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PubMed1980

Effect of sodium cyanate on Plasmodium falciparum in vitro.

Sodium cyanate at concentrations as low as 0.5 mM inhibited the growth of Plasmodium falciparum (FCR-3 Strain) utilizing the Trager-Jensen continuous culture system. At concentration higher than 1 mM, the parasites were irreversibly destroyed. Utilizing synchronized cultures, the relative susceptibilities of early and late trophozite forms were examined, and it was found that both developmental forms were equally susceptible to the action of cyanate. Pretreatment of red cells with sodium cyanate prior to infection did not alter the intracellular growth of the parasite. Consequently, the effect of the drug is likely to be on the parasite per se rather than the red cell. The mechanism of action is probably the carbamylation of essential, parasite proteins that eventually impair growth and/or function. Published pharmacological studies in humans would predict that the level of cyanate at which growth inhibition occurs in vitro can be achieved in vivo and that the adverse effects will likely be minimal for short treatment periods.

Animals↗
PubMed1976

Modification of chymotrypsin with the specific cyanate reagent N-acetyl-p-cyanato-l-phenylalanine ethyl ester.

The specific cyanate reagentN-acetyl-p-cyanato-L-phenylalanine ethyl ester (compound 1) was synthesized in an attempt to selectively modify the binding pocket of chymotrypsin (EC 3.4.21.1) while leaving the catalytic residues un touched. The reagent reacts with chymotrypsin to yield chiefly an inactive derivative 3a, with the active site Ser-195 carbamylated and the alpha-amino group, with the reagent 1 yields a modified enzyme(compound 4) with an additional carbamyl group on Ser-195.Neither derivative 3a nor 4reacts with diisopropylfluorophosphate under conditions where chymotrypsinogen is modified, indicating that Ser-195 is altered. Both derivatives 3a and 4 are retained on a 4-phenylbutylamine affinity colomn demonstrating that the substrate binding pocket is intact in both derivatives. The results indicate the potential value of aryl cyanates as protein reagents for the selective modification of nucleophilic sites. However, it is apparent that reaction at unreactive residues in the binding pocket of chymotrypsin with cyanates or similar reagents will require blockage of the more nucleophilic catalytic residues.

Binding Sites↗
PubMed1991

Metabolic effects of cyanate on mice at sea level and in chronic hypobaric hypoxia.

In order to evaluate the toxic effects of Sodium Cyanate (NaOCN), it was orally administered to growing mice at sea level (SL-CN) and to mice chronically exposed to intermittent hypobaric hypoxia (IHH-CN). The effects on body weight, in-vivo O2 consumption (VO2) and the respiratory function of liver mitochondria were evaluated. At sea level, the animals on cyanate lost weight in contrast with the controls that gained weight. When exposed to IHH, the controls lost weight and the animals on cyanate regained weight. After 2 months observation the weights of the IHH-CN and IHH-C were similar. The VO2 after one month of treatment was similar in the SL-C and in the SL-CN but it was lower in the IHH-CN when compared with IHH-C. The substrate-stimulated respiration of isolated liver mitochondria (ST4) was not affected by NaOCN, but the ADP-stimulated respiration (ST3) was reduced. The ratio ST3/ST4 (RCR) was also lower. These changes were present in both SL and in IHH and were much larger after three months of treatment. The toxic effects of chronic administration of NaOCN are discussed.

Administration, Oral↗
PubMed1983

Mutagenicity of cyanate, a decomposition product of MNU.

Knox reported that the short-term effects of the carcinogen methylnitrosourea (MNU) were due to the formation of its decomposition product, the cyanate ion. He showed that cell survival and DNA synthesis decreased as the concentration of MNU and the cyanate ion (NCO-) increased in the medium. Further, the product of MNU decomposition comigrated with NCO- when added to his chromatographic test system. However, Knox did not study the mutagenicity of MNU or its breakdown products. We compared the mutagenicity of MNU and potassium cyanate (KNCO) in mammalian cells. Our results demonstrate that, although it is toxic to cells, KNCO does not induce ouabain-resistant mutants in cultured Chinese hamster cells (V79).

Animals↗
PubMed1999

Bioactivation of cyanide to cyanate in sulfur amino acid deficiency: relevance to neurological disease in humans subsisting on cassava.

Neurological disorders have been reported from parts of Africa with protein-deficient populations and attributed to cyanide (CN-) exposure from prolonged dietary use of cassava, a cyanophoric plant. Cyanide is normally metabolized to thiocyanate (SCN-) by the sulfur-dependent enzyme rhodanese. However, in protein-deficient subjects where sulfur amino acids (SAA) are low, CN may conceivably be converted to cyanate (OCN-), which is known to cause neurodegenerative disease in humans and animals. This study investigates the fate of potassium cyanide administered orally to rats maintained for up to 4 weeks on either a balanced diet (BD) or a diet lacking the SAAs, L-cystine and L-methionine. In both groups, there was a time-dependent increase in plasma cyanate, with exponential OCN- increases in SAA-deficient rats. A strongly positive linear relationship between blood CN- and plasma OCN- concentrations was observed in these animals. These data are consistent with the hypothesis that cyanate is an important mediator of chronic cyanide neurotoxicity during protein-calorie deficiency. The potential role of thiocyanate in cassava-associated konzo is discussed in relationship to the etiology of the comparable pattern of motor-system disease (spastic paraparesis) seen in lathyrism.

Animals↗
PubMed1976

Reduced high-energy phosphate levels in rat hearts. II. Effects of sodium cyanate.

The effects of increased blood-oxygen affinity, due to carbamylation of hemoglobin in vivo, on aerobic metabolism in the heart were studied in rats. Adult male rats were injected intraperitoneally 3 times weekly for 10 wk with sodium cyanate (60 mg/kg). Significant derangement of blood-oxygen interaction was observed. Oxygen-dissociation curves were left shifted by 13 mmHg (35.1-21.8), and the overall deoxygenation rate (k) was reduced 41% (6.142-3.624; s(-1)); P is less than 0.001 for each parameter. Heart ATP and PCr levels were reduced (ATP: 19.4-16.7; PCr: 15.0-11.0, mum/g dry wt; P is less than 0.001 for each). In addition, glycogen levels fell (161.4-112.9, mum C6/g dry wt; P is less than 0.001). Myocardial lactate levels increased 54% (2.6-4.0, mum/g dry wt; P is less than 0.01) in the cyanate-treated group. These findings strongly suggest a hypoxia-induced activation of glycolysis as a consequence of altered oxidative metabolism in rats treated with sodium cyanate.

Adenosine Triphosphate↗
PubMed1988

Chronic administration of sodium cyanate decreases O2 extraction ratio in dogs.

It has been proposed that an increase in the affinity of hemoglobin for O2 may be beneficial in severe hypoxemia. To test this hypothesis, we compared the response to progressive hypoxemia in dogs with normal hemoglobin affinity (P50 = 32.4 +/- 0.7 Torr) to dogs with a left shift of the oxyhemoglobin dissociation curve (P50 = 21.9 +/- 0.5 Torr) induced by chronic oral administration of sodium cyanate. Animals were anesthetized, paralyzed, and mechanically ventilated. The inspired O2 fraction was progressively lowered by increasing the inspired fraction of N2. The lowest level of O2 transport required to maintain base-line O2 consumption (VO2) was 9.3 +/- 0.8 ml.min-1.kg-1 for control and 16.5 +/- 1.1 ml.min-1.kg-1 for the sodium cyanate-treated dogs (P less than 0.01). Other measured parameters at this level of O2 transport were, for experimental vs. control: arterial PO2 19.3 +/- 2.4 (SE) Torr vs. 21.8 +/- 1.6 Torr (NS); arterial O2 content 10.0 +/- 1.2 ml/dl vs. 4.9 +/- 0.4 ml/dl (P less than 0.01); mixed venous PO2 14.0 +/- 1.5 Torr vs. 13.8 +/- 1.0 Torr (NS); mixed venous O2 content 6.8 +/- 1.0 ml/dl vs. 2.3 +/- 0.2 ml/dl (P less than 0.01); and O2 extraction ratio 32.7 +/- 2.8% vs. 51.2 +/- 3.8% (P less than 0.01). We conclude that chronic administration of sodium cyanate appears to be detrimental to O2 transport, since the experimental dogs were unable to increase their O2 extraction ratios to the same level as control, thus requiring a higher level of O2 transport to maintain their base-line VO2 values.

Animals↗
PubMed1975

Effects of high-dose cyanate upon cerebral energy metabolism of the rat.

The effect of sodium cyanate (25, 50, 75, and 100 mg/kg body weight i.p. daily for 10 days) upon cerebral metabolism and the EEG of Wistar rats was studied. This treatment resulted in a dose-related carbamylation of hemoglobin and left shift in the oxygen dissociation curve. Animals receiving the highest dose of cyanate developed a significant systemic metabolic acidosis. In brain there was dose-dependent decrease in phosphocreatine, TCO2 and cytoplasmic NADH/NAD+ ratio, reflecting the calculated drop in intracellular pH. Glucose levels were elevated despite a normal calculated energy charge, which suggests a balanced slowing of the energy-producing and energy-utilizing systems. The higher doses of cyanate produced spontaneous seizure activity on the EEG.

Animals↗
PubMed1984

Prolonged red cell survival following in vitro treatment with potassium cyanate. A study in patients undergoing open-heart surgery.

Red cel survival was prospectively studied, using Chromium-51 isotope, in 48 patients undergoing cardiopulmonary bypass for single valve replacement (SVR, 24 patients) or coronary bypass graft procedures (CABG, 24 patients). The red cells were labelled on the day before the open heart surgery. Cells from randomly selected patients were treated for 30 min with potassium cyanate (0.5 mg/100 ml) in 5% invertose solution or with 5% invertose alone. The mean red cell survival in the SVR and the CABG group was 21.3 and 23 days, respectively, when the cells had been treated with cyanate, and 12.7 and 12 days when only invertose had been used. In the cyanate groups the loss of isotope during cardiopulmonary bypass and in the first three postoperative days was significantly less than in the control groups indicating improved tolerance to the traumatic effects of cardiopulmonary bypass.

Cardiopulmonary Bypass↗
PubMed1984

Improved red cell survival in patients with chronic subclinical haemolysis due to artificial heart valve. Observations after in vitro treatment of the cells with potassium cyanate.

Red cell survival was studied with use of Chromium-51 isotope and standard haematologic tests of haemolysis. The study comprised 30 patients with normally functioning single artificial heart valves of various types. They were investigated on 2 or 3 occasions. Red cells labelled with Cr-51 were treated for 30 min with potassium cyanate (0.5 mg/100 ml) in 5% invertose or with only 5% invertose. The mean red cell survival without cyanate treatment was 25 (+/- 4.2) days. Following cyanate treatment this figure improved to 31 (+/-4.8) days. Low-grade chronic intravascular haemolysis was associated with all the valve types. Abnormal results were found in 67% and 62% of the tests in patients with ball-type valve (deBakey and Starr-Edwards, respectively). The figures for tilting disc values (Lillehei-Kaster and Björk-Shiley) were 51 and 45.5%, while Carpentier-Edwards bioprosthetic valves gave 15.5% abnormal test results. The findings thus suggested that ball valves are more haemolytic than tilting disc valves, which in turn are more haemolytic than tissue valves.

Anemia, Hemolytic↗
PubMed1984

Cyanate binding to the ferric heme octapeptide from cytochrome c. A model for anion binding to high spin ferric hemoproteins.

Equilibrium constants for the binding of cyanate to the ferric heme c octapeptide in 50% ethylene glycol, 50% aqueous buffer were measured spectrophotometrically. Equilibrium constants measured at several temperatures from -20 degrees C to 0 degrees C exhibited an apparent van't Hoff relationship yielding thermodynamic values of delta Ho = -1.3 X 10(3) +/- 0.9 X 10(3) J/mol (-3.1 X 10(2) +/- 2 X 10(2) cal/mol), delta So = -3 +/- 3 J/K X mol (-0.6 +/- 0.8 cal/K X mol). The equilibrium constant for cyanate binding at 25 degrees C and pH 7.4 is 1.21 which is approximately 2 to 3 orders of magnitude lower than that observed for cyanate binding to methemoglobin and metmyoglobin. Krel, the ratio of the hemoprotein to model heme octapeptide binding constants, for NCO- is smaller than Krel for N3- suggesting that hydrogen bonding between the terminal ligand atoms and the distal histidine in hemoglobin and myoglobin does not contribute to the increased protein ligand stabilization observed for these anions relative to the model. A donor-acceptor interaction between the distal histidine and the electrophilic middle atoms of these bound ligands is proposed.

Animals↗
PubMed1984

The mechanism of action of two anti-sickling agents: sodium cyanate and glyceraldehyde.

Two compounds that inhibit the sickling of erythrocytes in vitro are sodium cyanate and glyceraldehyde. The former compound reacts selectivity with the NH2-terminus of the alpha-chain of hemoglobin S and thereby leads to an increased oxygen affinity of the protein and inhibition of erythrocyte sickling. The toxicity associated with oral administration of sodium cyanate precludes its use in the treatment of sickle cell anemia; administration by extracorporeal routes is still under consideration. The compound glyceraldehyde also inhibits the sickling of erythrocytes in vitro but does so by a different mechanism than sodium cyanate; it interferes directly with the gelation of deoxyhemoglobin S. Glyceraldehyde also displays selectivity; only five of a total 24 amino groups per alpha beta dimer of hemoglobin S are reactive. Preclinical studies on this compound as a potential treatment for sickle cell anemia are in progress.

Antisickling Agents↗
PubMed1977

14C cyanate as a tag for red cell survival in normal and uremic man.

14C cyanate was employed as a red cell tag. Incubated cells were washed before reinjection to remove free cyanate. Neither early or late elution was observed, and the mean red cell life span of 10 normal subjects was 115+/-12 days. In nine uremic subjects the mean life span corrected for blood loss was 73 days with a mean red cell turnover of about 0.79 times basal. Survival curves in normal subjects were similar to those observed with DF32P and in uremic subjects to those with 51Cr corrected for elution. These observatios show the reliability of 14C cyanate as a nonelutable red cell tag.

Carbon Radioisotopes↗
PubMed1977

Mechanism of inhibition of hemoglobin S polymerization by cyanate.

We have studied the effect of carbamylation on hemoglobin S (HbS) polymerization with the use of a new quantitative gelling technique. HbS gels fromed in the presence of nitrogen and dithionite (with or without carbon monoxide) at pH 7 in 0.15M phosphate were separated into sol and gel phases by centrifugation at 130,000 g. Hb concentration to the sol phase ([Hb]sol) of nonligated HbS was found to be constant (10.5 +/- 092 mM heme) over a range of original Hb concentrations from 11 to 17 mM at 24degrees C. This suggests that the HbS sol-gel equilibrium behaves as simple two-phase system. Increasing levels of total carbamylation from 0.65 to 3.65 moles CNO-/mole Hb tetramer (0.36 to 2.2 moles N-terminal/mole Hb4) progressively increases [Hb]sol. Specific activity of 14CNO-HbS was similar in the sol and gel phases, whereas COHbS appeared to be completely excluded from polymer structure of the gel. A comparison of the solubility of uncarbamylated and heavily carbamylated HbS at Co saturations ranging from 3 to 61 percent showed that the larges difference in [Hb]sol occured at the lowest ligand saturation rather than at intermediate states of ligation. Inhibition of HbS polymerization by carbamylation under these conditions, therefore, is not primarily the result of an effect on the T in equilibrium R comformational equilibrium. Our findings indicate that cyanate can interfere with HbS polymerization directly, possibly by alteration of surface binding sit(s) which are critical to aggregation. This direct action of cyanate may contribute significantly to the hematologic improvement achieved by cyanate treatment in sickle cell disease.

Anemia, Sickle Cell↗
PubMed2003

Progress in the palladium-catalyzed cyanation of aryl chlorides.

The development of new palladium catalysts for the cyanation of various aryl and heteroaryl chlorides is described. The combination of amine co-catalysts with chelating phosphine ligands, for example, 1,4-bis(diphenylphosphino)butane (dppb) or 1,5-bis(diphenylphosphino)pentane (dpppe), allows an efficient cyanation of chloroarenes with simple potassium cyanide. General palladium-catalyzed cyanation of nonactivated and deactivated chloroarenes is possible for the first time. Studies of the oxidative addition of aryl halides to palladium triphenylphosphine complexes in the presence and absence of amines suggest that the co-catalyst is capable of preventing catalyst deactivation caused by the presence of excess cyanide ions in solution.

Journal Article↗
PubMed2005

One-dimensional zinc-based coordination polymers incorporating cyanate anions.

Two one-dimensional zinc-based coordination polymers containing cyanate anions are reported. catena-Poly[sodium [[tricyanatozinc(II)]-mu-1,4-diazabicyclo[2.2.2]octane-kappa2N:N']], [Na[Zn(NCO)3(C6H12N2)]]n, consists of linear [tricyanatozinc(II)]-mu-1,4-diazabicyclo[2.2.2]octane strands in which the Zn2+ cations adopt trigonal-bipyramidal coordination on sites of -6m2 point symmetry. Na+ cations lie between the strands on sites of -3m point symmetry, coordinated in a distorted octahedral geometry by six O atoms of the cyanate anions. catena-Poly[[dicyanatozinc(II)]-mu-4,4'-bipyridine-kappa2N:N'], [Zn(NCO)2(C10H8N2)]n, crystallizes in the space group P2(1)/n with Z' = 5. The structure consists of zigzag strands formed by Zn2+ cations linked via 4,4'-bipyridine. Each Zn2+ cation adopts a tetrahedral coordination, with two sites occupied by 4,4'-bipyridine and two cyanate anions completing the coordination sphere. The structure is closely comparable with the thiocyanate and halide analogues [ZnX2(C10H8N2)] (X = NCS, Cl or Br).

Journal Article↗