Sames Sicsic

Structure–activity relationships of some 3-substituted-4-hydroxycoumarins as HIV-1 protease inhibitors

The screening of the HIV-1 protease (PR) inhibitory activity (IC-50) of various substituted 3-phenyl-4-hydroxycoumarins, 3-benzyl-4-hydroxycoumarins, 3-phenoxy-4-hydroxy-coumarins, 3-benzenesulfonyl-4-hydroxycoumarins and 3-(7-coumarinyloxy)-4-hydroxycoumarins was performed. The data indicate the importance of substituents at positions 5 and 7 of the coumarin ring on the inhibitory potency of the HIV-1-PR.

Chemical modification of chitosan by glycidyl trimethylammonium chloride. characterization of modified chitosan by 13C- and 1H-NMR spectroscopy

Abstract Modification of chitosan by glycidyl trimethylammonium chloride is studied. The structure of the modified chitosan is discussed using elemental analysis and i.r. and NMR spectroscopies. All the results are consistent with N-monoalkylation.

Metal-organic compounds: a new approach for drug discovery. N1-(4-methyl-2-pyridyl)-2,3,6-trimethoxybenzamide copper(II) complex as an inhibitor of human immunodeficiency virus 1 protease.

The use of metal-organic complexes is a potentially fruitful approach for the development of novel enzyme inhibitors. They hold the attractive promise of forming stronger attachments with the target by combining the co-ordination ability of metals with the unique stereoelectronic properties of the ligand. We demonstrated that this approach can be successfully used to inhibit the protease of the human immunodeficiency virus (type 1). Several ligands bearing substituents designed to interact with the catalytic site of the enzyme when complexed to Cu(2+) were synthesised. The inhibition pattern of the resulting copper(II) complexes was analysed. We showed that the copper(II) complex of N1-(4-methyl-2-pyridyl)-2,3,6-trimethoxybenzamide (C1) interacts with the active site of the enzyme leading to competitive inhibition. On the other hand, N2-pyridine-amide ligands and oxazinane carboxamide ligand were found to be poor chelators of the cupric ion under the enzymatic assay conditions. In these cases, the observed inhibition was attributed to released cupric ions which react with cysteine residues on the surface of the protease. While unchelated metal cations are not likely to be useful agents, metal chelates such as C1 should be considered as promising lead compounds for the development of targeted drugs.

Chemoenzymatic approach to carbocyclic analogues of ribonucleosides and nicotinamide ribose.

Abstract Resolution of(±) methyl-4- cis -acetamido-cyclopent-2-ene carboxylate 1 was performed by enzymatic enantioselective hydrolysis using pig liver esterase with ee of 87 % and 97 %.

Design, synthesis, and biological evaluation of new 5-HT4 receptor agonists: application as amyloid cascade modulators and potential therapeutic utility in Alzheimer's disease.

Serotonin 5-HT(4) receptor (5-HT(4)R) agonists are of particular interest for the treatment of Alzheimers disease because of their ability to ameliorate cognitive deficits and to modulate production of amyloid beta-protein (Abeta). However, despite the range of 5-HT(4)R agonists synthesized to date, potent and selective 5-HT(4)R agonists are still lacking. In the present study, two libraries of molecules based on the scaffold of ML10302, a highly specific and partial 5-HT(4)R agonist, were efficiently prepared by parallel supported synthesis and their binding affinities and agonist activities evaluated. Furthermore, we showed that, in vivo, the two best candidates exhibited neuroprotective activity by increasing the level of the soluble form of the amyloid precursor protein (sAPPalpha) in the cortex and hippocampus of mice. Interestingly, one of these compounds could also inhibit Abeta fibril formation in vitro.

A new approach for using cofactor dependent enzymes: example of alcohol dehydrogenase

The use of enzymes requiring a cofactor as substrate in organic synthesis is still a problem since the cofactors are expensive. This study deals with a new approach consisting of using fragments of NAD+. Three fragments of NAD(H) are examined. The activities of NMN+ and NMNH are greatly improved by the addition of adenosine in ethanol oxidation and in cyclohexanone reduction, respectively. Nicotinamide monocucleoside is not active in the ethanol oxidation but the addition of AMP promotes this reaction.

Synthesis and activity of HIV protease inhibitors

Abstract We report here the synthesis and activity of HIV protease inhibitors. In the first stage hydrophobic compounds incorporating a ‘carba’ bond surrogate or a beta-homologated residue were synthesized. Secondly, we synthesized cyclic compounds in which we incorporated 2-quinoline carboxylic acid in the P3 position and the amino-hydroxyindane moiety in the P3. The last part of this work was dedicated to a structure/activity study of a peptide substrate. These modifications allowed us to work up the synthesis of new pseudopeptide bonds: amino-amide and hydroxy-amide. Compounds with activity in the micromolar range were actually a starting point for the synthesis of new protease inhibitors.

Enzymatic asymmetric synthesis of cis-4-cyclopentene-1,3-dimethanol monoacetate.

Abstract Asymmetric synthesis of cis-4-cyclopentene-1,3-dimethanol monoacetate was performed via enzymatic hydrolysis of the diacetate or enzymatic acetylation of the diol precursor. Esterases and lipases were studied, and Candida cylindracea lipase was shown to afford the (−)- enantiomer with ee >97%.

Asymmetric microbial reduction of tetralones

The reduction of α- and β-tetralones [3,4-dihydronaphthalen-2(1H)-ones] and of 4-substituted-α-tetralones with Sporobolomyces pararoseus and Rhodotorula rubra is described. Both strains were grown in well aerated fermentors, in some cases improving the conversion yields up to 100%, and modifying the known selectivity of the reductions performed with S. pararoseus. All the reductions performed with R. rubra are enantioselective giving rise to (S)-alcohols, but they are weakly influenced by substituents at the 4-position. With this strain (S)-β-tetralol could be obtained with 90% ee and 100% conversion yield. Reductions performed with S. pararoseus are not enantioselective giving rise to (S)-and (R)-alcohols indicating the possible action of two reductases. These two reductases are strongly influenced by substituents at the 4-position, allowing only anti entry of the hydride, giving rise to cis-alcohols. cis-(1 R,4R)-4-Methyl-4-phenyl-1,2,3,4-tetrahydro-1-naphthol 12 could be obtained enantiomerically pure with an excellent conversion yield. The crystal structure of the Mosher ester derivative of compound 12 is described.

Entrapment of l-tryptophan producing Escherichia coli in different matrices: activity of immobilized cells

Abstract Cells of Escherichia coli induced for l -tryptophan synthase [ l -serine hydro-lyase (adding indole-glycerol-phosphate), EC 4.2.1.20] have been assayed in DMF and DMSO aqueous solvents as reaction medium. Up to 20% DMF/water, cells retained 90% of their tryptophan synthase activity. Concentrations of 20 mM indole, which did not inhibit this reactivity, could be reached with 5% DMF/water. Four matrices were compared for cell immobilization: polyacrylamide, foam particles of bovine seum albumin, alginate and κ-carrageenan. The best activity was retained with the latter matrix, and the preparations thus obtained allowed high productivity of l -tryptophan. Various systems of production of l -tryptophan with κ-carrageenan and DMF/water were studied .