Derivatives of Sodium Boranocarbonate as Novel CO-Releasing Molecules (CO-RMs)

Despite the apparent and well-known toxic effects of carbon monoxide (CO), studies on the intriguing biological roles of this molecule are rapidly emerging. Recent investigations have brought to the limelight various physiological effects of CO which include, among others, vasorelaxation and inhibition of organ rejection after transplantation. The importance of CO in biology can be compared with another gas, nitric oxide (NO), an essential and ubiquitous signalling molecule. This parallelism led to the tantalising concept of using CO for therapeutic purposes wherein compounds that transport and deliver this gas to a target tissue would clearly facilitate both the clinical feasibility and the specificity of CO therapy. Sodium boranocarbonate, Na[H3 BCO2H] (1) was the first water-soluble and non-transition metal containing CO-releasing molecule (CO-RM) to be identified. In order to tune the rate of CO release, we modified 1 and synthesised and characterized various derivatives which release CO under physiological conditions but at rates different from the parent compound 1. The synthesis, structure and CO-releasing properties of ester and amide derivatives of 1 will be presented together with some biological studies carried out with a selection of the compounds

Naphthalen-1-aminium chloride

In the crystal structure of the title compound, C10H10N+·Cl−, the two components are connected via N—H⋯Cl hydrogen bonds, forming a layer parallel to the bc plane

Derivatives of sodium boranocarbonate as novel CO-releasing molecules (CO-RMs)

Despite the apparent and well-known toxic effects of carbon monoxide (CO), studies on the intriguing biological roles of this molecule are rapidly emerging. Recent investigations have brought to the limelight various physiological effects of CO which include, among others, vasorelaxation and inhibition of organ rejection after transplantation. The importance of CO in biology can be compared with another gas, nitric oxide (NO), an essential and ubiquitous signalling molecule. This parallelism led to the tantalising concept of using CO for therapeutic purposes wherein compounds that transport and deliver this gas to a target tissue would clearly facilitate both the clinical feasibility and the specificity of CO therapy. Sodium boranocarbonate, Na[H3 BCO2H] (1) was the first water-soluble and non-transition metal containing CO-releasing molecule (CO-RM) to be identified. In order to tune the rate of CO release, we modified 1 and synthesised and characterized various derivatives which release CO under physiological conditions but at rates different from the parent compound 1. The synthesis, structure and CO-releasing properties of ester and amide derivatives of 1 will be presented together with some biological studies carried out with a selection of the compounds

Spectral, viscometric and electrochemical studies on mixed ligand cobalt(III) complexes of certain diimine ligands bound to calf thymus DNA

The complex [Co(5,6-dmp)3]Cl3 (1) and the mixed ligand complexes [Co(bipy)2(5,6-dmp)]Cl3 (2), [Co(bipy)2(phen)]Cl3 (3), [Co(phen)2(bipy)]Cl3 (4), [Co(bipy)2(imp)]Cl3 (5) and [Co(phen)2(imp)]Cl3 (6) where BIPY=2,2'-bipyridine, PHEN=1,10-phenanthroline, 5,6-dmp=5,6-dimethyl-1,10-phenanthroline and IMP=imidazo[4,5-f][1,10]-phenanthroline, have been isolated and characterised by elemental analysis. The interaction of these complexes with calf thymus DNA has been explored by using absorption, emission and circular dichroic spectral and electrochemical studies and viscosity measurements. Absorption spectral studies and viscosity measurements reveal that the complexes 1 and 2 interact with DNA primarily by groove binding while 3 and 4 may possibly bind by two modes. The complexes 5 and 6 associate with DNA involving the non-classical intercalation of the imp ligand with DNA base pairs. Circular dichroic spectral studies reveal that calf thymus B-DNA becomes more A-like in structure on interaction with all the complexes except 5. The complex 5, in contrast, exhibit a spectral band shift of about 10 nm to longer wavelength, which is characteristic of A conformation of DNA. Electrochemical studies reveal that the phen complexes facilitate the electrostatic interaction of cobalt(III) complexes, preferentially in the higher oxidation state of cobalt. On the other hand, the presence of 5,6-dimethyl groups on phen favour DNA groove binding of complexes. The presence of hydrophobic imp ligand facilitates its intercalative interaction with the hydrophobic interior of the nucleic acid bases, interestingly, in the lower oxidation state of cobalt

Synthesis, structure and DNA interaction of cobalt(III) bis-complexes of 1,3-bis(2-pyridylimino)isoindoline and 1,4,7-triazacyclononane

The complex [CoL2](ClO4)·MeOH (1), where HL is the tridentate 3N ligand 1,3-bis(2-pyridylimino)isoindoline, has been isolated and its X-ray crystal structure successfully determined. It possesses a distorted octahedral structure in which both the ligands are coordinated meridionally to cobalt(III) via one deprotonated isoindoline (L-) and two pyridine nitrogen atoms. Interestingly, the average dihedral angle between pyridine and isoindoline rings is 25.9° , indicating that the ligand is twisted upon coordination to cobalt(III). The interaction of the complex with calf-thymus DNA has been studied using various spectral methods and viscosity and electrochemical measurements. For comparison, the DNA interaction of [Co(tacn)2]Cl3 (2), where tacn is facially coordinating 1,4,7-triazacyclononane, has been also studied. The ligand-based electronic spectral band of 1 and the N(σ ) → Co(III) charge transfer band of 2 exhibit moderate hypochromism with small or no blue shift on interaction with DNA. The intrinsic binding constants calculated reveal that the monopositive complex ion [CoL2]+ exhibits a DNA-binding affinity lower than the tripositive complex ion [Co(tacn)2]3+. The steric clashes with DNA exterior caused by the second L- ligand bound to cobalt(III), apart from the lower overall positive charge on the [CoL2]+ complex, dictates its DNA-binding mode to be surface binding rather than partial intercalative interaction expected of the extended aromatic chromophore of deprotonated isoindoline anion. An enhancement in relative viscosity of CT DNA on binding to 1 is consistent with its DNA surface binding. On the other hand, a slight decrease in viscosity of CT DNA was observed on binding to 2 revealing that the smaller cation leads to bending (kinking) and hence shortening of DNA chain length. The electrochemical studies indicate that the DNA-bound complexes are stabilised in the higher Co(III) rather than the lower Co(II) oxidation state, suggesting the importance of electrostatic forces of DNA interaction

Copper(II) complexes of 1,10-phenanthroline-derived ligands: studies on DNA binding properties and nuclease activity

A series of copper(II) complexes of the type [Cu(L)]2+, where L = N,N'-dialkyl-1,10-phenanthroline-2,9-dimethanamine and R = methyl (L1), n-propyl (L2), isopropyl (L3), sec-butyl (L4), or tert-butyl (L5) group, have been synthesized. The interaction of the complexes with DNA has been studied by DNA fiber electron paramagnetic resonance (EPR) spectroscopy, emission, viscosity and electrochemical measurements and agarose gel electrophoresis. In the X-ray crystal structure of [Cu(HL2)Cl2]NO3, copper(II) is coordinated to two ring nitrogens and one of the two secondary amine nitrogens of the side chains and two chloride ions as well and the coordination geometry is best described as trigonal bipyramidal distorted square based pyramidal (TBDSBP). Electronic and EPR spectral studies reveal that all the complexes in aqueous solution around pH 7 possess CuN3O2 rather than CuN4O chromophore with one of the alkylamino side chain not involved in coordination. The structures of the complexes in aqueous solution around pH 7 change from distorted tetragonal to trigonal bipyramidal as the size of the alkyl group is increased. The observed changes in the physicochemical features of the complexes on binding to DNA suggest that the complexes, except [Cu(L5)]2+, bind to DNA with partial intercalation of the derivatised phen ring in between the DNA base pairs. Electrochemical studies reveal that the complexes prefer to bind to DNA in Cu(II) rather than Cu(I) oxidation state. Interestingly, [Cu(L5)]2+ shows the highest DNA cleavage activity among all the present copper(II) complexes suggesting that the bulky N-tert-butyl group plays an important role in modifying the coordination environment around the copper(II) center, the Cu(II)/Cu(I) redox potential and hence the formation of activated oxidant responsible for the cleavage. These results were compared with those for bis(1,10-phenanthroline)copper(II), [Cu(phen)2]2+</SUP

Isostructural Nuclear and Luminescent Probes Derived From Stabilized [2 + 1] Rhenium(I)/Technetium(I) Organometallic Complexes

A convenient method to prepare ^99mTc analogues of a class of rhenium­(I) luminophores was developed, creating isostructural pairs of nuclear and optical probes. A two-step procedure and a new one-pot procedure were used to produce a series of [2 + 1] complexes of the type [Tc­(CO)₃(bipy)­L]⁺ in greater than 80% yield. The plasma stability of the reported compounds was evaluated, where the basicity of the monodentate pyridine type ligand (L) has a significant impact with half-lives ranging from 2 to 20 h. The ability to generate the radioactive complexes makes it possible to quantitate cell uptake of Re luminophores, which was demonstrated in MCF-7 breast cancer cells using ^99mTc analogues of two Re­(I)-based mitochondrial targeting dyes

Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells.

International audienceThe nuclear factor erythroid derived 2-related factor 2 (Nrf2) and the antioxidant protein heme oxygenase-1 (HO-1) are crucial components of the cellular stress response. These two systems work together to combat oxidative stress and inflammation and are attractive drug targets for counteracting different pathologies, including neuroinflammation. We aimed to identify the most effective Nrf2/HO-1 activators that modulate the inflammatory response in microglia cells. In the present study, we searched the literature and selected 56 compounds reported to activate Nrf2 or HO-1 and analyzed them for HO-1 induction at 6 and 24h and cytotoxicity in BV2 microglial cells in vitro. Approximately 20 compounds up-regulated HO-1 at the concentrations tested (5-20 μM) with carnosol, supercurcumin, cobalt protoporphyrin-IX and dimethyl fumarate exhibiting the best induction/low cytotoxicity profile. Up-regulation of HO-1 by some compounds resulted in increased cellular bilirubin levels but did not augment the expression of proteins involved in heme synthesis (ALAS 1) or biliverdin reductase. Bilirubin production by HO-1 inducers correlated with their potency in inhibiting nitrite production after challenge with interferon-γ (INF-γ) or lipopolysaccharide (LPS). The compounds down-regulated the inflammatory response (TNF-α, PGE2 and nitrite) more strongly in cells challenged with INF-γ than LPS, and silencing HO-1 or Nrf2 with shRNA differentially affected the levels of inflammatory markers. These findings indicate that some small activators of Nrf2/HO-1 are effective modulators of microglia inflammation and highlight the chemical scaffolds that can serve for the synthesis of potent new derivatives to counteract neuroinflammation and neurodegeneration