René Lazaro

In vivo antidiabetic actions of naglivan, an organic vanadyl compound in streptozotocin-induced diabetes☆☆☆

The vanadyl (+IV) form of vanadium has been demonstrated to have insulin-mimetic activity in vivo. In an effort to improve the poor gastrointestinal absorption of the ion, an organic complex of vanadyl (naglivan) was synthesized. We tested the antidiabetic effects of naglivan in rats made diabetic with streptozotocin (55 mg/kg, i.v.). Four days after the streptozotocin injection, one diabetic group (DVI) and a control group (CV) were treated with naglivan (50 mg/kg/day, equivalent to 0.06 mmol vanadium/kg/day) by oral gavage. Treatment in the DVI group was supplemented with daily insulin while a second diabetic group (DI) was administered daily titrated doses of insulin alone (Protamine Zinc, s.c.) to achieve stable euglycemia. The dose of exogenous insulin required to maintain normal glucose was significantly lower in the DVI group compared to the DI throughout the treatment period. At the end of week 3, exogenous insulin was withdrawn from both the DVI and DI groups, while naglivan treatment was continued in the CV and DVI groups for an additional 5 weeks. At termination, hearts were isolated and cardiac function (+dP/dt, -dP/dt and left ventricular developed pressure) was assessed in all the animals. After insulin was withdrawn, 4/8 DVI animals which continued to receive naglivan had consistent normoglycemia (as determined by % glycosylated hemoglobin) and an improved cardiac function. All the DI animals and 4/8 DVI rats were hyperglycemic and had depressed heart function despite having similar plasma insulin levels to the euglycemic DVI animals. As with vanadyl sulfate, there were no signs of long-term toxicity with regards to renal or liver function after 8 weeks of treatment. Thus, naglivan is an orally effective form of vanadyl with an oral potency 7.6 times greater than that of vanadyl sulfate (minimum effective dose: 0.06 mmol vanadium.kg-1.day-1) as compared to vanadyl sulfate (0.46 mmol vanadium.kg-1.day-1). The lack of incidence of diarrhea in either control or diabetic animals demonstrates that naglivan could be a more therapeutically desirable form of vanadyl.

New biocatalysts for peptide synthesis :Gels of copolymerized acrylic derivatives of α-chymotrypsin and polyoxyethylene

Abstract Copolymers of acrylated derivatives of α-chymotrypsin and polyethylene glycol (PEG*) have been prepared and used as biocatalysts for the synthesis of model peptides in organic solvent. AcTyrLeuNH 2 is quantitatively obtained even after a dozen of cycles.

Antitumoral cyclic peptide analogues of chlamydocin

A series of cyclic tetrapeptides bearing the bioactive alkylating group on an epsilon-amino-lysyl function have been examined for their antitumoral activity on L1210 and P388 murine leukemia cell lines. One analogue belonging to the chlamydocin family and bearing a beta-chloroethylnitrosourea group was found to be potent at inhibiting L1210 cell proliferation and had a higher therapeutic index than the reference compound bis-beta-chloroethylnitrosourea (BCNU) on the in vivo P388-induced leukemia model.

PYRROLIDINOPIPERAZINEDIONE AS CHIRAL AUXILIARY AND ITS USE IN ASYMMETRIC MANNICH SYNTHESIS

Abstract Functionalised diketopiperazines (DKPs) are easily obtained optically pure by disymmetrization of a mesopyrrolidine and can be easily converted to an α-amino amine containing compound. As a first example, one of the new chiral auxiliaries has been used to prepare an optically pure β-amino ester through a Mannich reaction.

CHEMICAL REACTIVITY IN MATRIX-ASSISTED LASER DESORPTION/IONIZATION MASS SPECTROMETRY

During the control of a multistep organic synthesis on a soluble polymer (PEG) by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry, a chemical reactivity was encountered when the matrix was acidic, for the samples where the amino moiety of the anchored compounds was protected as a Schiff base. Such imine hydrolysis was proven to be solely mediated by the acidic matrix during analyses since the expected protected structures were detected when the experiments were duplicated with a non-acidic matrix. Even if MALDI mass spectrometry was found to be more convenient than electrospray ionization mass spectrometry for the monitoring of liquid phase organic syntheses, the chemical reactivity imparted by the use of a matrix must be taken into account to avoid erroneous spectra interpretations. Copyright 1999 John Wiley & Sons, Ltd.

Detection of enzyme activity at trace levels: A new perspective for the direct screening of active catalytic antibodies

A very low level of enzyme activity (10−11 mol) has been detected using a PCR method following a vector hybridisation of a supported oligonucleotide. This methodology could be very useful for direct active catalytic antibody screening from a combinatorial library.

Enzymatic peptide synthesis by new supported biocatalysts

SummaryIt is well known that proteases can be successfully used for peptide synthesis in aqueous medium or in water-containing organic solvents. Copolymerized of acrylated derivatives ofα-chymotrypsin and polyethylene glycol (PEG) have been prepared and used as biocatalysts for the synthesis of model peptides in organic solvents containing a very low quantity of water. Trypsin has been similarly treated and used as a new biocatalyst particularly for the coupling of non-specific substrates.

Total synthesis and Ionophoric behaviour of a gramicidin A analogue.

Abstract A new gramicidin A analogue (GAA) containing a C-terminal β-alaninamide group instead of the natural ethanolamine moiety has been synthesized on a polyacrylic resin and examined after its incorporation into a black lipid membrane (BLM). Preliminary conductance data show that this peptide and the natural gramicidin both display the same ionophoric activity.

Electrospray mass spectrometry analysis of liquid-phase organic synthesis

Electrospray ionization mass spectrometry was found to be a valuable tool to follow multi-step organic liquid-phase syntheses. Such an analytical method is not limited to the monitoring of peptide synthesis but could be extended to any supported organic structures, in particular in the field of combinatorial chemistry.

Protected-aoe analogues of chlamydocin

c[(2S,9R)8-dithianAoe1-(2R)-Pro] 1 and c[(2R,9R)8-dithianNMe-Aoe1-(2S)Pro] 2 have been prepared as protected analogues of chlamydocin.