Structural Variety in Transition Metal Complexes of Tripodal Ligands Containing Mixed Quinolyl and Pyridyl Donors.

The syntheses of the tripodal tetraamine ligands 2-(pyridin-2-yl)-N,N-bis(quinolin-2-ylmethyl)ethan-1-amine (DQPEA), N-(pyridin-2-ylmethyl)-2-(quinolin-2-yl)-N-(2-(quinolin-2-yl)ethyl)ethan-1-amine (DQEPMA), 2-(pyridin-2-yl)-N,N-bis(2-(quinolin-2-yl)ethyl)ethan-1-amine (DQEPEA), N,N-bis(pyridin-2-ylmethyl)-2-(quinolin-2-yl)ethan-1-amine (QEDPMA), and 2-(pyridin-2-yl)-N-(2-(pyridin-2-yl)ethyl)-N-(2-(quinolin-2-yl)ethyl)ethan-1-amine (QEDPEA) containing mixed quinolyl and pyridyl moieties are reported, with 2-vinylquinoline being used to attach quinolylethyl arms to the aliphatic N atom. X-ray crystal structures of [(Mn(DQPEA))O](ClO) ⋅ (CHCN), [Cu(DQPEA)NCCH](ClO), [Zn(DQPEA)NCCH](ClO), [Pd(DQEPEA)Cl]Cl ⋅ 11HO are detailed, with four, five, and six-coordination observed. In addition, the dimeric complex [(DPEA)Co(μ-OH)Co(DPEA)](ClO) ⋅ 0.

Co(III) complexes of the pentadentate NHC ligand PY4Im: carbene-induced influences and the non-disappearing C NMR peak.

Co(III) complexes of the N-heterocyclic carbene ligand PY4Im (PY4Im = (1,3-bis(bis(2-pyridyl)methyl)imidazol-2-ylidene)) having the general formula [(PY4Im)Co(X)](ClO) (X = NCMe; = 3: OH, N, NCS, ONO, F; = 2: OCO, = 1; (N), = 0) were prepared and structurally characterised. X-ray structural data are consistent with the presence of a influence due to the coordinated carbene carbon, and this is also supported by computational results. C NMR spectra of the complexes did not display peaks corresponding to the carbene carbon, except in the case of the [(PY4Im)Co(OCO)] cation, where a peak at = 170.

Coumarin-Derived Caging Groups in the Spotlight: Tailoring Physiochemical and Photophysical Properties.

The development of light-responsive molecular tools enables spatiotemporal control of biochemical processes with superior precision. Amongst these molecular tools, photolabile caging groups are employed to prevent critical binding interactions between a bioactive molecule and its corresponding target. Only upon irradiation with light, the bioactive is released in its 'active' form and is now readily available to bind to its target.

All-photonic kinase inhibitors: light-controlled release-and-report inhibition.

Light-responsive molecular tools targeting kinases affords one the opportunity to study the underlying cellular function of selected kinases. In efforts to externally control lymphocyte-specific protein tyrosine kinase (LCK) activity, the development of release-and-report LCK inhibitors is described, in which (i) the release of the active kinase inhibitor can be controlled externally with light; and (ii) fluorescence is employed to report both the release and binding of the active kinase inhibitor. This introduces an unprecedented all-photonic method for users to both control and monitor real-time inhibitory activity.

Chelated OBOH or Chelated OCO: An Isoelectronic Conundrum.

The species originally reported as [Co(bipy)OBOH]·[BO(OH)]·HBO·HO·HO, a Co(II) complex containing a chelated OBOH ligand, is shown to be [Co(bipy)OCO]·[BO(OH)]·HBO·2HO, a Co(III) complex containing a chelated OCO ligand. This was confirmed by H and C NMR, MS, IR, and an X-ray crystal structure.

Converting avocado seeds into a ready to eat snack and analysing for persin and amygdalin.

Avocado seeds account for 13% of the waste from industrial production of cold-pressed avocado oil (CPAO). Therefore, the aim of this study was to valorise avocado seeds by converting it into an extruded snack product using a friction cooker and comparing their textural and physical characteristics to extruded brown rice and malted barley ready to eat (RTE) snacks. Concentration of toxins; amygdalin and persin were compared in extruded avocado seed and fresh avocado seeds.

The photophysical properties of naphthalene bridged disilanes.

Structural isomers of naphthalene-bridged disilanes were prepared catalytic intramolecular dehydrocoupling of disilyl precursors using Wilkinson's catalyst. Interestingly, it was observed that interchanging the side groups on the silicon atoms altered the photophysical properties of the bridged disilanes. Herein, we report the first example of naphthalene bridged disilanes forming excimers in non-polar solvents.

Photoresponsive Small Molecule Inhibitors for the Remote Control of Enzyme Activity.

The development of new and effective therapeutics is reliant on the ability to study the underlying mechanisms of potential drug targets in live cells and multicellular systems. A persistent challenge in many drug development programmes is poor selectivity, which can obscure the mechanisms involved and lead to poorly understood modes of action. In efforts to improve our understanding of these complex processes, small molecule inhibitors have been developed in which their OFF/ON therapeutic activity can be toggled using light.

Design and development of photoswitchable DFG-Out RET kinase inhibitors.

REarranged during Transfection (RET) is a transmembrane receptor tyrosine kinase that is required for development of multiple human tissues, but which is also an important contributor to human cancers. RET activation through rearrangement or point mutations occurs in thyroid and lung cancers. Furthermore, activation of wild type RET is an increasingly recognized mechanism promoting tumor growth and dissemination of a much broader group of cancers.

A Fluorescent Kinase Inhibitor that Exhibits Diagnostic Changes in Emission upon Binding.

The development of a fluorescent LCK inhibitor that exhibits favourable solvatochromic properties upon binding the kinase is described. Fluorescent properties were realised through the inclusion of a prodan-derived fluorophore into the pharmacophore of an ATP-competitive kinase inhibitor. Fluorescence titration experiments demonstrate the solvatochromic properties of the inhibitor, in which dramatic increase in emission intensity and hypsochromic shift in emission maxima are clearly observed upon binding LCK.

Highly fluorescent and HDAC6 selective scriptaid analogues.

Fluorescent scriptaid analogues with excellent HDAC6 selectivity (HDAC1/6 > 500) and potency (HDAC6 IC < 5 nM) have been synthesised and evaluated. The highly fluorescent nature of the compounds (up to Φ = 0.83 in DMSO and 0.

Shining New Light on the Spiropyran Photoswitch: A Photocage Decides between cis- trans or Spiro-Merocyanine Isomerization.

Photochromic molecules from the spiropyran family are known to undergo light-induced interconversion between the colorless spiro- and the colored merocyanine forms. Here, we show for the first time that small structural modifications open up for an additional photoisomerization mode: reversible cis- trans isomerization of the merocyanine. Moreover, the introduction of a photocage allows for light-activated switching between the two modes.

Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation.

Drugs that recapitulate aspects of the exercise adaptive response have the potential to provide better treatment for diseases associated with physical inactivity. We previously observed reduced skeletal muscle class IIa HDAC (histone deacetylase) transcriptional repressive activity during exercise. Here, we find that exercise-like adaptations are induced by skeletal muscle expression of class IIa HDAC mutants that cannot form a corepressor complex.

A fluorescent histone deacetylase (HDAC) inhibitor for cellular imaging.

Fluorescence microscopy studies using 4-morpholinoscriptaid (4MS) demonstrated rapid cellular uptake of this scriptaid analogue into the cytoplasm but no nuclear penetration. As 4MS and scriptaid have the same in vitro activity against HDACs and KASUMI-1 cells; 4MS exemplifies a rational approach to subtly modify ‘profluorogenic’ substrates for intracellular studies.

Improved synthesis and structural reassignment of MC1568: a class IIa selective HDAC inhibitor.

An improved synthesis and structural reassignment of the class IIa selective histone deacetylase (HDAC) inhibitor MC1568 are described.

Lack of blood pressure salt-sensitivity supports a preglomerular site of action of nitric oxide in Type I diabetic rats.

1. The relationship between sodium intake and blood pressure is affected differently by changes in angiotensin (Ang) II and preglomerular resistance, and this study measured that relationship to evaluate the link between nitric oxide and blood pressure early in diabetes. 2.

Blood pressure early in diabetes depends on a balance between glomerular filtration rate and the renin-angiotensin system.

Onset of diabetes increases plasma renin activity (PRA) and glomerular filtration rate (GFR), but blood pressure (BP) is normal. In this study, a 70% surgical reduction in kidney mass (RK) was used to decrease baseline GFR and to prevent hyperfiltration during diabetes, and angiotensin converting enzyme inhibitors (ACEI) were used to inhibit angiotensin II (AngII) production, to test the hypothesis that a balance between GFR and AngII is required for normal BP early in diabetes. Diabetes was induced with streptozotocin (STZ) (35 mg/kg intravenously); and after 7 days of hyperglycemia (range: 408 to 486 mg/dL), insulin was intravenously infused continuously for a 4-day normoglycemic recovery period.

Angiotensin II hypertension is attenuated in interleukin-6 knockout mice.

Plasma levels of IL-6 correlate with high blood pressure under many circumstances, and ANG II has been shown to stimulate IL-6 production from various cell types. This study tested the role of IL-6 in mediating the hypertension caused by high-dose ANG II and a high-salt diet. Male C57BL6 and IL-6 knockout (IL-6 KO) mice were implanted with biotelemetry devices and placed in metabolic cages to measure mean arterial pressure (MAP), heart rate (HR), sodium balance, and urinary albumin excretion.

Hypertensive response to acute stress is attenuated in interleukin-6 knockout mice.

This study tested the hypothesis that the inflammatory cytokine, interleukin-6, contributes to the hypertensive response to acute psychosocial stress, caused by switching male mice to a cage previously occupied by a different male mouse. Male C57BL6 (WT) and interleukin-6 (IL-6) knockout (KO) mice were implanted with biotelemetry devices to monitor mean arterial pressure, heart rate, and motor activity in the unrestrained state. Baseline mean arterial pressure was 98+/-1 and 103+/-1 for WT and IL-6 KO mice.