Metal–metal bonded alkaline-earth distannyls

The first families of alkaline-earth stannylides [Ae(SnPh₃)₂·(thf)_x] (Ae = Ca, x = 3, 1; Sr, x = 3, 2; Ba, x = 4, 3) and [Ae{Sn(SiMe₃)₃}₂·(thf)_x] (Ae = Ca, x = 4, 4; Sr, x = 4, 5; Ba, x = 4, 6), where Ae is a large alkaline earth with direct Ae–Sn bonds, are presented. All complexes have been characterised by high-resolution solution NMR spectroscopy, including ¹¹⁹Sn NMR, and by X-ray diffraction crystallography. The molecular structures of [Ca(SnPh₃)₂·(thf)₄] (1′), [Sr(SnPh₃)₂·(thf)₄] (2′), [Ba(SnPh₃)₂·(thf)₅] (3′), 4, 5 and [Ba{Sn(SiMe₃)₃}₂·(thf)₅] (6′), most of which crystallised as higher thf solvates than their parents 1–6, were established by XRD analysis; the experimentally determined Sn–Ae–Sn′ angles lie in the range 158.10(3)–179.33(4)°. In a given series, the ¹¹⁹Sn NMR chemical shifts are slightly deshielded upon descending group 2 from Ca to Ba, while the silyl-substituted stannyls are much more shielded than the phenyl ones (δ¹¹⁹Sn/ppm: 1′, −133.4; 2′, −123.6; 3′, −95.5; 4, −856.8; 5, −848.2; 6′, −792.7). The bonding and electronic properties of these complexes were also analysed by DFT calculations. The combined spectroscopic, crystallographic and computational analysis of these complexes provide some insight into the main features of these unique families of homoleptic complexes. A comprehensive DFT study (Wiberg bond index, QTAIM and energy decomposition analysis) points at a primarily ionic Ae–Sn bonding, with a small covalent contribution, in these series of complexes; the Sn–Ae–Sn′ angle is associated with a flat energy potential surface around its minimum, consistent with the broad range of values determined by experimental and computational methods.

The complete series of heterobimetallic alkaline-earth distannyls [Ae{SnR₃}₂·(thf)_x] (Ae = Ca, Sr, Ba) have been prepared for R = Ph and SiMe₃, and their bonding and electronic properties have been comprehensively investigated.     

Cytotoxic Flavonoids from the Leaves and Twigs of Murraya tetramera

Cytotoxic flavonoids of Murraya tetramera were investigated in this study. A novel flavonoid and twelve known flavonoids, including seven flavones (1–7), three flavanones (8–10), and three chalcones (11–13) were isolated from the leaves and twigs of Murraya tetramera. Chemical structures were elucidated by NMR combined with MS spectral analysis, and the new compound (6) was confirmed as 3′,5′-dihydroxy-5,6,7,4′-tetramethoxyflavone. Furthermore, all the isolated flavonoids were evaluated for their cytotoxicities against murine melanoma cells (B16), and human breast cancer cells (MDA-MB-231) by CCK-8 assay. Among them, compounds 7, 13, and 5 exhibited potent cytotoxic activities against B16 cell lines (IC₅₀ = 3.87, 7.00 and 8.66 μg/mL, respectively). Compounds 5, 13, and 12 displayed potent cytotoxicities against MDA-MB-231 cell lines (IC₅₀ = 3.80, 5.95 and 7.89 μg/mL, respectively). According to the correlation of the structure and activity analysis, 5-hydroxyl and 8-methoxyl substituents of the flavone, 8-methoxyl substituent of the flavanone, and 3′,5′-methoxyl substituents of the chalcone could be critical factors of the high cytotoxicity. The results indicated that the active flavonoids have potential to be developed as leading compounds for treating cancers.     

Oxy-Polybrominated Diphenyl Ethers from the Indonesian Marine Sponge,Lamellodysidea herbacea: X-ray,SAR, and Computational Studies

Polybrominated diphenyl ether (PBDE) compounds, derived from marine organisms, originate from symbiosis between marine sponges and cyanobacteria or bacteria. PBDEs have broad biological spectra; therefore, we analyzed structure and activity relationships of PBDEs to determine their potential as anticancer or antibacterial lead structures, through reactions and computational studies. Six known PBDEs (1–6) were isolated from the sponge, Lamellodysdiea herbacea; ¹³C NMR data for compound 6 are reported for the first time and their assignments are confirmed by their theoretical ¹³C NMR chemical shifts (RMSE < 4.0 ppm). Methylation and acetylation of 1 (2, 3, 4, 5-tetrabromo-6-(3′, 5′-dibromo-2′-hydroxyphenoxy) phenol) at the phenol functional group gave seven molecules (7–13), of which 10, 12, and 13 were new. New crystal structures for 8 and 9 are also reported. Debromination carried out on 1 produced nine compounds (1, 2, 14, 16–18, 20, 23, and 26) of which 18 was new. Debromination product 16 showed a significant IC₅₀ 8.65 ± 1.11; 8.11 ± 1.43 µM against human embryonic kidney (HEK293T) cells. Compounds 1 and 16 exhibited antibacterial activity against Gram-positive Staphylococcus aureus and Gram-negative Klebsiella pneumoniae with MID 0.078 µg/disk. The number of four bromine atoms and two phenol functional groups are important for antibacterial activity (S. aureus and K. pneumoniae) and cytotoxicity (HEK293T). The result was supported by analysis of frontier molecular orbitals (FMOs). We also propose possible products of acetylation and debromination using analysis of FMOs and electrostatic charges and we confirm the experimental result.     

Unexpected effect of catalyst concentration on photochemical CO2 reduction by trans(Cl)–Ru(bpy)(CO)2Cl2: new mechanistic insight into the CO/HCOO– selectivity

Photochemical CO₂ reduction catalysed by trans(Cl)–Ru(bpy)(CO)₂Cl₂ (bpy = 2,2′-bipyridine) efficiently produces carbon monoxide (CO) and formate (HCOO^–) in N,N-dimethylacetamide (DMA)/water containing [Ru(bpy)₃]²⁺ as a photosensitizer and 1-benzyl-1,4-dihydronicotinamide (BNAH) as an electron donor. We have unexpectedly found catalyst concentration dependence of the product ratio (CO/HCOO^–) in the photochemical CO₂ reduction: the ratio of CO/HCOO^– decreases with increasing catalyst concentration. The result has led us to propose a new mechanism in which HCOO^– is selectively produced by the formation of a Ru(i)–Ru(i) dimer as the catalyst intermediate. This reaction mechanism predicts that the Ru–Ru bond dissociates in the reaction of the dimer with CO₂, and that the insufficient electron supply to the catalyst results in the dominant formation of HCOO^–. The proposed mechanism is supported by the result that the time-course profiles of CO and HCOO^– in the photochemical CO₂ reduction catalysed by [Ru(bpy)(CO)₂Cl]₂ (0.05 mM) are very similar to those of the reduction catalysed by trans(Cl)–Ru(bpy)(CO)₂Cl₂ (0.10 mM), and that HCOO^– formation becomes dominant under low-intensity light. The kinetic analyses based on the proposed mechanism could excellently reproduce the unusual catalyst concentration effect on the product ratio. The catalyst concentration effect observed in the photochemical CO₂ reduction using [Ru(4dmbpy)₃]²⁺ (4dmbpy = 4,4′-dimethyl-2,2′-bipyridine) instead of [Ru(bpy)₃]²⁺ as the photosensitizer is also explained with the kinetic analyses, reflecting the smaller quenching rate constant of excited [Ru(4dmbpy)₃]²⁺ by BNAH than that of excited [Ru(bpy)₃]²⁺. We have further synthesized trans(Cl)–Ru(6Mes-bpy)(CO)₂Cl₂ (6Mes-bpy = 6,6′-dimesityl-2,2′-bipyridine), which bears bulky substituents at the 6,6′-positions in the 2,2′-bipyridyl ligand, so that the ruthenium complex cannot form the dimer due to the steric hindrance. We have found that this ruthenium complex selectively produces CO, which strongly supports the catalytic mechanism proposed in this work.     

Isolation,Structure Elucidation and In Silico Prediction of Potential Drug-Like Flavonoids from Onosma chitralicum Targeted towards Functionally Important Proteins of Drug-Resistant Bad Bugs

Admittedly, the disastrous emergence of drug resistance in prokaryotic and eukaryotic human pathogens has created an urgent need to develop novel chemotherapeutic agents. Onosma chitralicum is a source of traditional medicine with cooling, laxative, and anthelmintic effects. The objective of the current research was to analyze the biological potential of Onosma chitralicum, and to isolate and characterize the chemical constituents of the plant. The crude extracts of the plant prepared with different solvents, such as aqueous, hexane, chloroform_, ethyl acetate, and butanol, were subjected to antimicrobial activities. Results corroborate that crude (methanol), EtoAc, and n-C₆H₁₄ fractions were more active against bacterial strains. Among these fractions, the EtoAc fraction was found more potent. The EtoAc fraction was the most active against the selected microbes, which was subjected to successive column chromatography, and the resultant compounds 1 to 7 were isolated. Different techniques, such as UV, IR, and NMR, were used to characterize the structures of the isolated compounds 1–7. All the isolated pure compounds (1–7) were tested for their antimicrobial potential. Compounds 1 (4′,8-dimethoxy-7-hydroxyisoflavone), 6 (5,3′,3-trihydroxy-7,4′-dimethoxyflavanone), and 7 (5′,7,8-trihydroxy-6,3′,4′-trimethoxyflavanone) were found to be more active against Staphylococcus aureus and Salmonella Typhi. Compound 1 inhibited S. typhi and S. aureus to 10 ± 0.21 mm and 10 ± 0.45 mm, whereas compound 6 showed inhibition to 10 ± 0.77 mm and 9 ± 0.20 mm, respectively. Compound 7 inhibited S. aureus to 6 ± 0.36 mm. Compounds 6 and 7 showed significant antibacterial potential, and the structure–activity relationship also justifies their binding to the bacterial enzymes, i.e., beta-hydroxyacyl dehydratase (HadAB complex) and tyrosyl-tRNA synthetase. Both bacterial enzymes are potential drug targets. Further, the isolated compounds were found to be active against the tested fungal strains. Whereas docking identified compound 7, the best binder to the lanosterol 14α-demethylase (an essential fungal cell membrane synthesizing enzyme), reported as an antifungal fluconazole binding enzyme. Based on our isolation-linked preliminary structure-activity relationship (SAR) data, we conclude that O. chitralicum can be a good source of natural compounds for drug development against some potential enzyme targets.     

New Flavone C-Glycosides from Scleranthus perennis and Their Anti-Collagenase Activity

Three new flavone glycosides, one known flavone glycoside, and the phenolic derivative apiopaenonside were isolated and identified from the ethyl acetate fraction of the aerial parts of Scleranthus perennis. The planar structures were elucidated through extensive analysis of UV-Vis, IR, and ¹H NMR and ¹³C NMR spectral data, including the 2D techniques COSY, HSQC, and HMBC, as well as ESI mass spectrometry. The isolated compounds were established as 5,7,3′-trihydroxy-4′-acetoxyflavone-8-C-β-d-xylopyranoside-2′′-O-glucoside (1), 5,7,3′-trihydroxy-4′-methoxyflavone-8-C-β-d-xylopyranoside-2′′-O-glucoside (2), 5,7-dihydroxy-3′-methoxy-4′-acetoxyflavone-8-C-β-d-xylopyranoside-2′′-O-glucoside (3), 5,7-dihydroxy-3′-methoxy-4′-acetoxyflavone-8-C-β-d-xylopyranoside-2′′-O-(4′′′-acetoxy)-glucoside (4), and apiopaenonside (5). Moreover, all isolated compounds were evaluated for anti-collagenase activity. All compounds exhibited moderate inhibitory activity with IC₅₀ values ranging from 36.06 to 70.24 µM.     

Synthesis,Neuroprotection, and Antioxidant Activity of 1,1′-Biphenylnitrones as α-Phenyl-N-tert-butylnitrone Analogues in In Vitro Ischemia Models

Herein, we report the neuroprotective and antioxidant activity of 1,1′-biphenyl nitrones (BPNs) 1–5 as α-phenyl-N-tert-butylnitrone analogues prepared from commercially available [1,1′-biphenyl]-4-carbaldehyde and [1,1′-biphenyl]-4,4′-dicarbaldehyde. The neuroprotection of BPNs 1-5 has been measured against oligomycin A/rotenone and in an oxygen–glucose deprivation in vitro ischemia model in human neuroblastoma SH-SY5Y cells. Our results indicate that BPNs 1–5 have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN), and they are quite similar to N-acetyl-L-cysteine (NAC), which is a well-known antioxidant agent. Among the nitrones studied, homo-bis-nitrone BPHBN5, bearing two N-tert-Bu radicals at the nitrone motif, has the best neuroprotective capacity (EC₅₀ = 13.16 ± 1.65 and 25.5 ± 3.93 μM, against the reduction in metabolic activity induced by respiratory chain blockers and oxygen–glucose deprivation in an in vitro ischemia model, respectively) as well as anti-necrotic, anti-apoptotic, and antioxidant activities (EC₅₀ = 11.2 ± 3.94 μM), which were measured by its capacity to reduce superoxide production in human neuroblastoma SH-SY5Y cell cultures, followed by mononitrone BPMN3, with one N-Bn radical, and BPMN2, with only one N-tert-Bu substituent. The antioxidant activity of BPNs 1-5 has also been analyzed for their capacity to scavenge hydroxyl free radicals (82% at 100 μM), lipoxygenase inhibition, and the inhibition of lipid peroxidation (68% at 100 μM). Results showed that although the number of nitrone groups improves the neuroprotection profile of these BPNs, the final effect is also dependent on the substitutent that is being incorporated. Thus, BPNs bearing N-tert-Bu and N-Bn groups show better neuroprotective and antioxidant properties than those substituted with Me. All these results led us to propose homo-bis-nitrone BPHBN5 as the most balanced and interesting nitrone based on its neuroprotective capacity in different neuronal models of oxidative stress and in vitro ischemia as well as its antioxidant activity.     

New Bifunctional Bis(azairidacycle) with Axial Chirality via Double Cyclometalation of 2,2′-Bis(aminomethyl)-1,1′-binaphthyl

As a candidate for bifunctional asymmetric catalysts containing a half-sandwich C–N chelating Ir(III) framework (azairidacycle), a dinuclear Ir complex with an axially chiral linkage is newly designed. An expedient synthesis of chiral 2,2′-bis(aminomethyl)-1,1′-binaphthyl (1) from 1,1-bi-2-naphthol (BINOL) was accomplished by a three-step process involving nickel-catalyzed cyanation and subsequent reduction with Raney-Ni and KBH₄. The reaction of (S)-1 with an equimolar amount of [IrCl₂Cp*]₂ (Cp* = η⁵–C₅(CH₃)₅) in the presence of sodium acetate in acetonitrile at 80 °C gave a diastereomeric mixture of new dinuclear dichloridodiiridium complexes (5) through the double C–H bond cleavage, as confirmed by ¹H NMR spectroscopy. A loss of the central chirality on the Ir centers of 5 was demonstrated by treatment with KOC(CH₃)₃ to generate the corresponding 16e amidoiridium complex 6. The following hydrogen transfer from 2-propanol to 6 provided diastereomers of hydrido(amine)iridium retaining the bis(azairidacycle) architecture. The dinuclear chlorido(amine)iridium 5 can serve as a catalyst precursor for the asymmetric transfer hydrogenation of acetophenone with a substrate to a catalyst ratio of 200 in the presence of KOC(CH₃)₃ in 2-propanol, leading to (S)-1-phenylethanol with up to an enantiomeric excess (ee) of 67%.     

Flavones from Combretum quadrangulare Growing in Vietnam and Their Alpha-Glucosidase Inhibitory Activity

Combretum quadrangulare Kurz is widely used in folk medicine in Eastern Asia and is associated with various ethnopharmacological properties including hepatoprotective, antipyretic, analgesic, antidysenteric, and anthelmintic activities. Previous phytochemical investigations reported the presence of numerous triterpenes (mostly cycloartanes, ursanes, lupanes, and oleananes) along with dozens of flavonoids. However, the extracts of C. quadrangulare and isolated flavonoids have not been evaluated for their alpha-glucosidase inhibition. In the frame of our efforts dedicated to the chemical investigation of Vietnamese medicinal plants and their biological activities, a phytochemical study of the MeOH extract of the leaves of C. quadrangulare using bioactive guided isolation was undertaken. In this paper, the isolation and structure elucidation of twelve known compounds, 5-hydroxy-3,7,4′-trimethoxyflavone (1), ayanin (2), kumatakenin (3), rhamnocitrin (4), ombuin (5), myricetin-3,7,3′,5′-tetramethyl ether (6), gardenin D (7), luteolin (12), apigenin (13), mearnsetin (14), isoorientin (15), and vitexin (16) were reported. Bromination was applied to compounds 2 and 3 to provide four new synthetic analogues 8–11. All isolated and synthesized compounds were evaluated for alpha-glucosidase inhibition and antibacterial activity. Compounds 4 and 5 showed moderate antibacterial activity against methicillin-resistant Staphylococcus aureus while others were inactive. All compounds failed to reveal any activity toward extended spectrum beta-lactamase-producing Escherichia coli. Compounds 2, 4, 6–9, and 11–14 showed good alpha-glucosidase inhibition with IC₅₀ values in the range of 30.5–282.0 µM. The kinetic of enzyme inhibition showed that 8 and 11 were noncompetitive type inhibition against alpha-glucosidase. In silico molecular docking model indicated that compounds 8 and 11 were potential inhibitors against enzyme α-glucosidase.     

An Alternative Preparation of 1-(N,N-Dimethylaminomethyl)-1′-(diphenylphosphanyl)ferrocene: Synthesis and Structural Characterization of AuI and PdII Complexes with this Hybrid Ligand

1-(N,N-Dimethylaminomethyl)-1′-(diphenylphosphanyl)ferrocene (1) was synthesized in good yield by lithiation of 1-bromo-1′-(diphenylphosphanyl)ferrocene and subsequent reaction with Eschenmoser''s salt (dimethylmethylideneammonium iodide). Making use of an easily accessible, nontoxic starting material, this procedure represents a convenient alternative to the original synthetic protocol based on stepwise lithiation/functionalization of 1,1′-bis(tributylstannyl)ferrocene and reductive amination [M. E. Wright, Organometallics 1990, 9, 853–856]. Compound 1 has typical hybrid-donor properties. When reacted with [AuCl(tht)] (tht=tetrahydrothiophene), it afforded the expected Au^I phosphane complex [AuCl(1-κP)] (2). An attempted removal of the chloride ligand from 2 with AgClO₄ produced an ill-defined material formulated as Au(1)ClO₄. The uncoordinated amine substituent reacted with traces of hydrogen chloride formed by slow decomposition typically occurring in solution. In this manner, complexes [AuCl(Ph₂PfcCH₂NHMe₂)]Cl (3, fc=ferrocene-1,1′-diyl) and [AuCl(Ph₂PfcCH₂NHMe₂)]ClO₄ (4) were isolated from crystallizations experiments with 2 and Au(1)ClO₄, respectively. On a larger scale, complex 3 was prepared easily from 2 and hydrogen chloride. The course of reactions between [PdCl₂(cod)] (cod=cycloocta-1,5-diene) and 1 were found to depend on the ligand-to-metal ratio. Whereas the reaction with two equivalents of 1 afforded bis(phosphane) complex trans-[PdCl₂(1-κP)₂] (5), that of a Pd:P ratio 1:1 produced ligand-bridged dimer [(μ-1)PdCl₂]₂ (6). With hydrogen chloride, complex 6 reacted to afford zwitterionic complex [PdCl₃(1H-κP)] (7), which was also formed when ligand 1 and [PdCl₂(cod)] were allowed to react slowly by liquid-phase diffusion of their chloroform solutions. The compounds were characterized by spectroscopic methods (multinuclear NMR and ESI–MS), and the molecular structures of complex 2–4, 6⋅2CHCl₃ and 7⋅1.5CHCl₃ were determined by single-crystal X-ray diffraction analysis.     

Secoiridoid Glucosides and Anti-Inflammatory Constituents from the Stem Bark of Fraxinus chinensis

Qin Pi (Fraxinus chinensis Roxb.) is commercially used in healthcare products for the improvement of intestinal function and gouty arthritis in many countries. Three new secoiridoid glucosides, (8E)-4′′-O-methylligstroside (1), (8E)-4′′-O-methyldemethylligstroside (2), and 3′′,4′′-di-O-methyl-demethyloleuropein (3), have been isolated from the stem bark of Fraxinus chinensis, together with 23 known compounds (4–26). The structures of the new compounds were established by spectroscopic analyses (1D, 2D NMR, IR, UV, and HRESIMS). Among the isolated compounds, (8E)-4′′-O-methylligstroside (1), (8E)-4′′-O-methyldemethylligstroside (2), 3′′,4′′-di-O-methyldemethyloleuropein (3), oleuropein (6), aesculetin (9), isoscopoletin (11), aesculetin dimethyl ester (12), fraxetin (14), tyrosol (21), 4-hydroxyphenethyl acetate (22), and (+)-pinoresinol (24) exhibited inhibition (IC₅₀ ≤ 7.65 μg/mL) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leuckyl-L-phenylalanine/cytochalasin B (fMLP/CB). Compounds 1, 9, 11, 14, 21, and 22 inhibited fMLP/CB-induced elastase release with IC₅₀ ≤ 3.23 μg/mL. In addition, compounds 2, 9, 11, 14, and 21 showed potent inhibition with IC₅₀ values ≤ 27.11 μM, against lipopolysaccharide (LPS)-induced nitric oxide (NO) generation. The well-known proinflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), were also inhibited by compounds 1, 9, and 14. Compounds 1, 9, and 14 displayed an anti-inflammatory effect against NO, TNF-α, and IL-6 through the inhibition of activation of MAPKs and IκBα in LPS-activated macrophages. In addition, compounds 1, 9, and 14 stimulated anti-inflammatory M2 phenotype by elevating the expression of arginase 1 and Krüppel-like factor 4 (KLF4). The above results suggested that compounds 1, 9, and 14 could be considered as potential compounds for further development of NO production-targeted anti-inflammatory agents.     

Activity of Compounds from Temperate Propolis against Trypanosoma brucei and Leishmania mexicana

Ethanolic extracts of samples of temperate zone propolis, four from the UK and one from Poland, were tested against three Trypanosoma brucei strains and displayed EC₅₀ values < 20 µg/mL. The extracts were fractionated, from which 12 compounds and one two-component mixture were isolated, and characterized by NMR and high-resolution mass spectrometry, as 3-acetoxypinobanksin, tectochrysin, kaempferol, pinocembrin, 4′-methoxykaempferol, galangin, chrysin, apigenin, pinostrobin, cinnamic acid, coumaric acid, cinnamyl ester/coumaric acid benzyl ester (mixture), 4′,7-dimethoxykaempferol, and naringenin 4′,7-dimethyl ether. The isolated compounds were tested against drug-sensitive and drug-resistant strains of T. brucei and Leishmania mexicana, with the highest activities ≤ 15 µM. The most active compounds against T. brucei were naringenin 4′,7 dimethyl ether and 4′methoxy kaempferol with activity of 15–20 µM against the three T. brucei strains. The most active compounds against L. mexicana were 4′,7-dimethoxykaempferol and the coumaric acid ester mixture, with EC₅₀ values of 12.9 ± 3.7 µM and 13.1 ± 1.0 µM. No loss of activity was found with the diamidine- and arsenical-resistant or phenanthridine-resistant T. brucei strains, or the miltefosine-resistant L. mexicana strain; no clear structure activity relationship was observed for the isolated compounds. Temperate propolis yields multiple compounds with anti-kinetoplastid activity.     

Saccharpiscinols A–C: Flavans with Potential Anti-Inflammatory Activities from One Actinobacteria Saccharomonospora piscinae

Phytochemical investigation and chromatographic separation of extracts from the actinobacteria strain Saccharomonospora piscinae that was isolated from dried fishpond sediment of Kouhu township, in the south of Taiwan, led to the isolation of three new compounds, saccharpiscinols A–C (1–3, respectively), and three new natural products, namely (2S)-5,7,3′,4′-tetrahydroxy-6,8-dimethylflavanone (4), methyl-4-hydroxy-2-methoxy-6-methylbenzoate (5), and (±)-7-acetyl-4,8-dihydroxy-6-methyl-1-tetralone (6). Compounds 4–6 were reported before as synthesized products, herein, they are reported from nature for the first time. The structures of the new compounds were unambiguously elucidated on the basis of extensive spectroscopic data analysis (1D- and 2D-NMR, MS, and UV) and comparison with literature data. The effect of some isolates on the inhibition of NO production in lipopolysaccharide-activated RAW 264.7 murine macrophages was evaluated. Saccharpiscinol A showed inhibitory activities against LPS-induced NO production.     

2,2′-Bipyridyl formation from 2-arylpyridines through bimetallic diyttrium intermediate

An alkylyttrium complex supported by an N,N′-bis(2,6-diisopropylphenyl)ethylenediamido ligand, (ArNCH₂CH₂NAr)Y(CH₂SiMe₃)(THF)₂ (1, Ar = 2,6-ⁱPr₂C₆H₃), activated an ortho-phenyl C–H bond of 2-phenylpyridine (2a) to form a (2-pyridylphenyl)yttrium complex (3a) containing a five-membered metallacycle. Subsequently, a unique C(sp²)–C(sp²) coupling of 2-phenylpyridine proceeded through a bimetallic yttrium intermediate, derived from an intramolecular shift of the yttrium center to an ortho-position of the pyridine ring in 3a, to yield a bimetallic yttrium complex (4a) bridged by two-electron reduced 6,6′-diphenyl-2,2′-bipyridyl. Aryl substituents at the ortho-position of the pyridine ring were key in order to destabilize the μ,κ²-(C,N)-pyridyldiyttrium intermediate prior to the C(sp²)–C(sp²) bond formation.     

Taming the beast: fluoromesityl groups induce a dramatic stability enhancement in boroles

The electron-deficient pentaarylborole 1-(2′,4′,6′-tris(trifluoromethyl)phenyl)-2,3,4,5-tetraphenylborole (1) has been synthesised with the long-term aim of developing borole-based optoelectronic materials. The bulky 2,4,6-tris(trifluoromethyl)phenyl (FMes) group on the boron atom of 1 significantly improves (>600 times) its air stability relative to its mesityl analogue. Moreover, 1 shows good thermal stability without undergoing the dimerisation or isomerisation reactions reported for some other boroles. A triarylborole analogue (2), belonging to a new class of borole with the 3- and 4-positions of the BC₄ ring linked by a –(CH₂)₃– group, has also been synthesised to elucidate the influence of carbon-bonded substituents on the stability of boroles. Both boroles were prepared through the reaction of Li[FMesBF₃] and divinyldilithium reagents, a new and general method for borole syntheses. Compound 2 was found to isomerise through a [1,3]-H shift and double-bond rearrangement to an s-trans-butadienylborane species under highly basic (NaOH) conditions. The increased steric crowding at the boron centre through incorporation of the FMes group does not preclude binding of Lewis bases to either 1 or 2, as demonstrated by their fully reversible binding of pyridine. Interestingly, 1 exhibits a blue-shifted absorption spectrum, as compared with its mesityl analogue, a result contrary to previous understanding of the influence of substituent electronics on the absorption spectra of boroles. Most importantly, these boroles exhibit much greater air-stability than previously reported analogues without sacrificing the strong electron-accepting ability that makes boroles so attractive; indeed, 1 and 2 have very low reduction potentials of –1.52 and –1.69 eV vs. Fc/Fc⁺, respectively.     

Trifluoromethyl substitution enhances photoinduced activity against breast cancer cells but reduces ligand exchange in Ru(ii) complex

A series of five ruthenium complexes containing triphenyl phosphine groups known to enhance both cellular penetration and photoinduced ligand exchange, cis-[Ru(bpy)₂(P(p-R-Ph)₃)(CH₃CN)]²⁺, where bpy = 2,2′-bipyridine and P(p-R-Ph)₃ represent para-substituted triphenylphosphine ligands with R = –OCH₃ (1), –CH₃ (2) –H (3), –F (4), and –CF₃ (5), were synthesized and characterized. The photolysis of 1–5 in water with visible light (λ_irr ≥ 395 nm) results in the substitution of the coordinated acetonitrile with a solvent molecule, generating the corresponding aqua complex as the single photoproduct. A 3-fold variation in quantum yield was measured with 400 nm irradiation, Φ₄₀₀, where 1 is the most efficient with a Φ₄₀₀ = 0.076(2), and 5 the least photoactive complex, with Φ₄₀₀ = 0.026(2). This trend is unexpected based on the red-shifted metal-to-ligand charge transfer (MLCT) absorption of 1 as compared to that of 5, but can be correlated to the substituent Hammett para parameters and pK_a values of the ancillary phosphine ligands. Complexes 1–5 are not toxic towards the triple negative breast cancer cell line MDA-MB-231 in the dark, but 3 and 5 are >4.2 and >19-fold more cytotoxic upon irradiation with blue light, respectively. A number of experiments point to apoptosis, and not to necrosis or necroptosis, as the mechanism of cell death by 5 upon irradiation. These findings provide a foundation for understanding the role of phosphine ligands on photoinduced ligand substitution and show the enhancement afforded by –CF₃ groups on photochemotherapy, which will aid the future design of photocages for photochemotherapeutic drug delivery.

Ru(ii) complexes exhibit photoinduced exchange of coordinated CH₃CN and photocytotoxicity against breast cancer cells highly dependent on the substituents of the ancillary triphenylphospine ligand.     

Synthesis,Biomacromolecular Interactions,Photodynamic NO Releasing and Cellular Imaging of Two [RuCl(qn)(Lbpy)(NO)]X Complexes

Two light-activated NO donors [RuCl(qn)(Lbpy)(NO)]X with 8-hydroxyquinoline (qn) and 2,2′-bipyridine derivatives (Lbpy) as co-ligands were synthesized (Lbpy₁ = 4,4′-dicarboxyl-2,2′-dipyridine, X = Cl⁻ and Lbpy₂ = 4,4′-dimethoxycarbonyl-2,2′-dipyridine, X = NO₃⁻), and characterized using ultraviolet–visible (UV-vis) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, nuclear magnetic resonance (¹H NMR), elemental analysis and electrospray ionization mass spectrometry (ESI-MS) spectra. The [RuCl(qn)(Lbpy₂)(NO)]NO₃ complex was crystallized and exhibited distorted octahedral geometry, in which the Ru–N(O) bond length was 1.752(6) Å and the Ru–N–O angle was 177.6(6)°. Time-resolved FT-IR and electron paramagnetic resonance (EPR) spectra were used to confirm the photoactivated NO release of the complexes. The binding constant (K_b) of two complexes with human serum albumin (HSA) and DNA were quantitatively evaluated using fluorescence spectroscopy, Ru-Lbpy₁ (K_b~10⁶ with HSA and ~10⁴ with DNA) had higher affinity than Ru-Lbpy₂. The interactions between the complexes and HSA were investigated using matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) and EPR spectra. HSA can be used as a carrier to facilitate the release of NO from the complexes upon photoirradiation. The confocal imaging of photo-induced NO release in living cells was successfully observed with a fluorescent NO probe. Moreover, the photocleavage of pBR322 DNA for the complexes and the effect of different Lbpy substituted groups in the complexes on their reactivity were analyzed.     

Synthesis,Structure and Cytotoxicity Testing of Novel 7-(4,5-Dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-Imine Derivatives

The appropriate 1-arylhydrazinecarbonitriles 1a–c are subjected to the reaction with 2-chloro-4,5-dihydro-1H-imidazole (2), yielding 7-(4,5-dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-imines 3a–c, which are subsequently converted into the corresponding amides 4a–e, 8a–c, sulfonamides 5a–n, 9, ureas 6a–I, and thioureas 7a–d. The structures of the newly prepared derivatives 3a–c, 4a–e, 5a–n, 6a–i, 7a–d, 8a–c, and 9 are confirmed by IR, NMR spectroscopic data, as well as single-crystal X-ray analyses of 5e and 8c. The in vitro cytotoxic potency of these compounds is determined on a panel of human cancer cell lines, and the relationships between structure and antitumor activity are discussed. The most active 4-chloro-N-(2-(4-chlorophenyl)-7-(4,5-dihydro-1H-imidazol-2-yl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)benzamide (4e) and N-(7-(4,5-dihydro-1H-imidazol-2-yl)-2-(p-tolyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)-[1,1′-biphenyl]-4-sulfonamide (5l) inhibits the growth of the cervical cancer SISO and bladder cancer RT-112 cell lines with IC₅₀ values in the range of 2.38–3.77 μM. Moreover, N-(7-(4,5-dihydro-1H-imidazol-2-yl)-2-phenyl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)-4-phenoxybenzenesulfonamide (5m) has the best selectivity towards the SISO cell line and induces apoptosis in this cell line.     

Desymmetrizing Heteroleptic [Cu(P^P)(N^N)][PF6] Compounds: Effects on Structural and Photophysical Properties,and Solution Dynamic Behavior

The preparation, characterization and electrochemical and photophysical properties of a series of desymmetrized heteroleptic [Cu(P^P)(N^N)][PF₆] compounds are reported. The complexes incorporate the chelating P^P ligands bis(2-(diphenylphosphanyl)phenyl)ether (POP) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (xantphos), and 6-substituted 2,2′-bipyridine (bpy) derivatives with functional groups attached by –(CH₂)_n– spacers: 6-(2,2′-bipyridin-6-yl)hexanoic acid (1), 6-(5-phenylpentyl)-2,2′-bipyridine (2) and 6-[2-(4-phenyl-1H-1,2,3,triazol-1-yl)ethyl]-2,2′-bipyridine (3). [Cu(POP)(1)][PF₆], [Cu(xantphos)(1)][PF₆], [Cu(POP)(2)][PF₆], [Cu(xantphos)(2)][PF₆], and [Cu(xantphos)(3)][PF₆] have been characterized in solution using multinuclear NMR spectroscopy, and the single crystal structure of [Cu(xantphos)(3)][PF₆]^.0.5Et₂O was determined. The conformation of the 6-[2-(4-phenyl-1H-1,2,3,triazol-1-yl)ethyl]-substituent in the [Cu(xantphos)(3)]⁺ cation is such that the α- and β-CH₂ units reside in the xanthene ‘bowl’ of the xantphos ligand. The 6-substituent desymmetrizes the structure of the [Cu(P^P)(N^N)]⁺ cation and this has consequences for the interpretation of the solution NMR spectra of the five complexes. The NOESY spectra and EXSY cross-peaks provide insight into the dynamic processes operating in the different compounds. For powdered samples, emission maxima are in the range 542–555 nm and photoluminescence quantum yields (PLQYs) lie in the range 13–28%, and a comparison of PLQYs and decay lifetimes with those of [Cu(xantphos)(6-Mebpy)][PF₆] indicate that the introduction of the 6-substituent is not detrimental in terms of the photophysical properties.     

Synthesis of Platinum(II) N-Heterocyclic Carbenes Based on Adenosine

Organometallic derivatization of nucleosides is a highly promising strategy for the improvement of the therapeutic profile of nucleosides. Herein, a methodology for the synthesis of metalated adenosine with a deprotected ribose moiety is described. Platinum(II) N-heterocyclic carbene complexes based on adenosine were synthesized, namely N-heterocyclic carbenes bearing a protected and unprotected ribose ring. Reaction of the 8-bromo-2′,3′,5′-tri-O-acetyladenosine with Pt(PPh₃)₄ by C8−Br oxidative addition yielded complex 1, with a Pt^II centre bonded to C-8 and an unprotonated N7. Complex 1 reacted at N7 with HBF₄ or methyl iodide, yielding protic carbene 2 or methyl carbene 3, respectively. Deprotection of 1 to yield 4 was achieved with NH₄OH. Deprotected compound 4 reacted at N7 with HCl solutions to yield protic NHC 5 or with methyl iodide yielding methyl carbene 6. Protic N-heterocyclic carbene 5 is not stable in DMSO solutions leading to the formation of compound 7, in which a bromide was replaced by chloride. The cis-influence of complexes 1–7 was examined by ³¹P{¹H} and ¹⁹⁵Pt NMR. Complexes 2, 3, 5, 6 and 7 induce a decrease of ¹J_Pt,P of more than 300 Hz, as result of the higher cis-influence of the N-heterocyclic carbene when compared to the azolato ligand in 1 and 4.