Speckle Tracking Echocardiography in Non-ST-Segment Elevation Acute Coronary Syndromes.

Non-ST-segment elevation acute coronary syndromes (NSTE-ACSs) are a group of clinical conditions characterized by acute myocardial ischemia. Conventional echocardiography is generally used to evaluate cardiac function using wall motion analysis and left ventricular ejection fraction but may be insufficient to explore all the complex features of NSTE-ACSs, which may vary substantially from patient to patient in terms of severity of ischemia and extent of involved myocardium. In the last years, speckle tracking echocardiography (STE) has become a widely available technique for the non-invasive assessment of cardiac function and has been repeatedly applied in the setting of NSTE-ACSs. In this review we summarize current evidence about the use of STE in patients with NSTE-ACSs, trying to underline advantages and limitations in comparison with conventional echocardiography for: diagnosis of NSTE-ACS, differential diagnosis, identification of high-risk patients, and prediction of outcome.

Potent isozyme-selective inhibition of human glutathione S-transferase A1-1 by a novel glutathione S-conjugate.

Elevated levels of glutathione S-transferases (GSTs) are among the factors associated with an increased resistance of tumors to a variety of antineoplastic drugs. Hence a major advancement to overcome GST-mediated detoxification of antineoplastic drugs is the development of GST inhibitors. Two such agents have been synthesized and tested on the human Alpha, Mu and Pi GST classes, which are the most representative targets for inhibitor design. The novel fluorescent glutathione S-conjugate L-gamma-glutamyl-(S-9-fluorenylmethyl)-L-cysteinyl-glycine (4) has been found to be a highly potent inhibitor of human GSTA1-1 in vitro (IC50=0.11+/-0.01 microM). The peptide is also able to inhibit GSTP1-1 and GSTM2-2 isoenzymes efficiently. The backbone-modified analog L-gamma-(gamma-oxa)glutamyl-(S-9-fluorenylmethyl)-L-cysteinyl-glycine (6), containing an urethanic junction as isosteric replacement of the gamma-glutamyl-cysteine peptide bond, has been developed as gamma-glutamyl transpeptidase-resistant mimic of 4 and evaluated in the same inhibition tests. The pseudopeptide 6 was shown to inhibit the GSTA1-1 protein, albeit to a lesser extent than the lead compound, with no effect on the activity of the isoenzymes belonging to the Mu and Pi classes. The comparative loss in biological activity consequent to the isosteric change confirms that the gamma-glutamyl moiety plays an important role in modulating the affinity of the ligands addressed to interact with GSH-dependent proteins. The new specific inhibitors may have a potential in counteracting tumor-protective effects depending upon GSTA1-1 activity.

Synthesis and activity of novel glutathione analogues containing an urethane backbone linkage.

The new GSH analogues H-Glo(-Ser-Gly-OH)-OH (5), its O-benzyl derivative 4, and H-Glo(-Asp-Gly-OH)-OH (9), characterized by the replacement of central cysteine with either serine or aspartic acid, and containing an urethanic fragment as isosteric substitution of the scissile gamma-glutamylic junction, have been synthesized and characterized. Their ability to inhibit human GST P1-1 (hGST P1-1) in comparison with H-Glu(-Ser-Gly-OH)-OH and H-Glu(-Asp-Gly-OH)-OH, which are potent competitive inhibitors of rat GST 3-3 and 4-4, has been evaluated. In order to further investigate the effect of the isosteric substitution on the binding abilities of the new GSH analogues 4, 5 and 9, the previously reported cysteinyl-containing analogue H-Glo(-Cys-Gly-OH)-OH has been also evaluated as a co-substrate for hGSTP1-1.

Synthesis and biological evaluation of a novel pyroglutamyl-modified TRH analogue.

The TRH analogue 3, incorporating the (S)-isothiazolidine-1,1-dioxide-3-carboxylic acid (1) moiety in place of the native L-pyroglutamic acid (pGlu) residue, has been synthesized and fully characterized by 1H and 13C NMR. The effects of replacing pGlu with its sulphonamido counterpart on biological activity have been investigated. This peptide, which is significantly stabilized towards hydrolysis by pyroglutamyl peptidase type I (PP I, EC 3.4.19.3), has shown to maintain in vitro prolactin-releasing activity.

Synthesis and preliminary pharmacological evaluation of 5-hydroxy- and 5,6-dihydroxy-1,2,3,7,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline derivatives as dopamine receptor ligands.

A series of 5-hydroxy- and 5,6-dihydroxy-1,2,3,7,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline derivatives (5a--e and 6a--e) were synthesized as conformationally rigid analogues of 1-benzyltetrahydroisoquinoline and evaluated for their affinity at D(1) and D(2) dopamine receptors. All compounds showed lower D(1) and D(2) affinities than dopamine. The 5-hydroxy-1-methyl-2,3,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline 5a and the 5,6-dihydroxy analogue 6a showed D(2) agonist activity. This was proved by their effects on prolactin release from primary cultures of rat anterior pituitary cells. Molecular modeling studies showed that the geometric parameters (namely the distances from meta and para hydroxyl oxygens to the nitrogen and the height of nitrogen from the hydroxylated phenyl ring plane) of the dopaminergic pharmacophore embedded in our compounds have lower values in comparison with those observed in D(1) and D(2) selective ligands.

Novel glutathione analogues containing the dithiol and disulfide form of the Cys-Cys dyad.

The glutathione analogue gamma-(H-Glu-OH)-Cys-Cys-OH (5), containing the 8-membered disulfide ring -Cys-Cys replacing the native-Cys-Gly fragment, has been synthesized and characterized together with its reduced dithiol form gamma-(H-Glu-OH)-Cys-Cys-OH (6).

psi(SO2NH) transition state isosteres of peptides. Synthesis and bioactivity of sulfonamido pseudopeptides related to carnosine.

This paper reports the synthesis of tauryl dipeptides related to carnosine. In particular H-Tau-His-OH (5), H-Tau-His(pi-Me)-OH (6) and H-Tau-His(tau-Me)-OH (9) are described. The enzyme carnosinase has been isolated from pig kidney and after purification has been used to test the stability and the inhibitory activity of the three new analogues. H-Tau-His-OH (5) and H-Tau-His(tau-Me)-OH (9) were found to possess weak inhibitory properties towards carnosinase, while H-Tau-His(pi-Me)-OH (6) proved to be devoid of any significant activity. All the three sulfonamido pseudopeptides 5, 6 and 9 show stability to carnosinase activity.

Design and synthesis of glutathione analogues.

This review reports recent structural modifications (since 1989) performed on the glutathione molecular both in the oxidized and reduced form. Relevant chemical aspects, biochemical consequences and therapeutical implications are illustrated. Natural thiols related to glutathione are also considered.

Synthesis and activity of the glutathione analogue gamma-(L-gamma-oxaglutamyl)-L-cysteinyl-glycine.

An efficient synthesis of the backbone modified glutathione analogue gamma-(L-gamma-oxaglutamyl)-L-cysteinyl-glycine (7), characterized by the presence of an urethane O-CO-NH linkage replacing the gamma-glutamylic CH2CO-NH fragment is described. The new analogue has been fully characterized by 1H- and 13C-NMR, and FAB-MS. Compound 7 was tested for inhibition of gamma-glutamyl-transferase activity and was found to be a non-competitive inhibitor of hog kidney gamma-glutamyltransferase (EC 2.3.2.2).

Synthesis and activity of the glutathione analogue gamma-(L-gamma-azaglutamyl)-L-cysteinyl-glycine.

The backbone-modified glutathione analogue gamma-(L-gamma-azaglutamyl)-L-cysteinyl-glycine 7, characterized by the presence of a NHCONH urea linkage deriving from the replacement of the native Glu gamma-CH2 with the aza (NH) group, was synthesized and fully characterized by FAB-MS, 1H- and 13C-NMR. Potential of 7 and its oxidized form 6 as gamma-glutamyltransferase inhibitors was investigated. Both compounds 7 and 6 were found to be competitive inhibitors of hog kidney gamma-glutamyltransferase (EC 2.3.2.2.) by binding at the donor site: the reduced analogue is a more efficient inhibitor than glutathione of the gamma-glutamyl transfer reaction. Inhibition at the acceptor site, which is also present, appears to be more complex. In particular, un-competitive inhibition is observed for compound 7. The results indicate that gamma-azapeptides of type 7 may represent interesting targets in the search for stable inhibitors of gamma-glutamyltransferases.

Nine-membered cyclodepsitripeptides containing the retroisomeric sequence of ergot peptides.

In order to examine factors influencing cyclodepsitripeptide formation and stability, three cyclic peptide models containing the alpha-hydroxyacyl-alpha-aminoacylprolyl sequence, corresponding to the peptide lactone cyclo(-Xha-Pro-Xaa-) (Xha = Hiv, Lac; Xaa = Phe, DPhe, DAla), retroisomeric with respect to the ergot oxa-cyclolic peptide moiety, have been considered. Starting from 2,5-dioxomorpholines, aminoacyl incorporation reaction led, through intermediate tetrahedral adducts (aza-cyclols), to the corresponding nine-membered cyclodepsitripeptides cyclo(-Hiv-Pro-DPhe-) 4a, cyclo(-Lac-Pro-DPhe-) 4b, and cyclo (-Hiv-Pro-DAla-) 4c. Compounds 4a-c contain a CONH peptide bond in the nine-membered ring and are stable on standing. Solution conformations of 4a-c, as inferred by NMR spectra and NOE experiments, have been studied. A cis-cis-trans backbone conformation, analogous to that observed in the case of previously studied nine-membered cyclodepsitripeptides containing two proline residues in the ring, is proposed for 4a-c.

Serine-containing 10-membered cyclodepsipeptides. Synthesis and molecular structure of PhCH2CO-DSer-Pro-Pro- and PhCH2CO-DSer-Pro-DPro-.

As a part of a research program aimed at studying synthesis and conformation of small ring peptides, the cyclization of diastereoisomeric N-phenylacetyl-seryl-propyl-proline tripeptides has been examined. Two 10-membered peptide lactones, PhCH2CO-DSer-Pro-Pro- 5a and PhCH2CO-DSer-Pro-DPro- 5b, have been isolated by treating the corresponding linear p-nitrophenyl esters with DBU in dry benzene. In these two compounds the serine lactone fragment (a common structural feature of several bioactive cyclodepsipeptides) is inserted into a highly strained small ring system. The conformation in the crystal of 5a and 5b has been studied by X-ray analysis. Both the 10-membered rings of 5a and 5b adopt an overall cis-cis-trans conformation in which the lactone junction is trans. The deviations from planarity of the peptide units vary from delta omega = 30 degrees for the DSer-Pro bond in 5b to delta omega = 5-6 degrees for the DSer-Pro bond in 5a and Pro-DPro bond in 5b. The skeletal atoms of 5b, containing the Pro-DPro sequence, are related by a pseudo-symmetry mirror plane passing through the Pro carbonyl and the opposite DSer C beta H2 group. In both the molecules the exocyclic amide bond adopts an extended conformation with respect to the DSer-Pro ring junction; this arrangement gives rise to a C5-type ring structure which is well evidenced in the case of 5a.

Ten-membered cyclotripeptides. III. Synthesis and conformation of cyclo(-Me beta Ala-Phe-Pro-) and cyclo(-Me beta Ala-Phe-DPro-).

The 10-membered cyclotripeptide cyclo(-Me beta Ala-Phe-Pro) 3 and its diastereoisomer cyclo(-Me beta Ala-Phe-DPro-) 4 have been synthesized under mild cyclization conditions starting from linear precursors containing C-terminal proline. The crystal and molecular structure of the two models has been determined by X-ray crystallography. Analysis of the NMR spectra supported by NOE data clearly indicates that the conformations found in the crystals are retained in solution. Both cyclotripeptides exhibit a cis-cis-trans backbone conformation. The two tertiary peptide bonds, at the proline and Me beta Ala nitrogen atoms, adopt a cis conformation whereas the CO-NH junctions are trans in both the models. The deviations from planarity of the peptide units vary from delta omega values of ca. 18 degrees for the Pro-Me beta Ala and DPro-Me beta Ala bonds to ca. 7 degrees for Phe-Pro and Phe-DPro bonds. Relevant conformational details of 3 and 4, as revealed by X-ray and NMR analysis, are reported. Crystals of 3 are monoclinic: P2(1), a = 5.317(2), b = 17.059(6), c = 9.514(3) A, beta = 99.18(3), Z = 2. The final R and Rw are 0.054 and 0.071 respectively. Crystals of 4 are orthorhombic: P2(1)2(1)2(1), a = 8.797(2), b = 19.440(9), c = 21.605(10) A, Z = 8. The final R and Rw are 0.069 and 0.104 respectively.

Cyclization under mild conditions of salicyloyl-dipeptides.

Carboxy-activated linear peptides 6(a-c) of general formula Sal-Xaa-Pro-ONp (Xaa = Phe: Gly; Aib) were synthesized and treated at room temperature with 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) in benzene solution. The tetrahedral adducts (oxa-cyclols) 7, 11 and 12, tautomeric forms of the corresponding 10-membered cyclodepsitripeptides, have been isolated in each of the three models examined. These adducts, which contain the hydroxylated carbon atom located at the junction between two 6-membered rings, do not show a tendency to isomerize into the corresponding macrocyclic lactones, regardless of the nature of the substituents on the C alpha carbon atom of the central residue. Partially cyclized dimeric products 8 and 13, identified as N-(Sal-Xaa-Pro)-dioxopiperazines (Xaa = Phe;Aib), have been also isolated from the cyclization reactions.

[Interaction of methimazole and quinones. Spectrophotometric determination of methimazole in blood]. / Interazione del metimazolo e chinoni. Determinazione spettrofotometrica del metimazolo nel plasma.

A sensitive method for spectrophotometric determination of methimazole is based on the reaction of this compound with 2,3-dichloro-1,4-naphtoquinone in presence of ammonia. The colour thus formed is stable, reproducible and linear in the range 0,4 to 4 micrograms/ml of methimazole concentration. This method has been employed successfully for estimation of the antithyroid drug in plasma sample with good recovery (75 +/- 2%). The colour is due to formation of a red compound of molecular formula C14H11O2N3S, deduced from elemental analysis and mass spectrum.

[Spectrophotometric determination of penicillamine with phosphomolybdic acid]. / Determinazione spettrofotometrica della penicillamina con acido fosfomolibdico.

A sensitive method for spectrophotometric determination of penicillamine is described. It is based on the chromatic reaction of penicillamine with phosphomolybdic acid. The method has good sensitivity (1.49 divided by 11.92 microgram/ml) and it is proposed for a clinical control.