, Ag, and PtAg) and characterized them by HRTEM and STEM/EDX imaging to reveal their nanometer size (16 nm Fe3O4 and 1-5 nm M seeds) and uniformity. This represents one of the few examples of genuine multifunctional particles on the nanoscale. We show that these hybrid structures have excellent catalytic activity for the reduction of 4-nitrophenol (knorm = 2 × 10(7) s(-1) mol(Pd)(-1); 5 × 10(6) s(-1) mol(Au)(-1); 5 × 10(5) s(-1) mol(PtAg)(-1); 7 × 10(5) s(-1) mol(Ag)(-1)). These rates are the highest reported for nano-sized comparables, and are competitive with mesoparticles of similar composition. Due to their magnetic response, the particles are also suitable for magnetic recovery and maintain99% conversion for at least four cycles. Using this synthetic route, Fe3O4@SiO2-M particles show great promise for further development as a precursor to complicated anisotropic materials or for applications ranging from nanocatalysis to biomedical sensing.

Halting cancer progression by altering the tumor microenvironment is an exciting new frontier in oncology. One target for new therapies is the structural support provided by the extracellular matrix, which for cancer cells is often abnormal and undergoes drastic modification during angiogenesis, tumor proliferation, and metastasis. We have developed a new magnetic nanoparticle-based agent, Fe3O4–PEG–EDDA (EDDA: (Z)-octa-4-en-2,6-diyne-1,8-diamine), that is capable of generating radicals via Bergman cyclization of the pendant enediyne during mild hyperthermia treatment using an alternating magnetic field. We observe formation of a cyclized aromatic product in the Raman spectra of the thermally excited material and can detect polymeric product after periods of induction. When mixed with the basement membrane extract Matrigel, the nanoparticles do not interfere with normal biopolymer network formation. Applying the same hyperthermia conditions as in solution samples, Fe3O4–PEG–EDDA causes structural collapse...

Enediyne natural products are a class of compounds that were recognized for their potential as chemotherapeutic agents many years ago, but found to be highly cytotoxic due to their propensity for low thermal activation. Bergman cyclization of the enediyne moiety produces a diradical intermediate, and may subsequently induce DNA damage and account for the extreme cytotoxicity. While difficulties in controlling the thermal cyclization reaction have limited the clinical use of cyclic enediynes, we have previously shown that enediyne activity, and thus toxicity at physiological temperatures can be modulated by metallation of acyclic enediynes. Furthermore, the cytotoxicity of “metalloenediynes” can be potentiated by hyperthermia. In this study, we characterized a suite of novel metallated enediyne motifs that usually induced little or no cytotoxicity when two different human cancer cell lines were treated with the compounds at 37°C, but showed a significant enhancement of cytotoxicity after cells were exposed to moderate hyperthermia during drug treatment. Cultured U-1 melanoma or MDA-231 breast cancer cells were treated with various concentrations of Cu, Fe and Zn complexes of the enediyne (Z)-N,N′-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine (PyED) and clonogenic survival was assessed to determine the effects of the drugs at 37°C and 42.5°C. Toxicity at 37°C varied for each compound, but hyperthermia potentiated the cytotoxicity of each compound in both cell lines. Cytotoxicity was concentration-, time- and temperature-dependent. Heating cells during drug treatment resulted in enhanced apoptosis, but the role of cell cycle perturbation in the response of the cells to the drugs was less clear. Lastly, we showed that hyperthermia enhanced the number of DNA double-strand breaks (DSBs) induced by the compounds, and inhibited their repair after drug treatment. Thus, thermal enhancement of cytotoxicity may be due, at least in part, to the propensity of the enediyne moiety to induce DSBs, and/or a reduction in DSB repair efficiency. We propose that “tuning” of metalloenediyne toxicity through better-controlled reactivity could have potential clinical utility, since we envision that such compounds could be administered systemically as relatively non-toxic agents, but cytotoxicity could be enhanced in, and confined to a tumor volume when subjected to localized heating.

Enediynes are a highly cytotoxic class of compounds. However, metallation of these compounds may modulate their activation, and thus their cytotoxicity. We previously demonstrated that cytotoxicity of 2 different metalloenediynes, including (Z)-N,N′-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine] (PyED), is potentiated when the compounds are administered to HeLa cells during hyperthermia treatment at concentrations that are minimally or not cytotoxic at 37 °C. In this study, we further characterized the concentration-, time-and temperature-dependence of cytotoxicity of PyED on human U-1 melanoma cells. We also investigated the potential mechanisms by which PyED cytotoxicity is enhanced during hyperthermia treatment. Cell killing with PyED was dependent upon concentration, temperature during treatment, and time of exposure. Potentiation of cytotoxicity was observed when cells were treated with PyED at temperatures ≥39.5 °C, and enhancement of cell killing increased with temperature, and with increasing time at a given temperature. All cells exposed to PyED were shown to have DNA damage, but substantially more damage was observed in cells treated with PyED during heating. DNA repair was also inhibited in cells exposed to the drug during hyperthermia treatment. Thus, potentiation of PyED cytotoxicity by hyperthermia may be due to enhancement of drug-induced DNA lesions, and/or the inhibition of repair of sublethal DNA damage. While the selective thermal activation of PyED supports the potential clinical utility of metalloenediynes as cancer thermochemotherapeutic agents, therapeutic gain could be optimized by identifying compounds that produce minimal toxicity at 37 °C but which become activated and show enhancement of cytotoxicity within a tumor subjected to localized hyperthermic or thermal ablative treatment, or which might act as bifunctional agents. We thus also describe the development and initial characterization of a novel cofactor complex of PyED, platinated PyED (Pt-PyED). Pt-PyED binds to DNA like cisplatin, and much like PyED, cytotoxicity is greatly enhanced after treatment with the drug at elevated temperatures. However, in contrast to PyED, Pt-PyED is only minimally cytotoxic at 37 °C at concentrations at which cytotoxicity is enhanced by hyperthermia. Further development of cisplatin-based enediynes may result in compounds which, when activated, will possess multiple DNA binding modalities similar to cisplatin, but produce less side effects in tissues at normothermic temperatures.

A series of M(PyED)·X (X = 2Cl−, SO42−) pyridine–metalloenediyne complexes [M = Cu(II), Fe(II), or Zn(II)] and their independently synthesized, cyclized analogs have been prepared to investigate their potential as radical-generating DNA-damaging agents. All complexes possess a 1:1 metal-to-ligand stoichiometry as determined by electronic absorption spectroscopy and X-ray diffraction. Solution structural analysis reveals a pπ Cl → Cu(II) LMCT (22,026 cm−1) for Cu(PyED)·2Cl, indicating three nitrogens and a chloride in the psuedo-equatorial plane with the remaining pyridine nitrogen and solvent in axial positions. EPR spectra of the Cu(II) complexes exhibit an axially elongated octahedron. This spectroscopic evidence, together with density functional theory computed geometries, suggest six-coordinate structures for Cu(II) and Fe(II) complexes and a five-coordinate environment for Zn(II) analogs. Bergman cyclization via thermal activation of these constructs yields benzannulated product indicative of diradical generation in all complexes within 3 h at 37 °C. A significant metal dependence on the rate of the reaction is observed [Cu(II) > Fe(II) > Zn(II)], which is mirrored in in vitro DNA-damaging outcomes. Whereas in situ chelation of PyED leads to considerable degradation in the presence of all metals within 1 h under hyperthermia conditions, Cu(II) activation produces >50% compromised DNA within 5 min. Additionally, Cu(II) chelated PyED outcompetes DNA polymerase I to successfully inhibit template strand extension. Exposure of HeLa cells to Cu(PyBD)·SO4 (IC50 = 10 μM) results in a G2/M arrest compared with untreated samples, indicating significant DNA damage. These results demonstrate metal-controlled radical generation for degradation of biopolymers under physiologically relevant temperatures on short timescales.

One of the key concerns with the development of radical-generating reactive therapeutics is the ability to control the activation event within a biological environment. To that end, a series of quinoline–metalloenediynes of the form M(QuiED)·2Cl (M = Cu(II), Fe(II), Mg(II), or Zn(II)) and their independently synthesized cyclized analogs have been prepared in an effort to elucidate Bergman cyclization (BC) reactivity differences in solution. HRMS(ESI) establishes a solution stoichiometry of 1:1 metal to ligand with coordination of one chloride counter ion to the metal center. EPR spectroscopy of Cu(QuiED)·2Cl and Cu(QuiBD)·2Cl denotes an axially-elongated tetragonal octahedron (g|| > g⊥ > 2.0023) with a d x 2 - y 2 ground state, while the electronic absorption spectrum reveals a pπ Cl→Cu(II) LMCT feature at 19,000 cm−1, indicating a solution structure with three nitrogens and a chloride in the equatorial plane with the remaining quinoline nitrogen and solvent in the axial positions. Investigations into the BC activity reveal formation of the cyclized product from the Cu(II) and Fe(II) complexes after 12 h at 45 °C in solution, while no product is observed for the Mg(II) or Zn(II) complexes under identical conditions. The basis of this reactivity difference has been found to be a steric effect leading to metal–ligand bond elongation and thus, a retardation of solution reactivity. These results demonstrate how careful consideration of ligand and complex structure may allow for a degree of control and selective activation of these reactive agents.