Diphenyl cyclopropenone-centered polymers for site-specific CO-releasing and chain dissociation

The synthesis and stimuli-responsiveness of a diphenyl cyclopropenone(DPCP)-centered poly(methyl acrylate)(PMA)are presented.DPCP-centered PMA could release carbon monoxide(CO)upon UV light in a switched on-and-off manner.The CO-releasing process can be reported by the variations in photoluminescence spectra.In addition,DPCP moiety covalently embedded in the crosslinked polyurethane could also release CO under UV light.Of special,DPCP-centered PMA in solution was selectively dissociated at the phenol ester bond under the ultrasound,and a force-induced hydrolyzation reaction was revealed by D20 exchanging^1 H NMR spectra.The kinetic study reveals that small quantity of water could enhance the chain scission rate.This work provides a DPCP-centered polymer for sitespecific CO-releasing and chain dissociation.

The therapeutic effect of CORM-3 on acute liver failure induced by lipopolysaccharide/D- galactosamine in mice

BACKGROUND： Acute liver failure （ALF） is a severe and life- threatening clinical syndrome resulting in a high mortality and extremely poor prognosis. Recently, a water-soluble CO-releas- ing molecule （CORM-3） has been shown to have anti-inflam- matory effect. The present study was to investigate the effect of CORM-3 on ALF and elucidate its underlying mechanism. METHODS： ALF was induced by a combination of LPS/D-GalN in mice which were treated with CORM-3 or inactive CORM-3 （iCORM-3）. The efficacy of CORM-3 was evaluated based on survival, liver histopathology, serum aminotransferase activi- ties （ALT and AST） and total bilirubin （TBiL）. Serum levels of inflammatory cytokines （TNF-α, IL-6, IL-1β and IL-10） and liver immunohistochemistry of NF-KB-p65 were determined; the expression of inflammatory mediators such as iNOS, COX-2 and TLR4 was measured using Western blotting. RESULTS： The pretreatment with CORM-3 significantly improved the liver histology and the survival rate of mice compared with the controls; CORM-3 also decreased the levels of ALT, AST and TBiL. Furthermore, CORM-3 significantly inhibited the increased concentration of pro-inflammatory cytokines （TNF-α, IL-6 and IL-1β） and increased the anti-in- flammatory cytokine （IL-10） productions in ALF mice. More- over, CORM-3 significantly reduced the increased expression of iNOS and TLR4 in liver tissues and inhibited the nudear ex- pression of NF-KB-p65. CORM-3 had no effect on the increased expression of COX-2 in the ALF mice. An iCORM-3 failed to prevent acute liver damage induced by LPS/D-GalN. CONCLUSION： These findings provided evidence that CORM-3 may offer a novel alternative approach for the management of ALF through anti-inflammatory functions.

Interaction of CORM-2 with hydrophobic sites: Beyond CO

Carbon monoxide releasing molecules (CORMs) have been recently developed for research and pharmacological purposes. A considerable amount of studies demonstrated a wide spectrum of biological activities for lipophilic CORM-2 (tricarbonyldichlororuthenium (II) dimer). It is generally accepted that the liberated gas provides the specific activities to CORMs, with a little attention paid to any possible effect of complementary core molecules. However, the versatile repertoire of actions attributed to CORM-2 is surprisingly wide for CO, a molecule with the sole chemical activity of binding to ferrous iron in protein prosthetic groups. The study was designed to analyze CORM-2 and its core molecule (“i”CORM) activities at a molecular level. With respect to the hydrophobic nature of the compounds, we followed their interactions with several amphipathic entities: the heme sites of hemoproteins, heme binding proteins and cell membranes. CORM-2/“i”CORM decreased the Soret optical density of hemoglobin and myoglobin, indicating that both compounds interact with the protein amphipathic site in the heme pocket. Pre-addition of CORM-2/“i”CORM to the apo-forms of the plasma heme binding proteins, hemopexin and albumin, partially abolished their heme binding capacity. In contrast, the compounds had no effect on the preformed heme-protein complexes. Addition of CORM-2/“i”- CORM to blood or isolated erythrocytes revealed aggregation of the cells or lysis, depending on the rea-gent-to-cells ratio. It was concluded that the ruthenium containing core molecule of CORM-2 may be physiologically active due to non-specific hydrophobic interactions. As each type of CORMs is expected to have a different mode of action beyond CO activity, their potential therapeutic uses will require clarification.

Syntheses, Cytotoxicity and Properties of CO Releasing Molecules Containing Acetyl Salicylamide-3-pyridine

A series of CO-releasing molecules [M（CO）5L] （M=Cr, W, Mo, L=acetyl salicylamide 3-pyridine, 1--3; L= N,N-dimethyl-4-pyridine, 4-6; L=nicotinamide, 7--9; L=4-CHO-pyridine, 10--12） were synthesized. And in this paper, we have investigated mainly cytotoxicity and properties of the CO-releasing molecules containing acetyl salicyamide-3-pyridine, namely complexes 1--3. The stability of complexes 1 and 2 was evaluated by means of UV-Vis spectroscopy and 1H NMR spectra. The results indicate complexes 1 and 2 were stable in methanol and acidic aqueous solution, but unstable and decayed in basic media （pH 10.0）. Among all the complexes, complex 2 was the slowest CO-releaser, and its half-life was 73.8 min. Complex 9 containing nicotinamide was the fastest CO-releaser with half-life only 6.5 min. In addition, cytotoxic effects of all the complexes on the proliferation of fibroblast line were assayed by MTT. Among all the complexes, the IC50 of complex 1 was 6 μmol/L, revealing complex 1 possessed stronger antiproliferative activity than the control. Analysis by Flow cytometry revealed that complex 1 arrested Hela cells in S phase while complexes 2 and 8 arrested in G2/M phase. Cell apoptosis caused by the complexes mainly occurred in ＂Late apoptosis＂.