Characterization and initial demonstration of efficacy of a novel heat-activated metalloenediyne anti-cancer agent.

Background: Enediynes are anti-cancer agents that are highly cytotoxic due to their propensity for low thermal activation of radical generation. The diradical intermediate produced from Bergman cyclization of the enediyne moiety may induce DNA damage and cell lethality. The cytotoxicity of enediynes and difficulties in controlling their thermal cyclization has limited their clinical use.

Development of Magnesium Oxide-Silver Hybrid Nanocatalysts for Synergistic Carbon Dioxide Activation to Afford Esters and Heterocycles at Ambient Pressure.

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 nanoparticles (noble metal guest) for ambient pressure activation and insertion of CO 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.

Au-Cu@PANI Alloy Core Shells for Aerobic Fibrin Degradation under Visible Light Exposure.

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.

Enhancement of Cytotoxicity of Enediyne Compounds by Hyperthermia: Effects of Various Metal Complexes on Tumor Cells.

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.

Anion Control of Lanthanoenediyne Cyclization.

A suite of lanthanoenediyne complexes of the form Ln(macrocycle)X (Ln = La, Ce, Eu, Gd, Tb, Lu; X = NO, Cl, OTf) was prepared by utilizing an enediyne-containing [2 + 2] hexaaza-macrocycle (). The solid-state Bergman cyclization temperatures, measured via DSC, decrease with the denticity of X (bidentate NO, = 267-292 °C; monodentate Cl, = 238-262 °C; noncoordinating OTf, = 170-183 °C). C NMR characterization shows that the chemical shifts of the acetylenic carbon atoms also rely on the anion identity.

The Outliers: Metal-Mediated Radical Reagents for Biological Substrate Degradation.

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.

Characterization of Thermally Activated Metalloenediyne Cytotoxicity in Human Melanoma Cells.

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 two 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.

Metal-mediated diradical tuning for DNA replication arrest via template strand scission.

A series of M(PyED)·X (X = 2Cl, SO) 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 [Formula: see text] Cu(II) LMCT (22,026 cm) 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.

The role of ligand covalency in the selective activation of metalloenediynes for Bergman cyclization.

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-metal-loenediynes of the form M()·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.

A simple route to diverse noble metal-decorated iron oxide nanoparticles for catalysis.

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.

Chelation-induced diradical formation as an approach to modulation of the amyloid-β aggregation pathway.

Current approaches toward modulation of metal-induced Aβ aggregation pathways involve the development of small molecules that bind metal ions, such as Cu(ii) and Zn(ii), and interact with Aβ. For this effort, we present the enediyne-containing ligand ()-,'-bis[1-pyridin-2-yl-meth()-ylidene]oct-4-ene-2,6-diyne-1,8-diamine (), which upon chelation of Cu(ii) and Zn(ii) undergoes Bergman-cyclization to yield diradical formation. The ability of this chelation-triggered diradical to modulate Aβ aggregation is evaluated relative to the non-radical generating control pyridine-2-ylmethyl-(2-{[(pyridine-2-ylmethylene)-amino]-methyl}-benzyl)-amine ().

Utilizing redox-mediated Bergman cyclization toward the development of dual-action metalloenediyne therapeutics.

Reaction of 2 equiv of 1,2-bis((diphenylphosphino)ethynyl)benzene (dppeb, 1) with Pt(cod)Cl2 followed by treatment with N2H4 yields the reduced Pt(0) metalloenediyne, Pt(dppeb)2, 2. This complex is stable to both air oxidation and metal-mediated Bergman cyclization under ambient conditions due to the nearly idealized tetrahedral geometry. Reaction of 2 with 1 equiv of I2 in the presence of excess 1,4-cyclohexadiene (1,4-CHD) radical trap rapidly and near-quantitatively generates the cis-Bergman-cyclized, diiodo product 3 ((31)P: δ = 41 ppm, J(Pt-P) = 3346 Hz) with concomitant loss of 1 equiv of uncyclized phosphine chelate ((31)P: δ = -33 ppm).

Spin-state control of thermal and photochemical Bergman cyclization.

Thermal Bergman cyclization of Pt(II) dialkynylporphyrins reveals a marked reduction in the cyclization temperature relative to the free base and Zn(II) derivatives. In contrast, photogenerated (3)ππ* population produces no detectable Bergman photocyclization, suggesting that the photoreactivities of the related free base and Zn(II) derivatives occurs via the (1)ππ* state.

Conformational and electronic consequences in crafting extended, π-conjugated, light-harvesting macrocycles.

The synthesis of a new series of free-base, Ni(II) and Zn(II) 2,3,12,13-tetra(ethynyl)-5,10,15,20-tetraphenyl porphyrins is described. Upon heating, two of the four ethynyl moieties undergo Bergman cyclization to afford the monocyclized 2,3-diethynyl-5,20-diphenylpiceno[10,11,12,13,14,15-jklmn]porphyrin in 30 %, 10 %, and trace yields, respectively. The structures of all products were investigated by using quantum chemical calculations and the free-base analogue was isolated and crystallized; all compounds show significant deviation from the idealized planar structure.

Potentiation of metalloenediyne cytotoxicity by hyperthermia.

Purpose: Enediynes are potent inducers of DNA damage, but their clinical usefulness has been limited. Here we report the thermal enhancement of cytotoxicity of two novel metalloenediyne compounds at concentrations that are either not or minimally cytotoxic at 37°C, and present evidence regarding possible mechanisms for enhanced cytotoxicity.

Materials And Methods: HeLa cells were exposed to (Z)-N,N'-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine (PyED) (which becomes metallated in culture medium) or ((Z)-N,N'-bis[quinolin-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine)zinc(II) chloride (QuinED · ZnCl(2)) at 37°C or 42.

Gating the mechanistic pathway to the elusive 4-membered ring azeteoporphyrin.

Photolysis of metalated (Cu and Ni) and free base 2-diazo-3-oxochlorins within a frozen matrix (λ = 457.9 nm, toluene, 80 K) generates a single photointermediate with a hypsochromically shifted electronic absorption spectrum relative to the starting diazochlorins. The appearance of ketene (~2131 cm(-1)) and azete (~1670 cm(-1)) vibrations in infrared absorption and Raman spectra, respectively, identifies this intermediate as resulting from the Wolff rearrangement of the diazochlorins upon N(2) loss.

Modulating the light switch by (3)MLCT-(3)ππ* state interconversion.

The spectroscopic, electronic, and DNA-binding characteristics of two novel ruthenium complexes based on the dialkynyl ligands 2,3-bis(phenylethynyl)-1,4,8,9-tetraaza-triphenylene (bptt, 1) and 2,3-bis(4-tert-butyl-phenylethynyl)-1,4,8,9-tetraaza-triphenylene (tbptt, 2) have been investigated. Electronic structure calculations of bptt reveal that the frontier molecular orbitals are localized on the pyrazine-dialkynyl portion of the free ligand, a property that is reflected in a red shift of the lowest energy electronic transition (1: λ(max) = 393 nm) upon substitution at the terminal phenyl groups (2: λ(max) = 398 nm). Upon coordination to ruthenium, the low-energy ligand-centered transitions of 1 and 2 are retained, and metal-to-ligand charge transfer transitions (MLCT) centered at λ(max) = 450 nm are observed for [Ru(phen)(2)bptt](2+)(3) and [Ru(phen)(2)tbptt](2+)(4).

Expansion by contraction: diversifying the photochemical reactivity scope of diazo-oxochlorins toward development of in situ alkylating agents.

Irradiation of 2-diazo-3-oxochlorins (200 W, lambda > or = 345 nm, 10 degrees C) in the presence of nucleophilic and biomimetic substrates 1-butanol, tosylhydrazine, or tetrahydrofurfuryl alcohol generates Wolff-rearranged, pyrrole ring-contracted azeteoporphyrinoids in 11-34% yield, with the corresponding hydroxyporphyrins in up to 55% yield. For metalated diazo-oxochlorins, these products compete with intramolecular exocyclic ring formation by meso-phenyl ring addition, which occurs in up to 76% yield in the absence of substrate. The dependence of product distribution on substrate is established by photolysis in neat dichlorometane.

Structure modulated electronic contributions to metalloenediyne reactivity: synthesis and thermal Bergman cyclization of MLX2 compounds.

The synthesis of novel metalloendiyne complexes MLRX(2) (where L = 1,4-dibenzyl/diethyl-1,4-diaza-cyclododec-8-ene-6,10-diyne, X = halogen) are reported with their X-ray crystal structures and thermal Bergman cyclization temperatures. Two distinct types of constructs are obtained; the Zn(II) compounds are tetrahedral, while the Cu(II) and the Pd(II) compounds are all distorted- or square-planar. Each possesses structurally similar enediyne conformations and critical distances (3.

Diazo-containing molecular constructs as potential anticancer agents: from diazo[b]fluorene natural products to photoactivatable diazo-oxochlorins.

DNA is an established biological target for many organic natural products that react by alkylation or H-atom abstraction via key functional groups such as cyclopropane, aziridine, enediyne, and terminal diazo functionalities. Remarkably, although more than 20 natural product derivatives compose the latter class, the precise mechanism of action and specific biological target remain to be elucidated. Despite these biochemical uncertainties, more than 100 years of diazo/diazoketone chemistry exists.

Elucidation of the extraordinary 4-membered pyrrole ring-contracted azeteoporphyrinoid as an intermediate in chlorin oxidation.

Reaction of 2,3-dioxochlorins with benzeneselenic anhydride (BSA) results in the formation of unusual ring-contracted azetine derivatives that further react with BSA to afford porpholactones.