Azo- and butadiyne-linked 5,10-diarylporphyrins

Porphyrins are one of Nature’s essential building blocks that play an important role in several biological systems including oxygen transport, photosynthesis, and enzymes. Their capacity to absorb visible light, facilitate oxidation and reduction, and act as energy- and electron-transfer agents, in particular when several are held closely together, is of interest to chemists who seek to mimic Nature and to make and use these compounds in order to synthesise novel advanced materials. During this project 26 new 5,10-diarylsubstituted porphyrin monomers, 10 dimers, and 1 tetramer were synthesised. The spectroscopic and structural properties of these compounds were investigated using 1D/2D 1H NMR, UV/visible, ATR-IR and Raman spectroscopy, mass spectrometry, X-ray crystallography, electrochemistry and gel permeation chromatography. Nitration, amination, bromination and alkynylation of only one as well as both of the meso positions of the porphyrin monomers have resulted in the expansion of the synthetic possibilities for the 5,10-diarylsubstituted porphyrins. The development of these new porphyrin monomers has led to the successful synthesis of new azo- and butadiyne-linked dimers. The functionalisation of these compounds was investigated, in particular nitration, amination, and bromination. The synthesised dimers containing the azo bridge have absorption spectra that show a large split in the Soret bands and intense Q-bands that have been significantly redshifted. The butadiyne dimers also have intense, red-shifted Q-bands but smaller Soret band splittings. Crystal structures of two new azoporphyrins have been acquired and compared to the azoporphyrin previously synthesised from 5,10,15- triarylsubstituted porphyrin monomers. A completely new cyclic porphyrin oligomer (CPO) was synthesised comprising four porphyrin monomers linked by azo and butadiyne bridges. This is the first cyclic tetramer that has both the azo and butadiyne linking groups. The absorption spectrum of the tetramer exhibits a large Soret split making it more similar to the azo- dimers than the butadiyne-linked dimers. The spectroscopic characteristics of the synthesised tetramer have been compared to the characteristics of other cyclic porphyrin tetramers. The collected data indicate that the new synthesised cyclic tetramer has a more efficient ð-overlap and a better ground state electronic communication between the porphyrin rings.

Contribution of transmembrane domain V amino acids to β1l-adrenoceptor activity and affinity

Introduction. There are two binding sites on the β1-adrenoceptor (AR), β1H and β1L corresponding to high and low affinity binding sites respectively, which can be activated to cause cardiostimulation. Some β-blockers that block β1AR and β2ARs can activate β1LARs at higher concentrations than those required to cause blockade. The β2AR does not form a corresponding low affinity binding site and therefore we postulated that heterologous amino acids are responsible for the formation of β1LAR. Aim. To investigate whether heterologous amino acids of transmembrane domain V (TMDV) of β1AR and β2ARs contribute to β1LAR. Methods. β1ARs, β2ARs and mutant β1ARs containing all (β1(β2TMDV)AR) or single amino acids of TMDV of the β2AR were prepared and stably expressed in Chinese Hamster Ovary cells. Concentration-effect curves for cyclicAMP accumulation were carried out for (-)-CGP12177 in the absence or presence of (-)-bupranolol. Results. The potencies (pEC50) of (-)-CGP12177 were β2AR (9.24 ± 0.14, n = 5), β1(V230I)AR (9.07 ± 0.07, n = 10), β1(β2TMDV)AR (8.86 ± 0.10, n = 15), β1(R222Q)AR (8.09 ± 0.29, n = 6), β1AR (8.00 ± 0.11, n = 11). The affinities (pKB) of (-)-bupranolol were β2AR (9.82 ± 0.52, n = 5), β1(V230I)AR (7.64 ± 0.12, n = 8), β1(β2TMV)AR (8.06 ± 0.17, n = 8), β1(R222Q)AR (7.33 ± 0.23, n = 5), β1AR (7.23 ± 0.23, n = 5). Discussion. The potency of (-)-CGP12177 was higher at β2AR than at β1AR consistent with activation through a low affinity site at the β1AR (β1LAR). The presence of V230 in β1AR accounted for the lower potency of (-)-CGP 12177. The affinity of (-)-bupranolol was lower at β1AR compared to β2AR. The presence of V230 in β1AR accounted in part for the lower affinity. In conclusion TMDV of the β1AR contributes in part to the low affinity binding site of β1AR.

Contribution of transmembrane domain V amino acids to β1l-adrenoceptor activity and affinity

There are two binding sites on the β1-adrenoceptor (AR), β1H and β1L corresponding to high and low affinity binding sites respectively, which can be activated to cause cardiostimulation (reviewed Kaumann and Molenaar, 2008). Some β-blockers that block β1AR and β2ARs can activate β1LARs at higher concentrations than those required to cause blockade. The β2AR does not form a corresponding low affinity binding site (Baker et al 2002) and therefore we postulated that heterologous amino acids are responsible for the formation of β1LAR. Our aim was to investigate whether heterologous amino acids of transmembrane domain V (TMDV) of β1AR and β2ARs contribute to β1LAR. β1ARs, β2ARs and mutant β1ARs containing all (β1(β2TMDV)AR) or single amino acids of TMDV of the β2AR were prepared and stably expressed in Chinese Hamster Ovary cells. Concentration-effect curves for cyclicAMP accumulation were carried out for (-)-CGP12177 or (-)-isoprenaline in the absence or presence of (-)-bupranolol. _______________________________________________________________________ (-)-CGP 12177 (-)-Bupranolol affinity (pKB) pEC50 vs (-)-CGP 12177 vs (-)-isoprenaline _______________________________________________________________________ β1AR 8.00 ± 0.11 (11) 7.23 ± 0.23 (5) 9.52 ± 0.28 (5) β2AR (high density) 9.24 ± 0.14 (5) 9.82 ± 0.52 (8) xPaulxxxxxxx β2AR (low density) no effect β1(β2TMV)AR 8.86 ± 0.10 (15) 8.06 ± 0.17 (8) 9.08 ± 0.22 (6) β1(V230I)AR 9.07 ± 0.07 (10) 7.64 ± 0.12 (8) 9.36 ± 0.28 (9) β1(R222Q)AR 8.09 ± 0.29 (6) 7.33 ± 0.23 (5) 9.36 ± 0.08 (6) β1(V230A)AR 7.59 ± 0.09 (6) 7.32 ± 0.24 (4) 8.62 ± 0.18 (5) _______________________________________________________________________ The potency of (-)-CGP12177 was higher at β2AR than at β1AR consistent with activation through a low affinity site at the β1AR (β1LAR) but not β2AR. The presence of V230 in β1AR accounted for the lower potency of (-)-CGP 12177. The affinity of (-)-bupranolol at β1AR and mutants was higher when determined with (-)-isoprenaline than with (-)-CGP 12177. The affinity of (-)-bupranolol determined against (-)-CGP 12177 was lower at β1AR compared to β2AR. The presence of V230 in β1AR accounted in part for the lower affinity. In conclusion V230 of the β1AR contributes in part to the low affinity binding site of β1AR. Baker JG, Hall IP, Hill SJ (2002). Pharmacological characterization of CGP12177 at the human β2-adrenoceptor. Br J Pharmacol 137, 400−408 Kaumann AJ, Molenaar P (2008) The low-affinity site of the β1-adrenoceptor and its relevance to cardiovascular pharmacology. Pharmacol Ther 118, 303-336

meso-Porphyrinylphosphine Oxides: Mono- and Bidentate Ligands for Supramolecular Chemistry and the Crystal Structures of Monomeric [10,20-Diphenylporphyrinatonickel(II)-5,15-diyl]-bis-[P(O)Ph2] and Polymeric Self-Coordinated ([10,20-Diphenylporphyrinatozinc(II)-5,15-diyl]-bis-[P(O)Ph2])

A series of porphyrins substituted in one or two meso-positions by diphenylphosphine oxide groups has been prepared by the palladium catalysed reaction of diphenylphosphine or its oxide with the corresponding bromoporphyrins. Compounds {MDPP-[P(O)Ph2]n} (M = H2, Ni, Zn; H2DPP = 5,15-diphenylporphyrin; n = 1, 2) were isolated in yields of 60-95%. The reaction is believed to proceed via the conventional oxidative addition, phosphination and reductive elimination steps, as the stoichiometric reaction of η1-palladio(II) porphyrin [PdBr(H2DPP)(dppe)] (H2DPP = 5,15-diphenylporphyrin; dppe = 1,2-bis(diphenylphosphino)ethane) with diphenylphosphine oxide also results in the desired mono-porphyrinylphosphine oxide [H2DPP-P(O)Ph2]. Attempts to isolate the tertiary phosphines failed due to their extreme air-sensitivity. Variable temperature 1H NMR studies of [H2DPP-P(O)Ph2] revealed an intrinsic lack of symmetry, while fluorescence spectroscopy showed that the phosphine oxide group does not behave as a "heavy atom" quencher. The electron withdrawing effect of the phosphine oxide group was confirmed by voltammetry. The ligands were characterised by multinuclear NMR and UV-visible spectroscopy as well as mass spectrometry. Single crystal X-ray crystallography showed that the bis(phosphine oxide) nickel(II) complex {[NiDPP-[P(O)Ph2]2} is monomeric in the solid state, with a ruffled porphyrin core and the two P=O fragments on the same side of the average plane of the molecule. On the other hand, the corresponding zinc(II) complex formed infinite chains through coordination of one Ph2PO substituent to the neighbouring zinc porphyrin through an almost linear P=O---Zn unit, leaving the other Ph2PO group facing into a parallel channel filled with disordered water molecules. These new phosphine oxides are attractive ligands for supramolecular porphyrin chemistry.

Nitrone [2]rotaxanes: Simultaneous chemical protection and electrochemical activation of a functional group

We report on the use of the hydrogen bond accepting properties of neutral nitrone moieties to prepare benzylic-amide-macrocycle-containing [2]rotaxanes in yields as high as 70 %. X-Ray crystallography shows the presence of up to four intercomponent hydrogen bonds between the amide groups of the macrocycle and the two nitrone groups of the thread. Dynamic 1H NMR studies of the rates of macrocycle pirouetting in nonpolar solutions indicate that amide-nitrone hydrogen bonds are particularly strong, ~1.3 and ~0.2 kcal mol-1 stronger than similar amide-ester and amide-amide interactions, respectively. In addition to polarizing the N-O bond through hydrogen bonding, the rotaxane structure affects the chemistry of the nitrone groups in two significant ways: The intercomponent hydrogen bonding activates the nitrone groups to electrochemical reduction, a one electron reduction of the rotaxane being stablized by a remarkable 400 mV (8.1 kcal mol-1) with respect to the same process in the thread; encapsulation, however, protects the same functional groups from chemical reduction with an external reagent (and slows down electron transfer to and from the electroactive groups in cyclicvoltammetry experiments). Mechanical interlocking with a hydrogen bonding molecular sheath thus provides a route to an encapsulated polarized functional group and radical anions of significant kinetic and thermodynamic stability.

Photoinduced conjugation of Dithioester- and Trithiocarbonate-Functional RAFT polymers with alkenes

We report the photoinduced conjugation of polymers synthesized via reversible addition−fragmentation chain transfer (RAFT) polymerization with a number of low molecular weight (functional) olefins. Upon irradiation of a solution of an aliphatic alkene and the benzyl dithioacetic acid ester (CPDA) or dodecyl trithiocarbonate (DoPAT) functional poly(alkyl acrylate) at the absorption wavelength of the thiocarbonyl group (315 nm), incorporation of the alkene at the polymer chain-end occurred. The most efficient systems identified with regard to the rate of reaction and yield were poly(butyl acrylate)/CPDA/ethyl vinyl ether (78% monoinsertion product after 1 h) and poly(butyl acrylate)/CPDA/1-pentene (73% insertion product after 7 h) at ambient temperature. An in-depth analysis of the reaction mechanism by 1H NMR and online size-exclusion chromatography-electrospray ionization tandem mass spectrometry (SEC/ESI−MSn) revealed that a possible [2 + 2] photoaddition mechanism of conjugation does not take place. Instead, fast β-cleavage of the photoexcited RAFT-end group with subsequent radical addition of an alkene was observed for all employed systems. The presented reaction thus provides a means of spatial and temporal control for the conjugation of alkenes to thiocarbonyl thio-capped macromolecules via the use of UV radiation.

N-Aryl stilbazolium dyes as sensitizers for solar cells

Eight new N-arylstilbazolium chromophores with electron donating –NR2 (R = Me or Ph) substituents have been synthesized via Knoevenagel condensations and isolated as their PF6− salts. These compounds have been characterized by using various techniques including 1H NMR and IR spectroscopies and electrospray mass spectrometry. UV–vis absorption spectra recorded in acetonitrile are dominated by intense, low energy π → π* intramolecular charge-transfer (ICT) bands, and replacing Me with Ph increases the ICT energies. Cyclic voltammetric studies show irreversible reduction processes, together with oxidation waves that are irreversible for R = Me, but reversible for R = Ph. Single crystal X-ray structures have been determined for three of the methyl ester-substituted stilbazolium salts and for the Cl− salts of their picolinium precursors. Time-dependent density functional theory calculations afford reasonable predictions of ICT energies, but greater rigour is necessary for –NPh2 derivatives. The four new acid-functionalized dyes give moderate sensitization efficiencies (ca. 0.2%) when using TiO2-based photoanodes, with relatively higher values for R = Ph vs Me, while larger efficiencies (up to 0.8%) are achieved with ZnO substrates.

Neuroprotective effects of low-dose lithium in individuals at ultra-high risk for psychosis. A longitudinal MRI/MRS study

Objectives: To investigate if low-dose lithium may counteract the microstructural and metabolic brain changes proposed to occur in individuals at ultra-high risk (UHR) for psychosis. Methods: Hippocampal T2 relaxation time (HT2RT) and proton magnetic resonance spectroscopy (1H-MRS) measurements were performed prior to initiation and following three months of treatment in 11 UHR patients receiving low-dose lithium and 10 UHR patients receiving treatment as usual (TAU). HT2RT and 1H-MRS percentage change scores between scans were compared using one-way ANOVA and correlated with behavioural change scores. Results: Low-dose lithium significantly reduced HT2RT compared to TAU (p=0.018). No significant group by time effects were seen for any brain metabolites as measured with 1H-MRS, although myo-inositol, creatine, choline-containing compounds and NAA increased in the group receiving low-dose lithium and decreased or remained unchanged in subjects receiving TAU. Conclusions: This pilot study suggests that low-dose lithium may protect the microstructure of the hippocampus in UHR states as reflected by significantly decreasing HT2RT. Larger scale replication studies in UHR states using T2 relaxation time as a proxy for emerging brain pathology seem a feasible mean to test neuroprotective strategies such as low-dose lithium as potential treatments to delay or even prevent the progression to full-blown disorder.

Homo- and heteronuclear meso,meso-(E)-Ethene-1,2-diyl-Linked Diporphyrins : preparation, X-ray crystal structure, electronic absorption and emission spectra and density functional theory calculations

Homo-and heteronuclear meso,meso-(E)-ethene-1,2-diyl-linked diporphyrins have been prepared by the Suzuki coupling of porphyrinylboronates and iodovinylporphyrins. Combinations comprising 5,10,15-triphenylporphyrin (TriPP) on both ends of the ethene-1,2-diyl bridge M 210 (M 2=H 2/Ni, Ni 2, Ni/Zn, H 4, H 2Zn, Zn 2) and 5,15-bis(3,5-di-tert-butylphenyl)porphyrinato-nickel(II) on one end and H 2, Ni, and ZnTriPP on the other (M 211), enable the first studies of this class of compounds possessing intrinsic polarity. The compounds were characterized by electronic absorption and steady state emission spectra, 1H NMR spectra, and for the Ni 2 bis(TriPP) complex Ni 210, single crystal X-ray structure determination. The crystal structure shows ruffled distortions of the porphyrin rings, typical of Ni II porphyrins, and the (E)-C 2H 2 bridge makes a dihedral angle of 50° with the mean planes of the macrocycles. The result is a stepped parallel arrangement of the porphyrin rings. The dihedral angles in the solid state reflect the interplay of steric and electronic effects of the bridge on interporphyrin communication. The emission spectra in particular, suggest energy transfer across the bridge is fast in conformations in which the bridge is nearly coplanar with the rings. Comparisons of the fluorescence behaviour of H 410 and H 2Ni10 show strong quenching of the free base fluorescence when the complex is excited at the lower energy component of the Soret band, a feature associated in the literature with more planar conformations. TDDFT calculations on the gas-phase optimized geometry of Ni 210 reproduce the features of the experimental electronic absorption spectrum within 0.1 eV. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Osteopenia in a teenage boy presenting with previously undiagnosed guanidinoacetate methyltransferase (GAMT) deficiency and response to creatine supplementation

A 16 y.o. fully ambulant boy born to consanguineous Indian parents, presented for assessment of a fragility femoral neck fracture sustained against a background of autism and moderately severe intellectual disability. He had a past history of infantile eczema, and epilepsy treated with anticonvulsants from 2 to 10 years of age, with no further seizures following cessation of anticonvulsants. He had a thin body habitus (see Table 1) with long fingers and a high arched palate. He had no speech and negligible social interaction, but physical examination was otherwise unremarkable. Positive investigations revealed an undetectable serum creatinine and a urinary metabolic screen which showed an elevated GUA:Phe of 160 (< 36) and a decreased creatinine of 0.3 mmol/l (1.2–29.5) consistent with the diagnosis of guanidinoacetate methyltransferase(GAMT) deficiency. He was commenced on oral creatine 5 g three times daily. Despite improvement in physical activity, height and bone density, there was no discernable improvement in his intellectual functioning. Proton and phosphorous brain and leg magnetic resonance spectroscopy(MRS) was performed at baseline and showed an increased inorganic phosphorus peak and decreased phosphocreatine synthesis in brain and decreased creatine concentration in muscle. Following creatine treatment total brain creatine(1H-MRS) and phosphocreatine/ATP ratio (31P-MRS) content increased to 30% and 60% of control values, respectively. Brain GUA returned to normal levels.

Incipient neurovulnerability and neuroprotection in early psychosis : a proton spectroscopy study of the anterior hippocampus at 3Tesla

Programmed cell death (PCD) and progenitor cell generation (of glial and in some brain areas also neuronal fate) in the CNS is an active process throughout life and is generally not associated with gliosis which means that PCD can be pathologically silent. The striking discovery that progenitor cell generation (of glial and in some brain areas neuronal fate) is widespread in the adult CNS (especially the hippocampus) suggest a much more dynamic scenario than previously thought and transcends the dichotomy between neurodevelopmental and neurodegenerative models of schizophrenia and related disorders. We suggest that the regulatory processes that control the regulation of PCD and the generation of progenitor cells may be disturbed in the early phase of psychotic disorders underpinning a disconnectivity syndrom at the onset of clinically overt disorders. An ongoing 1H-MRS study of the anterior hippocampus at 3 Tesla in mostly drug-naive first-episode psychosis patients suggests no change in NAA, but significant increases in myo-inositol and lactate. The data suggests that neuronal integrity in the anterior hippocampus is still intact at the early stage of illness or mainly only functionally impaired. However the increase in lactate and myo-inositol may reflect a potential disturbance of generation and PCD of progenitor cells (of glial and in selected brain areas also neuronal fate) at the onset of psychosis. If true the use of neuroprotective agents such as lithium or eicosapentaenoic acid (which inhibit PCD and support cell generation)in the early phase of psychotic disorders may be a potent treatment avenue to explore.

Valorization of solid tire wastes available in Bangladesh by thermal treatment

In this study available solid tire wastes in Bangladesh were characterized through proximate and ultimate analyses, gross calorific values and thermogravimetric analysis to investigate their suitability as feedstock for thermal recycling by pyrolysis technology. A new approach in heating system, fixedbed fire-tube heating pyrolysis reactor has been designed and fabricated for the recovery of liquid hydrocarbons from solid tire wastes. The tire wastes were pyrolysed in the internally heated fixed-bed fire-tube heating reactor and maximum liquid yield of 46-55 wt% of solid tire waste was obtained at a temperature of 475 oC, feed size 4 cm3, with a residence time of 5 s under N2 atmosphere. The liquid products were characterized by physical properties, elemental analysis, FT-IR, 1H-NMR, GC MS techniques and distillation. The results show that the liquid products are comparable to petroleum fuels whereas fractional distillations and desulphurization are essential to be used as alternative for diesel engine fuels.

Molecular and structural requirements of the ß1L-adrenoceptor

Noradrenaline which occurs naturally in the body binds to beta-adrenoceptors on the heart, causing the heart to beat faster and with greater force in response to increased demand. This enables the heart to provide oxygenated blood to vital organs. Prolonged overstimulation by noradrenaline can be harmful to the heart and lead to the progression of heart disease. In these circumstances beta-adrenoceptors are blocked with drugs called beta-blockers. Beta-blockers block the effects of noradrenaline by binding to the same site on the beta-adrenoceptor. Some beta-blockers such as CGP12177 can also cause increases in heart rate. Therefore it was proposed that CGP12177 could bind in a different place to noradrenaline. The aim of this study was to determine where CGP12177 binds to on the beta-adrenoceptor. The results have revealed a separate binding site named beta-1-low. These results may lead to the development of improved -blockers for the management of heart conditions.

Ruthenium(II) dichloro or dithiocyanato complexes with 4,4′:2′,2″:4″,4‴-quaterpyridinium ligands : towards photosensitisers with enhanced low-energy absorption properties

Fourteen new complexes of the form cis-\[RuIIX2(R2qpy2+)2]4+ (R2qpy2+ = a 4,4′:2′,2″:4″,4‴-quaterpyridinium ligand, X = Cl− or NCS−) have been prepared and isolated as their PF6− salts. Characterisation involved various techniques including 1H NMR spectroscopy and +electrospray or MALDI mass spectrometry. The UV–Vis spectra display intense intraligand π → π∗ absorptions, and also metal-to-ligand charge-transfer (MLCT) bands with two resolved maxima in the visible region. Red-shifts in the MLCT bands occur as the electron-withdrawing strength of the pyridinium groups increases, while replacing Cl− with NCS− causes blue-shifts. Cyclic voltammograms show quasi-reversible or reversible RuIII/II oxidation waves, and several ligand-based reductions that are irreversible. The variations in the redox potentials correlate with changes in the MLCT energies. A single-crystal X-ray structure has been obtained for a protonated form of a proligand salt, \[(4-(CO2H)Ph)2qpyH3+]\[HSO4]3·3H2O. Time-dependent density functional theory calculations give adequate correlations with the experimental UV–Vis spectra for the two carboxylic acid-functionalised complexes in DMSO. Despite their attractive electronic absorption spectra, these dyes are relatively inefficient photosensitisers on electrodes coated with TiO2 or ZnO. These observations are attributed primarily to weak electronic coupling with the surfaces, since the DFT-derived LUMOs include no electron density near the carboxylic acid anchors.

Physico-chemical/biological properties of tripolyphosphate cross-linked chitosan based

In this study, chitosan-PEO blend, prepared in a 15 M acetic acid, was electrospun into nanofibers (~ 78 nm diameter) with bead free morphology. While investigating physico-chemical parameters of blend solutions, effect of yield stress on chitosan based nanofiber fabrication was clearly evidenced. Architectural stability of nanofiber mat in aqueous medium was achieved by ionotropic cross-linking of chitosan by tripolyphosphate (TPP) ions. The TPP cross-linked nanofiber mat showed swelling up to ~ 300 % in 1h and ~ 40 % degradation during 30 d study period. 3T3 fibroblast cells showed good attachment, proliferation and viability on TPP treated chitosan based nanofiber mats. The results indicate non-toxic nature of TPP cross-linked chitosan based nanofibers and their potential to be explored as a tissue engineering matrix.