Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo

Following recent work on heterometallic titanocene–gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = S–C₆H₄–COO^–) bound to gold(i)-phosphane fragments through a thiolate group [(η-C₅H₅)₂TiMe(μ-mba)Au(PR₃)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound 5 [(η-C₅H₅)₂TiMe(μ-mba)Au(PPh₃)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1 : 1 ratio) in Caki-1 renal cells was demonstrated for 5 indicating the robustness of the heterometallic compound in vitro. Two compounds were selected for further in vivo studies on mice based on their selectivity in vitro against renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg per kg per every other day) with heterometallic compound 5 as compared with the previously described [(η-C₅H₅)₂Ti{OC(O)-4-C₆H₄-P(Ph₂)AuCl}₂] 3 which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect the in vivo efficacy of this class of compounds.     

Mutual stabilisation between MII 4L6 tetrahedra and MIIX4 2– metallate guests

A complex host–guest equilibrium employing metal ions incorporated into both the host and guest is discussed. M^IIX₄ ^2– metallate guests are shown to provide a good size and shape match for encapsulation within the M₄L₆ tetrahedral capsules, facilitating the generation of previously unreported Zn₄L₆ complexes. Displacement of the initial, primary template anion (ZnBr₄ ^2–) by a secondary template anion (ClO₄ ^–) is shown to result in the formation of a pentagonal-prismatic Zn₁₀L₁₅ structure that incorporates both Br^– and ClO₄ ^–. Furthermore, the formation of heterometallic complexes provides direct evidence for metal exchange between the guest and host complex.     

Synthesis and properties of 10-hydroxy-10-oxo-10<Emphasis Type="Italic">H</Emphasis>-10λ<Superscript>5</Superscript>-phenoxaphosphine-2,8-dicarboxylic acid and related polybenzoimidazoles

Oxidation of 10-hydroxy-2,8-dimethyl-10H-10⁵-phenoxaphosphine 10-oxide (1) with potassium permanganate in an alkaline medium afforded 10-hydroxy-10-oxo-10H-10⁵-phenoxaphosphine-2,8-dicarboxylic acid (2). The latter exists as a stable crystal hydrate containing two water molecules. With the aim of examining the possibility of performing the synthesis of polybenzoazoles based on acid 2, the model reaction of the latter with o-phenylenediamine in polyphosphoric acid (PPA) was studied. New high-molecular-weight phosphorus-containing polybenzoimidazoles were prepared by the reaction of 2 with various aromatic tetraamines in PPA and Eatons reagent.     

Catalytic arylsulfonyl radical-triggered 1,5-enyne-bicyclizations and hydrosulfonylation of α,β-conjugates

A catalytic bicyclization reaction of 1,5-enynes anchored by α,β-conjugates with arylsulfonyl radicals generated in situ from sulfonyl hydrazides has been established using TBAI (20 mol%) and Cu(OAc)₂ (5 mol%) as co-catalysts under convenient conditions. In addition, the use of benzoyl peroxide (BPO) as the oxidant and pivalic acid (PivOH) as an additive was proven to be necessary for this reaction. The reactions occurred through 5-exo-dig/6-endo-trig bicyclizations and homolytic aromatic substitution (HAS) cascade mechanisms to give benzo[b]fluorens regioselectively. A similar catalytic process was developed for the synthesis of γ-ketosulfones. These reactions feature readily accessible starting materials and simple one-pot operation.     

Small molecule antagonists of cell-surface heparan sulfate and heparin–protein interactions

Surfen, bis-2-methyl-4-amino-quinolyl-6-carbamide, was previously reported as a small molecule antagonist of heparan sulfate (HS), a key cell-surface glycosaminoglycan found on all mammalian cells. To generate structure–activity relationships, a series of rationally designed surfen analogs was synthesized, where its dimeric structure, exocyclic amines, and urea linker region were modified to probe the role of each moiety in recognizing HS. An in vitro assay monitoring inhibition of fibroblast growth factor 2 binding to wild-type CHO cells was utilized to quantify interactions with cell surface HS. The dimeric molecular structure of surfen and its aminoquinoline ring systems was essential for its interaction with HS, and certain dimeric analogs displayed higher inhibitory potency than surfen and were also shown to block downstream FGF signaling in mouse embryonic fibroblast cells. These molecules were also able to antagonize other HS–protein interactions including the binding of soluble RAGE to HS. Importantly, selected molecules were shown to neutralize heparin and other heparinoids, including the synthetic pentasaccharide fondaparinux, in a factor Xa chromogenic assay and in vivo in mice. These results suggest that small molecule antagonists of heparan sulfate and heparin can be of therapeutic potential for the treatment of disorders involving glycosaminoglycan–protein interactions.     

Unstrained C–C bond activation and directed fluorination through photocatalytically-generated radical cations

Expanding the repertoire of controlled radical fluorination techniques, we present a photosensitized unstrained C–C bond activation/directed monofluorination method using Selectfluor and 9-fluorenone. The reaction is amenable to the opening of multiple 1-acetal-2-aryl substituted rings to yield ω-fluoro carboxylic acids, esters, alcohols, and ketones with relative ease. Initial mechanistic insight suggests radical ion intermediates.     

Domain-swapped cytochrome cb 562 dimer and its nanocage encapsulating a Zn–SO4 cluster in the internal cavity

Protein nanostructures have been gaining in interest, along with developments in new methods for construction of novel nanostructures. We have previously shown that c-type cytochromes and myoglobin form oligomers by domain swapping. Herein, we show that a four-helix bundle protein cyt cb ₅₆₂, with the cyt b ₅₆₂ heme attached to the protein moiety by two Cys residues insertion, forms a domain-swapped dimer. Dimeric cyt cb ₅₆₂ did not dissociate to monomers at 4 °C, whereas dimeric cyt b ₅₆₂ dissociated under the same conditions, showing that heme attachment to the protein moiety stabilizes the domain-swapped structure. According to X-ray crystallographic analysis of dimeric cyt cb ₅₆₂, the two helices in the N-terminal region of one protomer interacted with the other two helices in the C-terminal region of the other protomer, where Lys51–Asp54 served as a hinge loop. The heme coordination structure of the dimer was similar to that of the monomer. In the crystal, three domain-swapped cyt cb ₅₆₂ dimers formed a unique cage structure with a Zn–SO₄ cluster inside the cavity. The Zn–SO₄ cluster consisted of fifteen Zn²⁺ and seven SO₄ ^2– ions, whereas six additional Zn²⁺ ions were detected inside the cavity. The cage structure was stabilized by coordination of the amino acid side chains of the dimers to the Zn²⁺ ions and connection of two four-helix bundle units through the conformation-adjustable hinge loop. These results show that domain swapping can be applied in the construction of unique protein nanostructures.     

Unveiling the nature of supramolecular crown ether–C60 interactions

A series of exTTF-(crown ether)₂ receptors, designed to host C₆₀, has been prepared. The size of the crown ether and the nature of the heteroatoms have been systematically changed to fine tune the association constants. Electrochemical measurements and transient absorption spectroscopy assisted in corroborating charge transfer in the ground state and in the excited state, leading to the formation of radical ion pairs featuring lifetimes in the range from 12 to 21 ps. To rationalize the nature of the exTTF-(crown ether)₂·C₆₀ stabilizing interactions, theoretical calculations have been carried out, suggesting a synergetic interplay of donor–acceptor, π–π, n–π and CH···π interactions, which is the basis for the affinity of our novel receptors towards C₆₀.     

Synthesis and reactivity of cyclo-tetra(stibinophosphonium) tetracations: redox and coordination chemistry of phosphine–antimony complexes

Reductive elimination of [R₃PPR₃]²⁺, [11(R)]²⁺, from the highly electrophilic Sb^III centres in [(R₃P)₃Sb]³⁺, [8(R)]³⁺, gives Sb^I containing cations [(R₃P)Sb]¹⁺, [9(R)]¹⁺, which assemble into frameworks identified as cyclo-tetra(stibinophosphonium) tetracations, [(R₃P)₄Sb₄]⁴⁺, [10(R)]⁴⁺. A phosphine catalyzed mechanism is proposed for conversion of fluoroantimony complexes [(R₃P)₂SbF]²⁺, [7(R)]²⁺, to [10(R)]⁴⁺, and the characterization of key intermediates is presented. The results constitute evidence of a novel ligand activation pathway for phosphines in the coordination sphere of hard, electron deficient acceptors. Characterization of the associated reactants and products supports earlier, albeit less definitive, detection of analogous phosphine ligand activation in Cu^III and Tl^III complexes, demonstrating that these prototypical ligands can behave simultaneously as reducing agents and σ donors towards a variety of hard acceptors. The reactivity of the parent cyclo-tetra(stibinophosphonium) tetracation, [10(Me)]⁴⁺, is directed by high charge concentration and strong polarization of the P–Sb bonds. The former explains the observed facility for reductive elimination to yield elemental antimony and the latter enabled activation of P–Cl and P–H bonds to give phosphinophosphonium cations, [Me₃PPR′2]¹⁺, including the first example of an H-phosphinophosphonium, [(Me₃P)P(H)R′]¹⁺, and 2-phosphino-1,3-diphosphonium cations, [(Me₃P)₂PR′]²⁺. Exchange of a phosphine ligand in [10(Me)]⁴⁺ with [nacnac]^1– gives [(Me₃P)₃Sb₄(nacnac)]³⁺, [15(Me)]³⁺, and with dmap gives [(Me₃P)₃Sb₄(dmap)]⁴⁺, [16]⁴⁺. The lability of P–Sb or Sb–Sb interactions in [10(Me)]⁴⁺ has also been illustrated by characterization of heteroleptically substituted derivatives featuring PMe₃ and PEt₃ ligands.     

A dual catalytic strategy for carbon–phosphorus cross-coupling via gold and photoredox catalysis

A new method for the P-arylation of aryldiazonium salts with H-phosphonates via dual gold and photoredox catalysis is described. The reaction proceeds smoothly at room temperature in the absence of base and/or additives, and offers an efficient approach to arylphosphonates. The reaction is proposed to proceed through a photoredox-promoted generation of an electrophilic arylgold(iii) intermediate that undergoes coupling with the H-phosphonate nucleophile.     

Linear scaling relationships and volcano plots in homogeneous catalysis – revisiting the Suzuki reaction

Linear free energy scaling relationships and volcano plots are common tools used to identify potential heterogeneous catalysts for myriad applications. Despite the striking simplicity and predictive power of volcano plots, they remain unknown in homogeneous catalysis. Here, we construct volcano plots to analyze a prototypical reaction from homogeneous catalysis, the Suzuki cross-coupling of olefins. Volcano plots succeed both in discriminating amongst different catalysts and reproducing experimentally known trends, which serves as validation of the model for this proof-of-principle example. These findings indicate that the combination of linear scaling relationships and volcano plots could serve as a valuable methodology for identifying homogeneous catalysts possessing a desired activity through a priori computational screening.     

A carbon–carbon hybrid – immobilizing carbon nanodots onto carbon nanotubes

The thrust of this work is to integrate small and uniformly sized carbon nanodots (CNDs) with single-walled carbon nanotubes (SWCNT) of different diameters as electron donors and electron acceptors, respectively, and to test their synergetic interactions in terms of optoelectronic devices. CNDs (denoted pCNDs, where p indicates pressure) were prepared by pressure-controlled microwave decomposition of citric acid and urea. pCNDs were immobilized on single-walled carbon nanotubes by wrapping the latter with poly(4-vinylbenzyl trimethylamine) (PVBTA), which features positively charged ammonium groups in the backbone. Negatively charged surface groups on the CNDs lead to attractive electrostatic interactions. Ground state interactions between the CNDs and SWCNTs were confirmed by a full-fledged photophysical investigation based on steady-state and time-resolved techniques. As a complement, charge injection into the SWCNTs upon photoexcitation was investigated by ultra-short time-resolved spectroscopy.     

C–H arylation of triphenylene,naphthalene and related arenes using Pd/C

A highly selective arylation of a number of polyaromatic hydrocarbons (PAHs) with aryliodonium salts and Pd/C as the only reagent is reported. The first C–H functionalization of triphenylene is explored, and proceeds at the most sterically hindered position. This non-chelate assisted C–H functionalization extends the reactivity profile of Pd/C and provides controlled access to π-extended PAHs, an important aspect of work towards the preparation of nanographenes. Mechanistic studies suggest in situ formation of catalytically active insoluble nanoparticles, and that the reaction likely proceeds via a Pd(0)/Pd(ii) type reaction manifold.     

Mechanical and optical properties of ultralarge flakes of a metal–organic framework with molecular thickness

The isolation of 2D-materials is already a success for graphene, graphene oxide, boron nitride and a few clays or metal chalcogenides, however despite the fact that some of them show very interesting physical properties, they lack useful functionalities. Metal–Organic Frameworks (MOFs) are multifunctional materials showing a wide range of physical and chemical properties that can be structurally designed by suitable selection of their building-blocks. This strategy may allow the production of layers with a variety of useful electronic and molecular recognition functionalities. Herein we isolate 2D-MOF flakes with areas of hundreds of square microns and an excellent control of the molecular thickness (from single up to ca. 50 layers). The samples exhibit such good photoluminescence and mechanical properties as to allow free-standing characterization of few layers’ flakes.     

A simple and effective “capping” approach to readily tune the fluorescence of near-infrared cyanines

Heptamethine cyanines are favorable for fluorescence imaging applications in biological systems owing to their near-infrared (NIR) absorption and emission. However, it is very difficult to quench the fluorescence of NIR dyes by the classic photoinduced electron transfer mechanism due to their relatively high-lying occupied molecular orbital energy levels. Herein, we present a simple and effective “capping” approach to readily tune the fluorescence of NIR cyanines. The resulting new functional NIR CyBX (X = O, N, or S) dyes not only retain the intact tricarbocyanine scaffold, but also have a built-in switch to regulate the fluorescence by spiro-cyclization. When compared to traditional cyanines, novel CyBX dyes have a superior character in that their NIR optical properties can be readily tuned by the intrinsic spiro-cyclization mechanism. We expect that this “capping” strategy can be extended across not only the visual spectrum but also to structurally distinct fluorophores.     

Acid/base-regulated reversible electron transfer disproportionation of N–N linked bicarbazole and biacridine derivatives

Regulation of electron transfer on organic substances by external stimuli is a fundamental issue in science and technology, which affects organic materials, chemical synthesis, and biological metabolism. Nevertheless, acid/base-responsive organic materials that exhibit reversible electron transfer have not been well studied and developed, owing to the difficulty in inventing a mechanism to associate acid/base stimuli and electron transfer. We discovered a new phenomenon in which N–N linked bicarbazole (BC) and tetramethylbiacridine (TBA) derivatives undergo electron transfer disproportionation by acid stimulus, forming their stable radical cations and reduced species. The reaction occurs through a biradical intermediate generated by the acid-triggered N–N bond cleavage reaction of BC or TBA, which acts as a two electron acceptor to undergo electron transfer reactions with two equivalents of BC or TBA. In addition, in the case of TBA the disproportionation reaction is highly reversible through neutralization with NEt₃, which recovers TBA through back electron transfer and N–N bond formation reactions. This highly reversible electron transfer reaction is possible due to the association between the acid stimulus and electron transfer via the acid-regulated N–N bond cleavage/formation reactions which provide an efficient switching mechanism, the ability of the organic molecules to act as multi-electron donors and acceptors, the extraordinary stability of the radical species, the highly selective reactivity, and the balance of the redox potentials. This discovery provides new design concepts for acid/base-regulated organic electron transfer systems, chemical reagents, or organic materials.     

Interaction between oxygen and polycrystalline palladium at O<Subscript>2</Subscript> pressures of 10<Superscript>−6</Superscript>–10 Pa

The interaction between oxygen and polycrystalline palladium (Pd(poly)) at \(P_{O_2 } \) = 2.6 × 10^?6–10 Pa and T = 300–1300 K was studied by the thermal desorption (TD) method. The interaction between O₂ and Pd(poly) is governed by the O₂ pressure and the sample temperature. At low pressures of \(P_{O_2 } \) (≤1.3 × 10^?5 Pa), O₂ is chemisorbed dissociatively on the Pd(poly) surface. During chemisorption, the O_ads-surface bond energy and the O₂ sticking coefficient gradually decrease as the surface coverage θ increases. At \(P_{O_2 } \) ≥ 10^?2 Pa and T ≤ 500 K, after the saturation of the O_ads layer (θ ～ 0.5), O_ads atoms penetrate under the surface layer of the metal to form surface palladium oxide. At \(P_{O_2 } \) ≥ 1 Pa and T > 500 K, after the saturation of the surface oxide film 2 ML in thickness (n ～ 2), O_ads atoms penetrate into the oxide film and then into the subsurface palladium layer and diffuse deep into the metal bulk. As a result, the oxygen uptake at 700 K is n ～ 50. Upon heating, the surface oxides decompose, desorbing O₂, which gives rise to a low-temperature TD peak with T _max = 715 K. The release of oxygen inserted in the subsurface layers of palladium shows itself as a distinct high-temperature TD peak with T _max ≥ 750 K.     

Task-specific ionic liquid and CO2-cocatalysed efficient hydration of propargylic alcohols to α-hydroxy ketones

The hydration of propargylic alcohols is a green route to synthesize α-hydroxy ketones. Herein a CO₂-reactive ionic liquid (IL), [Bu₄P][Im], was found to display high performance for catalyzing the hydration of propargylic alcohols in the presence of atmospheric CO₂, and a series of propargylic alcohols could be converted into the corresponding α-hydroxy ketones in good to excellent yields. In the IL/CO₂ reaction system, CO₂ served as a cocatalyst by forming α-alkylidene cyclic carbonates with propargylic alcohols, and was released via the rapid hydrolysis of the carbonates catalysed by the IL. This is the first example of the efficient hydration of propargylic alcohols under metal-free conditions.     

Palladium-catalyzed cross-coupling of α-bromocarbonyls and allylic alcohols for the synthesis of α-aryl dicarbonyl compounds

The palladium-catalyzed coupling of olefins and organohalides is a versatile approach for synthesizing complex molecules from simple starting materials. We have developed a palladium-catalyzed coupling of α-bromocarbonyl compounds with allylic alcohols for the generation of acyclic aryl-substituted dicarbonyl compounds. The reaction proceeds via a tandem olefin insertion of an α-acyl radical followed by a 1,2-aryl migration. In addition to providing preliminary evidence for a free radical mediated mechanism, we demonstrate unprecedented levels of 1,3-stereoinduction for the 1,2-migration step.     

Quantum Chemical Study of Niobium and Tantalum M<Subscript>4</Subscript>O<Subscript>10</Subscript> Oxide Clusters and M<Subscript>4</Subscript>O<Stack><Subscript>10</Subscript><Superscript>–</Superscript></Stack> Anions

Structural parameters and vibrational frequencies of the clusters (T_d)–Nb₄O₁₀, (C_3v)-TaNb₃O₁₀, (D_2d)-Nb₄O ₁₀ ^– , and (C_s)-TaNb₃O ₁₀ ^– were calculated. According to the (U)DFT/SDD calculations with BLYP, B3LYP, and PBE0 functionals magnetization of the anion (D_2d)-Nb₄O ₁₀ ^– is distributed equally among four niobium atoms. In the anion (C_s)-TaNb₃O ₁₀ ^– unpaired electron presumably occupies niobium atoms. The distinction in contributions from Nb atoms in the magnetization of the tantalum-containing cluster grows with the exchange component of the DFT functional in the series of functionals BLYP < B3LYP < PBE0 < UHF.