RESUMEN

BACKGROUND AND STUDY AIMS: A small amount of free air, visible on CT but not on plain chest radiography, which appeared following endoscopic submucosal dissection (ESD) of a gastric neoplasm without endoscopically visible perforation, was defined as a "transmural air leak", and a prospective, consecutive entry study was performed to determine its incidence and clinical significance. PATIENTS AND METHODS: Between January 2006 and September 2008, ESD was performed for 246 gastric lesions in 246 consecutive patients. Abdominal CT scan was performed 1 day after ESD. In addition, chest radiography and blood biochemistry tests were performed at different time points before and after ESD. RESULTS: Two hundred and nineteen lesions (89 %) were curatively removed by ESD. Among the total of 246 patients, we encountered endoscopically visible perforation during ESD in 2 patients (0.8 %), and clinically suspected perforation diagnosed by the presence of free air on chest radiography but invisible during ESD in 3 patients (1 %), while transmural air leak was observed in another 33 (13 %). Air leak occurred in cases where resection size was larger, procedure time longer, and the muscularis propria on the ulcer base was exposed at the end of ESD. Patients with air leaks developed pyrexia at a higher rate than those without (36 % vs. 16 %, P = 0.018). These patients recovered with antibiotics and required no endoscopic or surgical intervention. The presence of an air leak did not affect the duration of hospital stay. CONCLUSIONS: A transmural air leak was observed in 13 % of the patients undergoing ESD. Larger resection size, prolonged procedure time, and exposure of the muscularis propria on the ulcer base were risk factors for transmural air leak, but the outcome of patients with this complication was good.

Asunto(s)

RESUMEN

The stereochemical outcome of the 1,3- and 1,5-migration of an Fe(CO)3 group on (acyclic polyene)Fe(CO)3 complexes and their application to stereoselective construction of remote and contiguous stereogenic centers are described. Treatment of the [(eta(4)-4-7)triene]Fe(CO)3 complexes 1a-d bearing an electron-withdrawing group on the terminal position of an uncomplexed olefin with a base such as KN(SiMe3)2 (KHMDS) and LiCH2CN induced the 1,3-migration reaction of the Fe(CO)3 group, giving the [(eta4-2-5)triene]Fe(CO)3 complexes 2a-d in moderate to good yields, depending on the electron-withdrawing groups. From an experiment using the chiral (trienenitril)Fe(CO)3 complex 5, it is revealed that the 1,3-migration proceeds with inversion of configuration. Similarly, the 1,5-migration reaction of the[(eta4-6-9)tetraenone]Fe(CO)3 complexes 9 occurred with a catalytic amount of KHMDS, giving the [(eta4-2-5)tetraenone]Fe(CO)3 complexes 10 with retention of configuration. Furthermore, we have succeeded in the first regio- and stereoselective nucleophilic substitution of the (3,5-diene-1,2-diol) Fe(CO)3 complexes (15 --> 24a-h) with various nucleophiles via the ortho esters 21. By using iterative manipulation of the above two reactions, remote stereocontrol of the terminal substituents on acyclic polyene (9 --> 12) and construction of contiguous stereogenic centers (19, 28) have been achieved.

RESUMEN

Whereas palladium-catalyzed reaction of N-arylsulfonyl-alpha-amino allenes with an aryl iodide (4 equiv) in the presence of potassium carbonate (4 equiv) in DMF at around 70 degrees C affords the corresponding 3-pyrroline derivatives, the reaction in refluxing 1,4-dioxane under otherwise identical conditions yields exclusively or most predominantly the corresponding 2-alkenylaziridines bearing an aryl group on the double bond. Similarly, N-arylsulfonyl-beta-amino allenes can be also cyclized into the corresponding alkenylazetidines bearing a 2,4-cis-configuration under palladium-catalyzed cyclization conditions in DMF.

RESUMEN

The asymmetric total synthesis of the marine metabolite, halicholactone 1, is described. The bisallylic triol 6 with three chiral centers at C8, C12, and C15 was constructed by [2,3]-sigmatropic rearrangement of the sulfoxide 18, which was prepared stereoselectively using the chirality of (diene)Fe(CO)3 complexes. Introduction of the trans-substituted cyclopropane subunit into 21 was successfully achieved using the modified regio- and stereoselective Simmons-Smith reaction. The use of RCM (ring-closing metathesis) methodology (4-->35) was pivotal for the formation of a nine-membered unsaturated lactone fragment of halicholactone 1. As this approach is flexible and stereoselective, other oxylipins could be synthesized by the protocol described herein.

Asunto(s)

RESUMEN

The intermolecular pinacol-type coupling reaction and allylation reaction of optically active imines bearing a beta-hydroxy group were performed stereoselectively with metallic samarium after treatment of the imines with trimethylaluminum.

RESUMEN

We have previously found that T22 ([Tyr(5,12), Lys7]-polyphemusin II) has strong anti-human immunodeficiency virus (HIV) activity, and that T22 inhibits T cell-line-tropic HIV-1 infection mediated by CXCR4/fusin. T22 is an 18-residue peptide amide, which takes an antiparallel beta-sheet structure that is maintained by two disulfide bridges. Structure-activity relationship (SAR) studies on T22 have disclosed the contributions of each region of T22 to activity or cytotoxicity, and have provided the following useful information to develop new CXCR4 antagonists: The number of Arg residues in the N-terminal and C-terminal regions of T22 is closely related to anti-HIV activity. Addition of a variety of functional groups at the N-terminal end results in increases in activity. Disulfide rings, especially the major disulfide loop, are indispensable for anti-HIV activity and maintenance of the beta-sheet structure. Trp3 can be replaced by other aromatic residues (Tyr, Phe and L-2-naphthylalanine). Between two repeats of Tyr-Arg-Lys, which are a characteristic structure in T22, Tyr-Arg-Lys in the N-terminal portion is more closely associated with anti-HIV activity and maintenance of the beta-sheet structure. A positive charge in the side chain at the (i + 1) position of the beta-turn region is necessary for strong activity. Through these studies, we have found several compounds having higher selectivity indexes (50% cytotoxic concentration/50% effective concentration) than that of T22.

Asunto(s)

RESUMEN

T22 ([Tyr5,12,Lys7]-polyphemusin II) has been shown to have strong anti-human immunodeficiency virus (HIV) activity comparable to that of 3'-azido-2',3'-dideoxythymidine (AZT). T22, an 18-residue peptide amide, takes an antiparallel beta-sheet structure that is maintained by two disulfide bridges. Herein we synthesized several shortened analogs of T22 in order to search for a more suitable lead compound. A 14-residue analog having one disulfide bridge, TW70 (des-[Cys8,13, Tyr9,12]-[D-Lys10, Pro11]-T22), was found to have highly potent activity comparable to that of T22, and to take an antiparallel beta-sheet structure similar to that of T22. This indicates that the molecular size of T22 can be reduced without loss of activity or significant change in the secondary structure, and that TW70 may represent a novel lead compound. Furthermore, modifying the N-terminal alpha-amino group of TW70 with a fluoresceinthiocarbamoyl group, and the epsilon-amino group of D-Lys8 at the turn portion with a 5-aminopentanoyl group remarkably increased the selectivity index (50% cytotoxic concentration/50% effective concentration).

Asunto(s)

RESUMEN

A tachyplesin peptide analog, T22 ([Tyr5,12, Lys7]-polyphemusin II), and its shortened congener, TW70 (des-[Cys8,13, Tyr9,12]-[D-Lys10, Pro11]-T22) have strong anti-human immunodeficiency virus (HIV) activity, comparable to that of 3'-azido-2', 3'-dideoxythymidine (AZT). T22 and TW70 are extremely basic peptides, containing 5 Arg residues and 3 Lys residues. The number of positive charges might be related in part to high collateral cytotoxicities of T22 and TW70. Here we have synthesized several analogs, in which the number of positive charges has been reduced through amino acid substitutions using Glu or L-citrulline. As a result, several effective compounds have been found which possess higher selectivity indexes (SIs, 50% cytotoxic concentration/50% effective concentration) than those of T22 and TW70. Higher SIs were attributed mainly to a decrease in cytotoxicity.

Asunto(s)

RESUMEN

T22 ([Tyr5,12, Lys7]-polyphemusin II) is an 18-residue peptide amide, which has strong anti-HIV activity. T22 inhibits the T cell line-tropic (T-tropic) HIV-1 infection through its specific binding to a chemokine receptor CXCR4, which serves as a coreceptor for the entry of T-tropic HIV-1 strains. Herein, we report our finding of novel 14-residue CXCR4 inhibitors, T134 and T140, on the basis of the T22 structure. In the assays we examined, T140 showed the highest inhibitory activity against HIV-1 entry and the strongest inhibitory effect on the binding of an anti-CXCR4 monoclonal antibody (12G5) to CXCR4 among all the CXCR4 inhibitors that have been reported up to now.

Asunto(s)

RESUMEN

Cholecystokinin (CCK) is an important bioactive peptide that stimulates pancreatic enzyme secretion. Circulating CCK is secreted from endocrine cells in the upper small intestine in response to various luminal stimuli and to vascular administration of gastrin releasing peptides. However, the mechanism of its release has not been fully elucidated. In the present study, the vascularly perfused duodenojejunum was isolated from male Wistar rats. The effects of luminal infusion of sodium oleate (2 or 0.4%) or intra-arterial infusion of neuromedin C(10(-7) M) with or without atropine and with a recently synthesized specific bombesin antagonist (EABI) were examined. The CCK release produced by intra-arterial infusion of neuromedin C was inhibited by EABI in a dose-dependent manner. The CCK release produced by luminal sodium oleate was inhibited by atropine, but not affected by EABI. The CCK release stimulated by luminal sodium oleate is mediated, at least in part, by a cholinergic mechanism, but neuromedin C directly stimulates CCK release via its receptor on CCK-producing cells.

Asunto(s)

RESUMEN

The specific bombesin receptor antagonist, (E)-alkene bombesin isostere (EABI-1), [D-Phe6,Leu13psi[(E)CH=CH]Leu14]bombesin(6-14) is a potent antagonist in terms of inhibition of bombesin-stimulated amylase release from rat pancreatic acini. This study examined the effects of EABI-1 (L-L diastereomer) and three novel bombesin analogues on amylase release in rat pancreatic acini. EABI-2 is a L-D diastereomer of EABI-1. EABI-3 is an analogue, of which leucine at position 13 of EABI-1 was replaced with valine. EABI-4 is a L-D diastereomer of EABI-3 (L-L). The order of agonist potency was EABI-2>EABI-3>EABI-4. EABI-1 showed no agonist activity at concentrations up to 100nM. On the other hand, all of four analogues had antagonist activity. The order of antagonist potency was EABI-1>EABI-3>EABI-4>EABI-2. EABI-1 was a complete antagonist, EABI-2 and EABI-3 were partial agonists, and EABI-4 had a weak agonist effect. The present study provides a useful information on the future development of peptide analogues for anticancer agents and biological tools for investigating actions of bombesin family peptides.

Asunto(s)

RESUMEN

T22 ([Tyr5,12, Lys7]-polyphemusin II) has been shown to have strong anti-human immunodeficiency virus (HIV) activity, comparable to that of 3'-azide-2', 3'-dideoxythymidine (AZT). T22 takes an antiparallel beta-sheet structure maintained by two disulfide bridges and contains two antiparallel repeats of Cys-Tyr-Arg-Lys-Cys. As reported herein, fully reduced T22 was found by HPLC and ion spray mass spectrometric analyses to form a complex in a molar ratio of 1:1 with Zn(II) ion at neutral pH in aqueous solution. Complexation of Zn(II) ion to this peptide appears to result in tetracoordinate bonding to sulfur atoms of four Cys residues. We also found that the anti-HIV activity of the T22-Zn(II) complex was fourfold stronger than that of T22.

Asunto(s)

RESUMEN

We have previously found that T22 ([Tyr5, 12, Lys7]-polyphemusin II) exhibits strong anti-human immunodeficiency virus (HIV) activity comparable to that of 3'-azido-2', 3'-dideoxythymidine (AZT). The inhibition mechanism of T22 on HIV-replication has not been elucidated precisely yet, and hence the target molecules of T22 have not been identified. However, our recent research suggested that T22 exerts its effect by blocking virus-cell fusion at an early stage of HIV infection and that T22 might interact with an HIV envelope protein and/or a T-cell surface protein, both of which are critical for HIV infection. In this paper we demonstrated that T22 binds specifically to both gp120 (an envelope protein of HIV) and CD4 (a T-cell surface protein) and that both bindings can be inhibited by an anti-T22 antibody, using biosensor technology (BIAcoreTM) based on the principles of surface plasmon resonance. Linearization by the BIAcoreTM system (BIAlogue software) and nonlinear least squares analysis by curve fitting with exponential equations showed that both interactions have close dissociation constants (approximately 10(-7) M). The present study suggests that T22 inhibits the virus-cell fusion process through binding to both gp120 and CD4.

Asunto(s)

RESUMEN

As part of our continuing search for potential anticancer drug candidates that are selective against slowly growing solid tumors, we have synthesized several series of 1- and 2-substituted derivatives of the lead structure, 1-ethyl-2-methylnaphth[2,3-d]imidazole-4,9-dione (5). Their cytotoxic activity in the National Cancer Institute's in vitro cancer cell line panel is reported. In general, substitution of various alkyl, phenyl, or benzyl moieties did not improve activity, and compound 5 remains the most active naphth[2,3-d]imidazole-4,9-dione derivative. However, high levels of activity and selectivity were found with several related 2-(acylamino)-3-chloro-1,4-naphthoquinones (2f-j). Compound 2i, 2-[(2-fluorophenyl)acetamido]-3-chloro-1,4-naphthoquinone, has been selected for further in vivo testing and as an additional lead compound for further structural modification.

Asunto(s)

RESUMEN

T22 ([Tyr5,12, Lys7]-polyphemusin II) has been shown to have strong anti-human immunodeficiency virus (HIV) activity. The precise mechanism of action of T22 on HIV-replication has not been elucidated yet, nor have the targets of T22 been identified. However, our previous research suggested that T22 exerts its effect by blocking virus-cell fusion and that T22 might interact with an HIV envelope protein and/or a T-cell surface protein. Herein we use a novel biosensor based on the principles of surface plasmon resonance (BIAcore) to demonstrate that T22 binds specifically to both gp120 (an envelope protein of HIV) and CD4 (a T-cell surface protein) and that both bindings can be inhibited by an anti-T22 antibody. The data obtained suggest that T22 inhibits virus-cell fusion through the double binding to the above two proteins.

Asunto(s)

RESUMEN

Pyothorax-associated lymphoma (PAL) is a B cell lymphoma that develops in Japanese patients with tuberculosis-associated chronic pyothorax (TaCP). Epstein-Barr virus (EBV) has been shown to be causally related to PAL. To clarify the developmental process of PAL, the systemic and local presence of EBV, and serum profile of anti-EBV antibodies was investigated in TaCP. EBV genome was found in peripheral blood mononuclear cells by PCR in a 10(-4)-10(-5) amount of Raji cell-DNA in three of four patients with TaCP, but was also identified in patients with pyothorax caused by other diseases (2/2) or without pulmonary diseases (2/6). EBER1 in situ hybridization and EBNA2 immunocytochemistry revealed clusters of EBV-carrying cells in the cavity content (3/18) but not at the pyothorax wall; EBV(+) histological lymphoma cells were found in two cases and EBV(+) mononuclear cells were found in one case. A simultaneous increase in serum titers of anti-EBV viral capsid antigen IgG and IgA antibodies was observed in TaCP (4/16). These results suggest that a local factor, an inflammatory cavity, has a pivotal role in the development of PAL, which might be reflected in the serum titers of anti-EBV antibodies in patients with TaCP.

Asunto(s)

RESUMEN

All disulfide analogs (types I, II and III) of protegrin (PG)-1, an 18-residue antimicrobial peptide having two intramolecular disulfide bonds, were synthesized using regioselective disulfide bond formation. Random air-oxidation of the fully reduced PG-1 formed the type III PG-1. In addition, a type III analog containing an amidated carboxy-terminal residue was also prepared. Each analog showed significant and different antibacterial and anti-human immunodeficiency virus (HIV) activity. Deletion of two disulfide bridges caused a significant decrease in activity.

Asunto(s)

RESUMEN

Disulfide bond formation in S-acetamidomethyl (Acm) cysteine-containing peptides by successive treatments with silver trifluoromethanesulfonate (AgOTf) and dimethyl sulfoxide (DMSO)/aqueous HCl is described. An S-Acm cysteine was found to be quantitatively converted into cysteine by deprotection of the Acm group with AgOTf followed by DMSO/aqueous HCl treatment. Under these reaction conditions, no significant side reactions were observed with oxidation-sensitive amino acids such as Met, Tyr and Trp. Oxytocin and a Trp-containing peptide, urotensin II, were prepared by this method. Furthermore, regioselective two disulfide bond formation was found to be feasible by the combination of air oxidation and the AgOTf-DMSO/HCl system. This strategy has been successfully applied to the syntheses of tachyplesin I and endothelin I, which have two disulfide bonds and a Trp residue in the molecule.

Asunto(s)

RESUMEN

The short-chain pseudopeptide, [D-Phe6, Leu13 psi (CH2NH)Leu14]bombesin(6-14) (RDI), is reported to be a potent antagonist of bombesin, and development of this type of compound has greatly contributed to the investigation of biological actions of bombesin and its related peptides. We recently synthesized (E)-alkene bombesin isostere by replacing the peptide bond with an (E)-double bond: [D-Phe6, Leu13 psi [(E)CH = CH]Leu14] bombesin(6-14) (EABI). The present study examined the effect of EABI on amylase release from rat pancreatic acini. EABI showed no agonistic activity at concentrations up to 1 microM, and RBI showed slight agonistic activity at concentrations > 10 nM. EABI caused a dose-dependent inhibition of amylase release stimulated by 0.1 nM bombesin, with an IC50 of 6.7 +/- 1.7 nM, and induced almost-complete inhibition at 0.3 microM. RDI caused a dose-dependent inhibition of amylase release, with an IC50 of 68.7 +/- 16 nM. EABI caused a parallel and rightward shift of the entire dose-response curve of bombesin-stimulated amylase release, and the degree of the shift was dependent on the concentrations of EABI. EABI (100 nM) and RDI (100 nM) inhibited amylase releases stimulated by gastrin-releasing peptide (1 nM) and neuromedin-C (1 nM). In contrast, amylase release stimulated by cholecystokinin octapeptide (0.1 nM), carbachol (10 microM), vasoactive intestinal peptide (1 nM), and gastrin-17 (10 nM) was not inhibited by EABI and RDI. The results indicate that EABI is a potent and specific bombesin receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)