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The synthesis and single-crystal X-ray structure for tetraaquatetrakis(μ-2-propylvalerato)tetrakis(μ4-salicylhydroximato)dysprosiumtetramanganesesodium dimethylformamide tetrasolvate, [DyMn4Na(C7H4NO3)4(C8H15O2)4(H2O)4]·4C3H7NO or DyNa(2-PV)4[12-MCMnIII Nshi-4](H2O)4·4DMF, 1, where MC is metallacrown, shi3− is salicylhydroximate, 2-PV is 2-propylvalerate, and DMF is N,N-dimethylformamide, is reported. The slightly domed metallamacrocycle contains four ring MnIII ions and four shi3− ligands that generate an [MnIII—N—O] repeat unit that recurs four times. The ring MnIII ions are five-coordinate with a square-pyramidal shape. Furthermore, the metallacrown binds both a DyIII ion and a Na+ ion in the central cavity. The central ions are located on opposite faces of the cavity with the DyIII ion located on the convex side of the MC and the Na+ ion located on the concave side. Each central ion is eight-coordinate although they possess different geometries. The DyIII ion has a square-antiprismatic shape, while the Na+ ion has an extremely distorted biaugmented trigonal–prismatic shape. The four 2-propylvalerate anions help to tether the DyIII to the MC cavity by forming bridges between the DyIII ion and each ring MnIII ion. Moreover, the interstitial DMF molecules are hydrogen bonded to the water molecules that complete the coordination environment of the Na+ ion. The metallacrown framework (excluding the DyIII and Na+ ions), the bridging 2-propylvalerate, and the interstitial DMF molecule experience whole-molecule disorder due to the rotational orientation of the metallamacrocycle. Additionally, the main moiety alkyl chain of the 2-propylvalerate is disordered over two additional orientations, and the main moiety interstitial DMF molecule is disordered over one additional orientation. The main moiety of the metallacrown framework refined to 0.9030 (14), while the minor B-moiety refined to 0.0971 (14). The main moiety alkyl chain of the 2-propylvalerate refined to 0.287 (3): 0.309 (3): 0.307 (3), and the minor B-moiety alkyl chain refined to 0.0971 (14). Lastly, the main moiety interstitial DMF refined to 0.549 (3): 0.354 (3), and the minor B-moiety DMF refined to 0.0971 (14).

The synthesis and crystal structure for the title compound, hexa-aqua-hexa-kis(μ-2-hy-droxy-benzene-carbo-hydrox-a-mato)bis-(2-hy-droxy-benzene-carbo-hydrox-a-m-ato)tetra-indium(III) tetra-nitrate 8.57-hydrate + unknown solvent, [In

Coniferous trees of the genus Pinus (Pinaceae) are under continuous threats by numerous herbivorous insect species and pathogens attacking nearly all parts and tissues of the plants. To defend themselves, pine trees produce large amounts of oleoresin that is accumulated in a highly developed network of specialized resin ducts, which are distributed in the wood, bark, and needles. Such defense reactions in pines can be induced by the attack of herbivores. The banded pine weevil, Pissodes castaneus (De Geer, 1775) (Coleoptera, Curculionidae), is an important pest of Pinus in Brazil, where it has been an invasive species since 2001. The female lays its eggs under the tree bark of trees and the larvae feed in the phloem of the trunk and branches, interrupting the sap circulation and eventually causing its death. In the present study, we conducted detailed GC–MS analyses of volatiles emitted by twigs of Pinus taeda L. We analyzed how the attack by P. castaneus males and females affects the volatile pattern emitted by the twigs. When comparing volatiles produced by healthy plants and by female- and male-attacked P. taeda, qualitative and quantitative differences were detected, as the decreased production of limonene, germacrene D and (E)-caryophyllene and the increase of α-pinene. Laboratory bioassays showed that plants attacked by male and female P. castaneus were more attractive to the insects. Understanding about what compounds may attract or repel the insects may help in the development of more effective traps, as well as preventing stress to avoid infestation.

The terbium-aluminum metallacrowns (MC), TbAl4Na (left image & capillary) and Tb2Al8Na2 (right image & capillary) emit green light. Tb2Al8Na2 has a quantum yield value of 43.9%, the highest value observed in the solid state to date for a TbIII MC.

A series of heterotrimetallic manganese-lanthanide-sodium dimer metallacrowns has been synthesized and characterized by single-crystal X-ray analysis: {LnNa[12-MCMn(III)N(shi)-4]}2(iph)4, where LnIII = La (1), Ce (2), Pr (3), Nd (4), Sm (5), Eu (6), Gd (7), Tb (8), Dy (9), Ho (10), Er (11), Tm (12), Yb (13), Lu (14), and Y (15); MC is metallacrown; shi3− is salicylhydroximate; and iph2− is isophthalate. The manganese(III) ions and shi3− ligands generate the 12-MC-4 framework with one LnIII and Na+ ion bound to each [12-MCMn(III)N(shi)-4] on opposite sides of the central MC cavity. The carboxylate groups of the isophthalate ligands bridge between the central LnIII ion and each ring MnIII ion, and the meta-arrangement of the carboxylate groups joins two LnNa[12-MCMn(III)N(shi)-4] units together to form the dimer through the LnIII ions, which reside on the interior of the molecule. The identity of the central LnIII ion slightly impacts the size the [12-MCMn(III)N(shi)-4] framework. As the crystal radius of the LnIII ion increases from LuIII (1.02 A) to LaIII (1.19 A), the 12-MC-4 framework expands to accommodate the larger LnIII ion as the MC cavity increases in size (0.53 A for LuIII to 0.58 A for LaIII) and the average cross cavity MnIII-MnIII and oxime oxygen-oxime oxygen distances also increase (MnIII-MnIII distances: 6.48 A for LuIII to 6.52 A for LaIII; Ooxime-Ooxime distances: 3.66 A for LuIII to 3.75 A for LaIII). In addition, the larger LnIII ions reside further from the MC cavity as indicated by the LnIII-oxime oxygen mean plane (OoxMP) distance. The LnIII-OoxMP distance steadily decreases from LaIII (1.7527(12) A) to LuIII (1.5575(15) A). The complex {LaNa[12-MCMn(III)N(shi)-4]}2(iph)4(DMF)6(H2O)2 is a dimer of [12-MC-4] molecules linked by four isophthalate anions

The metallacrown compound, NiII(OAc)2[12-MCMn(III)N(shi)-4](CH3OH)6·2CH3OH·H2O, where MC is metallacrown, shi3− is salicyl­hydroximate, and −OAc is acetate, has an overall square shape that captures an NiII ion in a central cavity while the ring of the metallamacrocycle contains four MnIII ions. Two acetate anions, which are located on opposite faces of the MC, form bridges between the central NiII ion and two of the ring MnIII ions., The synthesis and crystal structure of the title compound [systematic name: di-μ-acetato-tetra­kis­(μ4-N,2-dioxido­benzene-1-carboximidato)hexa­methano­ltetra­manganese(III)nickel(II) methanol disolvate monohydrate], [Mn4Ni(C7H4NO3)4(C2H3O2)2(CH4O)6]·2CH4O·H2O or Ni(OAc)2[12-MCMn(III)N(shi)-4](CH3OH)6·2CH3OH·H2O, where MC is metallacrown, −OAc is acetate, and shi3− is salicyl­hydroximate, are reported. The macrocyclic metallacrown is positioned on an inversion center located on the NiII ion that resides in the central MC cavity. The macrocycle consists of an MnIII–N–O repeat unit that recurs four times to generate an overall square-shaped mol­ecule. Both the NiII and MnIII ions are six-coordinate with an octa­hedral geometry. In addition, the MnIII ions possess an elongated Jahn–Teller distortion along the z-axis of the coordination environment. The inter­stitial water mol­ecule is slightly offset from and disordered about an inversion center.

Two series of aluminum-lanthanide-sodium 12-metallacrown-4 compounds have been synthesized and characterized by single-crystal X-ray analysis. For the individual LnNa(ben)4[12-MCAl(III)N(shi)-4] molecules, where LnIII = Eu (1), Gd (2), Tb (3), Dy (4), Ho (5), Er (6), Tm (7), Yb (8), Lu (9), and Y (10), ben− is benzoate, MC is metallacrown, and shi3− is salicylhydroximate, two independent molecules are present in each unit cell. The aluminum(III) ions and shi3− ligands comprise the MC framework, while the LnIII and Na+ ions bind opposite of each other across the central MC cavity. The benzoate anions serve to tether the LnIII ion to the MC framework. When benzoate is replaced with the dicarboxylate anion isophthalate (iph2−), two [12-MCAl(III)N(shi)-4] units are connected to form a dimer of MCs: {LnNa[12-MCAl(III)N(shi)-4]}2(iph)4, where LnIII = Eu (11), Gd (12), Tb (13), Dy (14), Ho (15), Ho (16), Er (17), Yb (18), and Lu (19). As in 1–10, the aluminum(III) ions and shi3− ligands produce the MC frameworks, and one LnIII ion binds to each central MC cavity. However, there are two binding modes for the sodium ions. For 12–15 and 18, the sodium ions bind to the central MC cavity opposite of the LnIII ions as in 1–10. For 11, 16, 17, and 19, the sodium ions bind to the side of the MC framework by bonding to the phenolate and carboxylate oxygen atoms of two shi3− ligands and to the carboxylate oxygen atom of an iph2− ligand. In these structures, the MC cavity is vacant opposite of the LnIII ions. The substitution of isophthalate for benzoate does not significantly alter the [12-MCAl(III)N(shi)-4] framework as the size of the central MC cavity is not significantly different between analogous lanthanide individual and dimer MCs. However, the identity of the central LnIII ion does determine how close the LnIII ion can approach the mean plane of the oxime oxygen atoms (OoxMP) of the MC cavity. As the ion radius of the central LnIII ion decreases, the LnIII ion is able to more closely approach the OoxMP. For the individual MCs 1–10, the EuIII of 1 is the farthest away from the OoxMP (1.55 A) and this value steadily decreases to 1.44 A for the LuIII ion of 9. This same trend is true for the dimer MCs as the EuIII ion of 11 is 1.45 A from the OoxMP and the LuIII ion of 19 is 1.36 A from the OoxMP. Though the location of the sodium ions in the dimer MCs does influence the LnIII-OoxMP distance as the absence of the sodium ion in the MC cavity allows the LnIII ion to approach the MC cavity even closer. In 15 a sodium ion is opposite the HoIII ion and the HoIII-OoxMP distance is 1.47 A, while in 16 the sodium ion is bound to the side of the MC and the HoIII-OoxMP distance is 1.40 A. The complex GdNa[12-MCAl(III)N(shi)-4]}2(iph)4(DMF)2(H2O)8 is a dimer of [12-MC-4] molecules linked by four isophthalate anions.

The heterobimetallic metallacrown (MC), (TMA)$_2${Mn(OAc)$_2$[12-MC$_{Mn(III)Cu(II)N(shi)}$-4](CH$_3$OH)}$\cdot$2.90CH$_3$OH, 1, where TMA$^+$ is tetramethylammonium, $^-$OAc is acetate, and shi$^{3-}$ is salicylhydroximate, consists of a Mn$^{II}$ ion captured in the central cavity and alternating unambiguous and ordered manganese(III) and copper(II) sites about the MC ring, a first for the archetypal MC structure design. DC-magnetometry characterization and subsequent simulation with the Spin Hamiltonian $$H = -J_1(\mathbf{s}_1+\mathbf{s}_3)\cdot\mathbf{s}_5-J_2(\mathbf{s}_2+\mathbf{s}_4)\cdot\mathbf{s}_5-J_3\sum_{i=1}^{4}\mathbf{s}_i\cdot\mathbf{s}_{i+1} + d(s_{z,1}^2 + s_{z,3}^2) + \mu_B\sum_{j=1}^5 g_j\mathbf{s}_j\cdot\mathbf{B}$$ indicates an S = 5/2 ground state and a sizable axial zero-field splitting on Mn$^{III}$. AC-susceptibility measurements reveal that 1 displays slow magnetization relaxation akin to single-molecule magnet (SMM) behavior.

The two [3.3.1] metallacryptate complexes [DyAl6Na5(OAc)(Hshi)2(shi)7(DMF)8]·H2O·4DMF, 1, and [DyAl6Na5(OAc)(Hshi)2(shi)7(DMF)8.5]2·6.335DMF, 2, where shi3− is salicyl­hydroximate and DMF is N,N-di­methyl­formamide, both consist of an aluminium-based metallacryptand. In 1 and 2, the metallacryptand encapsulates a dysprosium(III) ion in the central cavity, and the resulting metallacryptates are connected to each other to generate a two-dimensional sheet., The two [3.3.1] metallacryptate complexes, namely, poly[[μ3-acetato-hexa­kis­(μ-N,N-di­methyl­formamide)­bis­(N,N-di­methyl­formamide)bis­[salicyl­hydroxi­mato(2−)]hepta­kis­[salicyl­hydrox­im­ato(3−)]hexa­aluminium(III)dysprosium(III)penta­sodium(I)] N,N-di­methyl­formamide tetra­solvate monohydrate], [DyAl6Na5(OAc)(Hshi)2(shi)7(DMF)8]·4DMF·H2O or {[DyAl6Na5(C7H5NO3)2(C7H4NO3)7(C2H3O2)(C3H7NO)8]·4C3H7NO·H2O}n, 1, and poly[[di-μ4-acetato-nona­kis­(μ-N,N-di­methyl­form­amide)­octa­kis­(N,N-di­methyl­formamide)tetra­kis­[sali­cyl­hydroximato(2-)]tetra­deca­kis­[salicyl­hydroximato(3−)]dodeca­aluminium(III)didysprosium(III)deca­sodium(I)] N,N-di­methyl­form­amide 6.335-solvate], [DyAl6Na5(OAc)(Hshi)2(shi)7(DMF)8.5]2·6.335DMF or {[Dy2Al12Na10(C7H5NO3)4(C7H4NO3)14(C2H3O2)2(C3H7NO)17]·6.335C3H7NO}n, 2, where shi3− is salicyl­hydroximate and DMF is N,N-di­methyl­formamide, both consist of an aluminium-based metallacryptand. In 1 and 2, the metallacryptand encapsulates a dysprosium(III) ion in the central cavity, and the resulting metallacryptates are connected to each other via sodium-DMF linkages to generate a two-dimensional sheet. The metallacryptates of 1 and 2 are the three-dimensional analogues of metallacrowns as the metallacryptates contain a metal–nitro­gen–oxygen cyclic repeat unit throughout the complexes. For 1 the building block of the two-dimensional sheet is comprised of only one type of metallacryptate, which is connected to four neighboring metallacryptates via four sodium–DMF linkages. In 2, the building block is a dimeric unit of two metallacryptates. Each dimeric metallacryptate unit is connected to four other dimeric units via six sodium–DMF linkages. The two metallacryptates of each dimeric unit can be considered enanti­omers of each other. In both 1 and 2, chirality is imparted to the metallacryptate due to the Λ and Δ propeller configurations of the four octa­hedral aluminium ions of the metallacryptand shell.

The metallacrown complexes DyIIINa(3-OHben)4[12-MCMn(III)N(shi)-4](H2O)4·10DMA, 1, and DyIIINa(4-OHben)4[12-MCMn(III)N(shi)-4](H2O)4·4DMF, 2, where MC is metallacrown, shi3− is salicyl­hydroximate, 3-OHben is 3-hy­droxy­benzoate, DMA is N,N-di­methyl­acetamide, 4-OHben is 4-hy­droxy­benzoate, and DMF is N,N-di­methyl­formamide, consist of a macrocyclic mol­ecule with an [MnIII—N—O] repeat unit. For both 1 and 2, a DyIII ion is captured on the convex side of the central cavity, while a Na+ ion is captured on the concave side of the cavity. Four 3-hy­droxy­benzoate or 4-hy­droxy­benzoate anions bridge between the ring MnIII ions and the central DyIII ion., The syntheses and crystal structures for the compounds tetra-μ-aqua-­tetra­kis­{2-[aza­nid­yl­ene(oxido)meth­yl]phenolato}tetra­kis­(μ2-3-hy­droxy­benzoato)dys­pro­s­ium(III)­tetra­manganese(III)sodium(I) N,N-di­methyl­acetamide deca­solvate, [DyMn4Na(C7H5O3)4(C7H4NO2)4(H2O)4]·10C4H9NO or [DyIIINa(4-OHben)4{12-MCMn(III)N(shi)-4}(H2O)4]·10DMA, 1, and tetra-μ-aqua-­tetra­kis­{2-[aza­nid­yl­ene(oxido)meth­yl]phenolato}tetra­kis­(μ2-3-hy­droxy­benzoato)dys­pros­ium(III)tetra­manganese(III)sodium(I) N,N-di­methylformamide tetra­solvate, [DyMn4Na(C7H5O3)4(C7H4NO2)4(H2O)4]·4C3H7NO or [DyIIINa(3-OHben)4{12-MCMn(III)N(shi)-4}(H2O)4]·4DMF, 2, and where MC is metallacrown, shi3− is salicyl­hydroximate, 3-OHben is 3-hy­droxy­benzoate, DMA is N,N-di­methyl­acetamide, 4-OHben is 4-hy­droxy­benzoate, and DMF is N,N-di­methyl­formamide, are reported. For both 1 and 2, the macrocyclic metallacrown consists of an [MnIII—N—O] ring repeat unit, and the domed metallacrown captures two ions in the central cavity: a DyIII ion on the convex side of the metallacrown and an Na+ ion the concave side. The MnIII ions are six-coordinate with an elongated tetra­gonally distorted octa­hedral geometry. Both the DyIII and Na+ ions are eight-coordinate. The DyIII ions possess a square-anti­prismatic geometry, while the Na+ ions have a distorted biaugmented trigonal–prismatic geometry. Four 3-hy­droxy­benzoate or 4-hy­droxy­benzoate ligands bridge each MnIII ion to the central DyIII ion. For 1, whole-mol­ecule disorder is observed for the main mol­ecule, excluding only the DyIII and Na+ ions, and the occupancy ratio refined to 0.8018 (14):0.1982 (14). Three DMA mol­ecules were refined as disordered with two in general positions by an approximate 180° rotation and the third disordered twice by general disorder as well as by an exact 180° rotation about a twofold axis that bis­ects it. The occupancy ratios refined to 0.496 (8):0.504 (8), 0.608 (9):0.392 (9), and 2×0.275 (7):2×0.225 (7), respectively. For 2, segments of the metallacrown are disordered including the DyIII ion, one of the Mn ions, two of the Mn-bound 4-hy­droxy­benzoate ligands, the Mn-bridging salicyl­hydroximate ligand, and portions of the remaining three shi3− ligands. The occupancy ratio for the metallacrown disorder refined to 0.849 (9):0.151 (9). Two DMF solvent mol­ecules are also disordered, each over two orientations. The disorder ratios refined to 0.64 (3):0.36 (3) and to 0.51 (2):0.49 (2), respectively. For 2, the crystal under investigation was refined as a non-merohedric twin by a 90° rotation around the real a axis [twin ratio 0.9182 (8):0.0818 (8)].

Alterations to synthetic conditions either by varying stochiometric ratios of the reactants or solvent choice yield two new metallacrowns (MCs): Mn(Hsal)2[12-MCMnIII(N)shi-4](DMF)6·4DMF, 1, where −Hsal is salicylate, shi3− salicylhydroximate, and DMF is N,N-dimethylformamide, and {Na2(OAc)2[12-MCMnIII(N)shi-4](MeOH)4(H2O)22MeOH}n, 2, where −OAc is acetate and MeOH is methanol. Compound 1 crystallizes in the monoclinic space group C2/c with a = 19.0264 (6) A, b = 23.1440 (8) A, c = 18.6704 (5) A, α = 90°, β = 90.3600 (10)°, γ = 90°, V = 8221.3 (4) A3, and Z = 4. Compound 2 crystallizes in the triclinic space group P $$\stackrel{-}{1}$$ with a = 7.8995 (7) A, b = 11.2374 (10) A, c = 14.5559 (13) A, α = 112.535 (3)°, β = 91.987 (3)°, γ = 98.558 (3)°, V = 1174.22 (18) A3, and Z = 1. Compound 1 is a discrete metallacrown molecule that contains four ring MnIII ions and a MnII ion captured in the metallacrown central cavity. The MnII ion is tethered to the metallacrown via two salicylate bridges that also bridge to the ring MnIII ions. Compound 2 is a one-dimensional chain of metallacrowns. The metallacrown consists of four ring MnIII ions and two sodium ions which are bound on opposite faces of the metallacrown cavity. Each di-sodium metallacrown is then linked to neighboring metallacrowns through acetate anion bridges to form a one-dimensional chain. The complex Na2(OAc)2[12-MCMnIII(N)shi-4](MeOH)4(H2O)2·2MeOH forms a one-dimensional chain of metallacrowns by linking together neighboring metallacrowns through acetate anion bridges.

Similar synthetic schemes yield two different metallacrown (MC) complexes: bis(μ-3-chlorobenzoato)hexakis(dimethylformamide)tetrakis(μ4-N,2-dioxidobenzene-1-carboximidato)tetramanganese(III)disodium(I), [Mn4Na2(C7H4ClO2)2(C7H4NO3)4(C3H7NO)6] or Na2(3-chlorobenzoate)2[12-MCMn(III)N(shi)-4](DMF)6, 1, and tetra-μ-aqua-tris(μ-3-chlorobenzoato)(dimethylformamide)tetrakis(μ4-N,2-dioxidobenzene-1-carboximidato)pentamanganese(III)sodium(I) dimethylformamide tetrasolvate 0.72-hydrate, [Mn5Na(C7H4ClO2)3(C7H4NO3)4(C3H7NO)(H2O)4]·4C3H7NO·0.718H2O or MnNa(3-chlorobenzoate)3[12-MCMn(III)N(shi)-4](DMF)(H2O)4·4DMF·0.72H2O, 2, where shi3− is salicylhydroximate and DMF is N,N-dimethylformamide. Both complexes have the same framework consisting of four MnIII ions in the MC ring and four shi3− ligands, resulting in an overall square-shaped molecule. The MnIII ions are either five- or six-coordinate with elongated bond lengths in the apical or axial direction, respectively. The structure of 1 is nearly planar, and the MC binds two Na+ ions on opposite faces of the MC central cavity. The 3-chlorobenzoate anions also bind on opposite faces of the MC and form bridges between the central Na+ ions and the ring MnIII ions. For 1 the metallacrown molecule, except for the central Na+ ion, exhibits whole molecule disorder over two sets of sites. Both moieties are centrosymmetric and are related to each other by a pseudo-mirror operation with opposite sense of rotation around the Na...Na axis. The occupancy ratio of the main disorder of the metallacrown molecules and 3-chlorobenzoate anions refined to 0.9276 (9):0.0724 (9). The structure of 2 is slightly domed, and the MC binds both an MnII ion and an Na+ ion in the MC central cavity. The MnII ion is located on the convex side of the MC, while the Na+ ion binds to the concave side. Complex 2 represents the first instance of a [12-MCMn(III)N(shi)-4] molecule binding both 3d transition metal and alkali metal ions in the central cavity. In addition, three 3-chlorobenzoate anions bind on the convex side of the MC and connect the MnII ion to three of the ring MnIII ions.

The title compound, [Mn(C3H7NO)4(H2O)2][Cu5(C7H4NO3)4]·C3H7NO or cis-[Mn(H2O)2(DMF)4]{Cu[12-MCCu(II)N(shi)-4]}·DMF, where MC is metallacrown, shi3− is salicylhydroximate, and DMF is N,N-dimethylformamide, crystallizes in the monoclinic space group P21/n. Two crystallographically independent metallacrown anions are present in the structure, and both anions exhibit minor main molecule disorder by an approximate (non-crystallographic) 180° rotation with occupancy ratios of 0.9010 (9) to 0.0990 (9) for one anion and 0.9497 (8) to 0.0503 (8) for the other. Each pentacopper(II) metallacrown contains four CuII ions in the MC ring and a CuII ion captured in the central cavity. Each CuII ion is four-coordinate with a square-planar geometry. The anionic {Cu[12-MCCu(II)N(shi)-4]}2− is charged-balanced by the presence of a cis-[Mn(H2O)2(DMF)4]2+ cation located in the lattice. In addition, the octahedral MnII counter-cation is hydrogen bonded to both MC anions via the coordinated water molecules of the MnII ion. The water molecules form hydrogen bonds with the phenolate and carbonyl oxygen atoms of the shi3− ligands of the MCs.

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...

The promise of drug repurposing is to accelerate the translation of knowledge to treatment of human disease, bypassing common challenges associated with drug development to be more time- and cost-efficient. Repurposing has an increased chance of success due to the previous validation of drug safety and allows for the incorporation of omics. Hypothesis-generating omics processes inform drug repurposing decision-making methods on drug efficacy and toxicity. This review summarizes drug repurposing strategies and methodologies in the context of the following omics fields: genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiomics, phenomics, pregomics, and personomics. While each omics field has specific strengths and limitations, incorporating omics into the drug repurposing landscape is integral to its success.

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

Drug repurposing is the application of approved drugs to treat diseases separate and distinct from their original indications. Herein, we define the scope of all practical precision drug repurposing using DrugBank, a publicly available database of pharmacological agents, and BioVU, a large, de-identified DNA repository linked to longitudinal electronic health records at Vanderbilt University Medical Center. We present a method of repurposing candidate prioritization through integration of pharmacodynamic and marketing variables from DrugBank with quality control thresholds for genomic data derived from the DNA samples within BioVU. Through the synergy of delineated "target-action pairs," along with target genomics, we identify ∼230 "pairs" that represent all practical opportunities for genomic drug repurposing. From this analysis, we present a pipeline of 14 repurposing candidates across 7 disease areas that link to our repurposability platform and present high potential for randomized controlled trial startup in upcoming months.

Knowledge of dynamo evolution in solar-type stars is limited by the difficulty of using active region monitoring to measure stellar differential rotation, a key probe of stellar dynamo physics. This paper addresses the problem by presenting the first ever measurement of stellar differential rotation for a main-sequence solar-type star using starspots and faculae to provide complementary information. Our analysis uses modelling of light curves of multiple exoplanet transits for the young solar-type star Kepler-71, utilizing archival data from the Kepler mission. We estimate the physical characteristics of starspots and faculae on Kepler-71 from the characteristic amplitude variations they produce in the transit light curves and measure differential rotation from derived longitudes. Despite the higher contrast of faculae than those in the Sun, the bright features on Kepler-71 have similar properties such as increasing contrast towards the limb and larger sizes than sunspots. Adopting a solar-type differential rotation profile (faster rotation at the equator than the poles), the results from both starspot and facula analysis indicate a rotational shear less than about 0.005 rad d-1, or a relative differential rotation less than 2 per cent, and hence almost rigid rotation. This rotational shear contrasts with the strong rotational shear of zero-age main-sequence stars and the modest but significant shear of the modern-day Sun. Various explanations for the likely rigid rotation are considered.

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

The three [3.3.1] metallacryptate complexes [Hpy]2[GdAl6(H2shi)2(shi)7(py)1.855(H2O)2]·7.396py·H2O, 1, [Hpy]2[DyAl6(H2shi)2(shi)7(py)1.891(H2O)2]·7.429py·H2O, 2, and [Hpy]2[YbAl6(H2shi)2(shi)7(py)1.818(H2O)2]·7.386py·H2O, 3, where Hpy+ is pyridinium, shi3− is salicyl­hydroximate, and py is pyridine, consist of an aluminium-based metallacryptand that captures an Ln III ion in the central cavity. The metallacryptand portions are comprised of an Al—N—O repeat unit; thus, they can be considered three-dimensional metallacrowns. The encapsulated Ln III ions are nine-coordinate with a spherical capped-square-anti­prism geometry, while the six AlIII ions are all octa­hedral. Four of the AlIII ions are chiral centers with 2 Δ and 2 Λ stereoconfigurations. The remaining two AlIII ions have trans chelate rings from two different shi3− ligands., The three isomorphous [3.3.1] metallacryptate complexes bis­(pyridinium) di­aqua­dipyridine­hexa­kis­[μ3-salicyl­hydroximato(3−)]bis­[μ2-salicyl­hydroxim­ato(1−)]hexa­aluminiumgadolinium–pyridine–water (1/7.396/1), (C5H6N)2[GdAl6(C7H6NO3)2(C7H4NO3)7(C5H5N)1.855(H2O)2]·7.396C5H5N·H2O or [Hpy]2[GdAl6(H2shi)2(shi)7(py)1.855(H2O)2]·7.396py·H2O, 1, bis­(pyridinium) di­aqua­dipyridine­hexa­kis­[μ3-salicyl­hydroximato(3−)]bis­[μ2-salicyl­hydroxim­ato(1−)]hexa­aluminiumdysprosium–pyridine–water (1/7.429/1), (C5H6N)2[DyAl6(C7H6NO3)2(C7H4NO3)7(C5H5N)1.855(H2O)2]·7.429C5H5N·H2O or [Hpy]2[DyAl6(H2shi)2(shi)7(py)1.891(H2O)2]·7.429py·H2O, 2, and bis­(pyrid­in­ium) di­aqua­dipyridine­hexa­kis­[μ3-salicyl­hydroximato(3−)]bis­[μ2-salicyl­hydrox­imato(1−)]hexa­aluminiumytterbium–pyridine–water (1/7.386/1), (C5H6N)2[YbAl6(C7H6NO3)2(C7H4NO3)7(C5H5N)1.855(H2O)2]·7.429C5H5N·H2O or [Hpy]2[YbAl6(H2shi)2(shi)7(py)1.818(H2O)2]·7.386py·H2O, 3, where Hpy+ is pyridinium, shi3− is salicyl­hydroximate, and py is pyridine, consist of an aluminium-based metallacryptand that captures an Ln III ion in the central cavity. The metallacryptand portions are comprised of an Al—N—O repeat unit; thus, they can be considered three-dimensional metallacrowns. The encapsulated Ln III ions are nine-coordinate with a spherical capped-square-anti­prism geometry, while the six AlIII ions are all octa­hedral. Four of the AlIII ions are chiral centers with 2 Δ and 2 Λ stereoconfigurations. The remaining two AlIII ions have trans chelate rings from two different shi3− ligands. For 1–3, a section of the main mol­ecule is disordered induced by the presence or absence of a pyridine ligand coordinated to one of the AlIII ions. In the absence of the pyridine moiety, an H2shi− ligand moves into the space otherwise occupied by the pyridine and the phenol oxygen atom coordinates to the AlIII ion. The movement of the H2shi− ligand induces movement for the Ln III ion, for another AlIII ion that also binds the same H2shi− ligand, and for one of the shi3− ligands coordinated to the latter AlIII ion. For 1–3 the occupancy ratio of the metallacryptand portions refined to 0.8550 (13):0.1450 (13), to 0.8909 (13):0.1091 (13), and to 0.8181 (14):0.1819 (14), respectively.

The title compound [Mn(OH2)2(C3H7NO)4][Cu5(C7H4NO3)4]·C3H7NO or cis-[Mn(H2O)2(DMF)4]{Cu[12-MCCu(II)N(shi)-4]}·DMF, where MC is metallacrown, shi3− is salicyl­hydroximate, and DMF is N,N-di­methyl­formamide, consists of a penta­copper(II) 12-metallacrown-4 anion that is charged-balanced with the cis-[Mn(DMF)4(OH2)2]2+ cation. In the {Cu[12-MCCu(II)N(shi)-4]}2− anion, all four CuII ions of the metallacrown ring and the one CuII ion of the central cavity are four-coordinate with a square-planar geometry. The MnII counter-cation is six-coordinate with an octa­hedral geometry., The title compound, [Mn(C3H7NO)4(H2O)2][Cu5(C7H4NO3)4]·C3H7NO or cis-[Mn(H2O)2(DMF)4]{Cu[12-MCCu(II)N(shi)-4]}·DMF, where MC is metallacrown, shi3− is salicyl­hydroximate, and DMF is N,N-di­methyl­formamide, crystallizes in the monoclinic space group P21/n. Two crystallographically independent metallacrown anions are present in the structure, and both anions exhibit minor main mol­ecule disorder by an approximate (non-crystallographic) 180° rotation with occupancy ratios of 0.9010 (9) to 0.0990 (9) for one anion and 0.9497 (8) to 0.0503 (8) for the other. Each penta­copper(II) metallacrown contains four CuII ions in the MC ring and a CuII ion captured in the central cavity. Each CuII ion is four-coordinate with a square-planar geometry. The anionic {Cu[12-MCCu(II)N(shi)-4]}2− is charged-balanced by the presence of a cis-[Mn(H2O)2(DMF)4]2+ cation located in the lattice. In addition, the octa­hedral MnII counter-cation is hydrogen bonded to both MC anions via the coordinated water mol­ecules of the MnII ion. The water mol­ecules form hydrogen bonds with the phenolate and carbonyl oxygen atoms of the shi3− ligands of the MCs.

Metastatic cancers impose significant burdens on patients, affecting quality of life, morbidity and mortality, and even during remission, microscopic metastases can lurk. Few therapies directly target tumor cell metastasis. Agents that interfere with this process would represent a new paradigm in cancer management, changing the ‘waiting game’ into a time of active prevention. These therapies could take multiple forms based on the pathways involved in the metastatic process. For example, a Phenome Wide Association Study showed that a single nucleotide polymorphism in the gene TBXA2R is associated with increased metastasis in multiple primary cancers (P = 0.003), suggesting clinical applicability of TBXA2R antagonists. Emerging data related to the role of platelets in metastasis are concordant with our sense that these pathways present significant opportunities for therapeutic development. Before real progress can be made towards clinical targeting of the metastatic process, however, foundational work is needed to define informative measures of critical elements such as circulating tumor cells and tumor DNA, and circulatory vs. lymphatic spread. These challenges require an expansion of team science and composition to obtain competitive funding. At our academic medical center, we have implemented a Cancer Metastasis Inhibition (CMI) program investigating this approach across multiple cancers.

Many animal models of disease are suboptimal in their representation of human diseases and lack of predictive power in the success of pivotal human trials. In the context of repurposing drugs with known human safety, it is sometimes appropriate to conduct the “last experiment first,” that is, progressing directly to human investigations. However, there are not accepted criteria for when to proceed straight to humans to test a new indication. We propose a specific set of criteria to guide the decision-making around when to initiate human proof of principle without preclinical efficacy studies in animal models. This approach could accelerate the transition of novel therapeutic approaches to human applications.

Two types of 3d-4f compounds are presented, [DyIII4MnIII4(OH)2(O2C2H3)3(shi)4(H2shi)4(Hsal)3(DMF)4].3DMF (Dy-1) and [LnIII6MnIII2MnIV2(shi)6(Hshi)4(H2shi)2(Hsal)4(DMF)8].4H2O (Ln-2) (Ln = Dy or Gd, H3shi = salicylhydroxamic acid, H2sal = salicylic acid). While neither Dy-1 and Dy-2 demonstrated a significant barrier to magnetization relaxation, out-of-phase ac magnetic susceptibility was observed in both cases. Gd-2 showed potential as a magnetocoolent with gravimetric entropy changes reaching a maximum of 18.89 J.kg−1.K−1 at 3 K and ΔH = 7 T. This value represents approximately 53% of the theoretical maximum.

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...

The potential impact of using human genetic data linked to longitudinal electronic medical records on drug development is extraordinary; however, the practical application of these data necessitates some organizational innovations. Vanderbilt has created resources such as an easily queried database of >2.6 million de-identified electronic health records linked to BioVU, which is a DNA biobank with more than 230,000 unique samples. To ensure these data are used to maximally benefit and accelerate both de novo drug discovery and drug repurposing efforts, we created the Accelerating Drug Development and Repurposing Incubator, a multidisciplinary think tank of experts in various therapeutic areas within both basic and clinical science as well as experts in legal, business, and other operational domains. The Incubator supports a diverse pipeline of drug indication finding projects, leveraging the natural experiment of human genetics.

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.

The Vanderbilt Institute for Clinical and Translational Research piloted the development of Project PLACENTA (PathLink Acquired gEstatioNal Tissue bAnk). This project investigated the feasibility of a fresh gestational tissue biobank, which provides tissue linked to electronic medical records for investigators interested in maternal-fetal health.We developed a pipeline for collection of placental tissue from Labor and Delivery within approximately 30 minutes of delivery. An email alert was developed, to signal delivery, with the ability to specifically flag patients with certain phenotypic traits. Once collected, 4 to 8 mm punch biopsy cores were snap frozen and subsequently used for DNA, RNA and protein extraction. Tissue was also collected for Formalin Fixed Paraffin Embedded (FFPE) histology, flow cytometry, and quality control measures.Of 60 deliveries using the email notification system, 25 (42%) were sent to Pathology or assigned to other research protocols and were not available for collection, 10 (16%) were discarded prior to arrival at Labor and Delivery, and 25 (42%) were available for collection. Twenty placentas were collected and averaged 38 minutes per collection. DNA extraction yielded an average of 53 µg/µl per sample and RNA extraction yielded 679 ng/µl on average per sample. Proteomic studies showed no degradation of protein, abundant and similar quantities of protein across samples and differentiation between the amnion, decidua, and villi. Histological studies showed good quality for interpretation and occasional pathology including multifocal chronic villitis, meconium laden macrophages, and Stage 2 acute chorioamnionitis. Flow cytometry demonstrated good cell viability after isolation.

A family of DyX4M(12-MCMnIII(N)shi-4) compounds were synthesized and magnetically characterized (X = salicylate, acetate, benzoate, trimethylacetate, M = NaI or KI). The bridging ligands were systematically varied while keeping the remainder of the MC-geometry constant. The type of monovalent cation, necessary for charge balance, was also altered. The dc magnetization and susceptibility of all compounds were similar across the series. Regardless of the identity of the countercation, the Dy(Hsal)4M 12-MC-4 compounds were the only compounds to show frequency-dependent ac magnetic susceptibility, a hallmark of single-molecule magnetism. This indicates that the nature of the bridging ligand in the 12-MCMnIII(N)shi-4 compounds strongly affects the out-of-phase magnetic properties. The SMM behavior appears to correlate with the pKa of the bridging ligand.

Single crystal X-ray structures are presented for three 12-metallacrown-4 complexes, Er III Na ( L ) 4 [ 11 - MC Mn III ( N ) shi - 4 ] , where L is trimethylacetate (OTMA), benzoate (OBen), or salicylate (OSal), MC is metallacrown, and shi3− is salicylhydroximate: ErIIINa(OTMA)4[ 12 - MC Mn III ( N ) shi - 4 ](H2O)3.73(DMF)0.27·7.45DMF·1.47H2O, 1, ErIIINa(OBen)4[ 12 - MC Mn III ( N ) shi - 3 ](H2O)4·4DMF·0.87H2O, 2, and ErIIINa(OSal)4[ 12 - MC Mn III ( N ) shi - 4 ](H2O)3.54(DMF)0.73·4DMF·0.24H2O, 3, where DMF is N,N-dimethylformamide. Compounds 1–3 demonstrate the facile ligand variation of a self-assembled supramolecular coordination complex containing three different metal types. In all three structures, the monoanion carboxylate ligands serve as bridges between the central ErIII ion and the ring MnIII ions. The structures of 1–3 are all domed towards the side of the central Na+ ion, and the 12-MC-4 frameworks of 1–3 are very similar regardless of the monoanion carboxylate bridge, as the metallacrown cavity radii of 1–3 are 0.55 A, 0.54 A, and 0.55 A, respectively. In addition, the cross cavity measurements indicate that the metallacrown frameworks are not significantly altered by the presence of different monoanion carboxylate ligands as the MnIII–MnIII cross cavity distances for 1–3 are 6.52 A, 6.51 A, and 6.49 A, respectively, and the oxime oxygen–oxime oxygen cross cavity distances for 1–3 are 3.71 A, 3.68 A, and 3.69 A, respectively. The conservation of the 12-MC-4 framework among the different structures will be important when assessing the physical and chemical properties of this class of molecules.

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...

More than half of the world is fed and fueled through the Haber-Bosch process, and ammonia consumption and global population continue to grow in tandem. However, resulting nitrogen oxyanion (NOx) waste threatens aquatic ecosystems by feeding harmful algal blooms. Molecular transition metal electrocatalysts are poised to selectively reduce these NOx waste products: macrocyclic complexes are particularly robust to electrocatalytic N–O bond activations. Here, two cobalt-based macrocycles with redox-active ligand frameworks prove capable of reducing nitrate and nitrite, with an intriguing dependence on surface interactions. With an applied potential under monochromatic irradiation, a cobalt(III)-based diiminomethyl macrocycle, [Co(DIM)Br2]+, can more efficiently reduce NO2 – to ammonia by bypassing an auto-destructive ligand-based radical. Similarly, an intermediate with ligand-radical character is active toward NO3 – reduction in cobalt(II) tetraphenylporphyrin (CoTPP) in bulk systems, but can be stabilized in aqueous conditions for more affordable onset potentials once immobilized. Inspired by surface influence, homogeneous and heterogeneous systems are blended into molecular catalyst-support assemblies: physisorbing CoTPP on nanosupports imparts catalyst durability and nitrate electroreduction in coordinating buffers. These hybrid assemblies remarkably improve onset potentials in previously inaccessible conditions, ultimately overcoming many compromises between overpotential and turnover in purely homogeneous designs. Figure 1

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.