Biomedical subjects

Jacques Renault

Publications and source records attributed to Jacques Renault.

8 recordsLinked to original sources

PubMed2006

Effect of polyamine homologation on the transport and biological properties of heterocyclic amidines.

Five sets of heterocyclic derivatives of various sizes and complexities coupled by an amidine function to putrescine, spermidine, or spermine were prepared. They were essentially tested to determine the influence of the polyamine chain on their cellular transport. To comment on affinity and on selective transport via the polyamine transport system (PTS), K(i) values for polyamine uptake were determined in L1210 cells, and the cytotoxicity and accumulation of the conjugates were determined in CHO and polyamine transport-deficient mutant CHO-MG cells, as well as in L1210 and alpha-difluoromethylornithine- (DFMO-) treated L1210 cells. Unlike spermine, putrescine and spermidine were clearly identified as selective motifs that enable cellular entry via the PTS. However, this property was clearly limited by the size of substituents: these polyamines were able to ferry a dihydroquinoline system via the PTS but did not impart any selectivity to bulkier substituents.

Amidines↗

PubMed2005

Synthesis of a laterally branched polyamine from alpha-methylene-gamma-butyrolactone.

[reaction: see text] A polyamine derivative was prepared from alpha-methylene-gamma-butyrolactone. This method used Michael addition and lactone aminolysis followed by the nucleophilic substitution of the hydroxyl group by an azido group. The coupling of a lipophilic alkyne led to a polyamine that will be probed as a gene transfer agent.

4-Butyrolactone↗

PubMed2005

Cytotoxicity of the polyamine oxidase inactivator MDL 72527 to cancer cells: comparison with a saturated structural analogue.

MDL 72527 (N1,N4-di-2,3-butadienyl-1,4-butanediamine) is a selective inactivator of polyamine oxidase with therapeutic potential. However, the development of lethal toxic effects due to prevention of spermine degradation is a considerable disadvantage of the compound. Since the cytotoxicity of MDL 72527 was postulated to be independent of its anti-polyamine oxidase activity, its cytotoxicity to cancer cells was compared with that of a close analogue that is devoid of structural features enabling mechanism-based inactivation of polyamine oxidase. N1,N4-di-n-butyl-1,4-butanediamine proved to be a cytotoxic agent of considerable potency, which induces mainly non-apoptotic cell death, whereas MDL 72527 causes under identical conditions both, apoptotic and non-apoptotic cell death. The sensitivity of cells to both compounds is presumably dependent of their glutathione content.

Animals↗

PubMed2004

Parallel supported synthesis of polyamine-imidazole conjugates.

[reaction: see text] A small collection of nine polyamine-imidazole conjugates, potentially acting as RNases A mimics, has been synthesized on SynPhase lanterns using amino alcohols and diamines as building blocks. Couplings were performed via S(N)2 alkylation of methanesulfonates with amines. The final introduction of N-4-nitrobenzyloxycarbonyldiamines allowed easy purification of the cleaved compounds.

Journal Article↗

PubMed2004

N1-dansyl-spermine: a potent polyamine antagonist.

The potential polyamine antagonist action of N1-dansyl-spermine (a potent NMDA antagonist) was assessed in two in vivo mouse models of polyamine action. Co-administration of N1-dansyl-spermine (2-10 microg, i.c.v.) with spermine (100 microg, i.c.v.) resulted in a dose-dependent antagonism of the spermine-induced CNS excitation (body tremor and fatal tonic convulsions). In addition, the same dose of N1-dansyl-spermine antagonised spermine's enhancement of NMDA-induced convulsions. These results suggest that N1-dansyl-spermine is in vivo a potent antagonist of the CNS effects of spermine and of its action at the positive polyamine modulatory site on the NMDA receptor.

Animals↗

PubMed2004

Polyamine derivatives as selective RNaseA mimics.

Site-selective scission of ribonucleic acids (RNAs) has attracted considerable interest, since RNA is an intermediate in gene expression and the genetic material of many pathogenic viruses. Polyamine-imidazole conjugates for site-selective RNA scission, without free imidazole, were synthesized and tested on yeast phenylalanine transfer RNA. These molecules catalyze RNA hydrolysis non-randomly. Within the polyamine chain, the location of the imidazole residue, the numbers of nitrogen atoms and their relative distances have notable influence on cleavage selectivity. A norspermine derivative reduces the cleavage sites to a unique location, in the anticodon loop of the tRNA, in the absence of complementary sequence. Experimental results are consistent with a cooperative participation of an ammonium group of the polyamine moiety, in addition to it's binding to the negatively charged ribose-phosphate backbone, as proton source, and the imidazole moiety as a base. There is correlation between the location of the magnesium binding sites and the RNA cleavage sites, suggesting that the protonated nitrogens of the polycationic chain compete with some of the magnesium ions for RNA binding. Therefore, the cleavage pattern is specific of the RNA structure. These compounds cleave at physiological pH, representing novel reactive groups for antisense oligonucleotide derivatives or to enhance ribozyme activity.

Anticodon↗

PubMed2004

Pharmacomodulation of a sulfamide 5-HT6 receptor ligand.

A series of N-omega-aminoalkyl- or N-omega-amidinoalkyl-2,4,6-triisopropyl benzenesulfonamides has been synthesized and their respective affinity indices on 5-HT6 receptor determined. This evaluation clearly showed that the compounds possessing an arylpiperazine moiety or an amidine function exhibited good affinity for the model.

Drug Design↗

PubMed2002

Effect of spermine conjugation on the cytotoxicity and cellular transport of acridine.

Polyamines are believed to be potent vectors for the selective delivery of chemotherapeutic agents into cancer cells. In this paper, we report the effect of spermine conjugation on the cytotoxic and transport properties of acridine. Six derivatives, composed of a spermine chain attached at its N(1) position to an acridine via an aliphatic chain, were synthesized. The aliphatic linker, comprised of 3-5 methylene units, was connected to the position-9 of the heterocycle through either an amide (amidoacridines 8-10) or an amine (aminoacridines 11-13) linkage. Independently of their architecture, all ligands showed a high affinity for DNA binding but a limited DNA sequence selectivity. In a whole cell assay with L1210 and Chinese hamster ovary (CHO) cells, the aminoacridines (IC(50) values around 2 microM) were more potent than the amidoacridines (IC(50) values between 20 and 40 microM). This was related to a less efficient transport for the latter. As determined from competitive uptake studies with [(14)C]spermidine, all conjugates had a high affinity for the polyamine transport system (PTS). However, on the basis of competitive studies with an excess of spermidine and on the differential effect on cell growth and accumulation in CHO and in the mutant PTS deficient CHO-MG cells, the accumulation of the conjugates through the PTS was found to be poor but still more efficient for the aminoacridines. alpha-Difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, which induces an up-regulation of the activity of the PTS, enhanced accumulation of all acridine conjugates through the PTS and had a synergistic effect on the potency of the acridine conjugates to inhibit cell growth. Despite their high affinity for the PTS, the low amount of derivatives transiting through the PTS is likely to be related to their ability to repress rapidly and efficiently the activity of the PTS and, consequently, to inhibit their own uptake via this system.

Acridines↗