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Biomedical subjects

F Legendre

Publications and source records attributed to F Legendre.

12 recordsLinked to original sources
PubMed2000

Determination by electrospray mass spectrometry of the outersphere association constants of DNA/platinum complexes using 20-mer oligonucleotides and ([Pt(NH(3))(4)](2+), 2Cl(-)) or ([Pt(py)(4)](2+), 2Cl(-)).

The cytotoxic effects of cisplatin, cis-diamminedichloroplatinum(II), are generally ascribed to the formation of DNA adducts. Several in vitro as well as in vivo studies showed that cisplatin binds preferentially to guanines belonging to (G)(n) sequences (n > or = 2). After mono- or diaquation of cisplatin, giving the cationic complexes cis-[PtCl(NH(3))(2)(H(2)O)](+) and cis-[Pt(NH(3))(2)(H(2)O)(2)](2+), DNA platination occurs in two steps: the cationic complex gives an outersphere association with DNA and the actual coordination then occurs by substitution of one aqua ligand by guanine-N7. For a better understanding of the (G)(n) selectivity of cisplatin giving the biologically active adducts, also necessary for the conception of new platinum drugs, the respective contribution of the outersphere association and actual guanine platination must be investigated. To check the role of outersphere association in the overall platination process, we used electrospray mass spectrometry (ESMS) to detect and quantify outersphere association between 20-mer oligonucleotides and platinum complexes. The 20-mer oligonucleotides were single- or double-stranded, with the same number of guanines either isolated or adjacent to each other. To deal only with outersphere association and check the influence of platinum ligands, the [Pt(NH(3))(4)](2+) and [Pt(py)(4)](2+) complexes were used. We characterized by ESMS all the different outersphere association species formed during titration of each oligonucleotide with the various platinum complexes and evaluated their affinity constants. The ESMS results demonstrate that the outersphere association depends on electrostatic interactions and on the ability of the platinum ligands to participate to hydrogen bonding, particularly within the duplex form.

Cisplatin↗
PubMed2000

A complete kinetic study of GG versus AG plantination suggests that the doubly aquated derivatives of cisplatin are the actual DNA binding species.

The hairpin-stabilized double-stranded oligonucleotides d(TATGGTATT4ATACCATA) (I) and d(TATAGTATT4ATACTATA) (II) were allowed to react with the three aquated forms of the antitumor drug cisplatin (cis-[PtCl2(NH3)2], 1) which are likely candidates for DNA binding, that is, cis-[PtC1(NH3)2(H2O)]+ (2), cis-[Pt(NH3)2(H2O)2]2+ (3), and its conjugate base cis-[Pt(OH)(NH3)2(H2O)]+ (4). The reaction between I and [Pt(NH3)3(H2O)]2+ (5) was also studied for comparison. All reactions were monitored by HPLC. The platination reactions of I and II were carried out in NaClO4 (0.1M) at 293 K and at a constant pH of 4.5 +/- 0.1 for 2, 3, and 5. The data relative to the platination by 4 were obtained from measurements in unbuffered NaClO4 solutions (0.1M) at a starting pH close to neutrality, where 3 and 4 are present in equilibrium. In this case, a fit function describing the pH-time curve allowed the determination of the actual concentrations of 3, 4, and the dihydroxo complex. The platination rate constants characterizing the bimolecular reactions between either I or II and 2, 3, and 4 were individually determined along with the rate constants for hydrolysis of the chloro-monoadducts and for the chelation reactions of the aqua-monoadducts. The reactivity of compounds 2-5, which have the general formula cis-[Pt(NH3)2(H2O)(Y)]2+/-, decreases in the order 3>4>5>>2, that is, Y= H2O > OH- >NH3 >> Cl-, which is the order of decreasing hydrogen-bond donating ability of Y. Deprotonation of 3 to 4 reduces the reactivity of the platinum complex only by a factor of approximately equals 2, and both complexes discriminate between the different purines of I and II in the same manner. Whereas 3 and 4 react approximately three times faster with the GG sequence of I than with the AG sequence of II, 2 shows a similar reactivity towards both sequences. In view of the well-established preferential binding of cisplatin to GG sequences of DNA in vivo and in vitro, this result suggests that the actual DNA platination species are derived from double hydrolysis of cisplatin.

Antineoplastic Agents↗
PubMed2000

A single d(GpG) cisplatin adduct on the estrogen response element decreases the binding of the estrogen receptor.

Both cisplatin and the estrogen receptor (ER) are known to bend DNA. The influence of the bending of sequences by the d(GpG)cisPt adduct binding of ER to estrogen response element (ERE)-like sequences was examined. Three ERE-like oligonucleotides with different affinities for ER and which include a GG in the linker sequence were designed in order to form a single central d(GpG)cisPt adduct. Using electrophoretic mobility shift assay and Scatchard analysis, it was shown that the presence of a single d(GpG)cisPt adduct in the linker sequence decreases the ER affinity for DNA. These results do not support a critical role of a DNA bend in the initial recognition of ERE by ER. Then, the platination of DNA outside of the ERE half-sites decreases the interaction of ER with ERE.

Animals↗
PubMed1993

CL307-24, a new antibiotic complex from Saccharopolyspora aurantiaca sp. nov. II. Physico-chemical and biological properties.

CL307-24I, the main component of the CL307-24 complex produced by Saccharopolyspora aurantiaca sp. nov., was found to be a potent inhibitor of yeast mitochondrial ATPase. CL307-24I displayed a high degree of activity towards some coryneform bacteria and also has been shown to possess an insecticidal activity. Its biological and physico-chemical properties clearly distinguish it from previously known ATPase inhibitors.

Adenosine Triphosphatases↗
PubMed1988

A simple screening method for insecticidal substances from actinomycetes.

A simple and selective assay system was developed in the search for new insecticidal substances from Actinomycetales strains propagated on solid culture media. The strains were first tested for their ability to produce antimicrobial compounds. Only strains displaying weak or no activity were retained and screened in the insecticidal bioassay. Microbial solid cultures were given as food to larvae and to adults of Musca domestica to detect insecticide producers. A second phase, after extraction of the active compounds, consisted of an evaluation of the insecticidal potency and a primarily biological identification of the products synthesized by the selected strain. Of 6,280 actinomycete strains which were screened, 47 were active but only 30 of these were finally chosen in the second phase of screening. All these strains, except one, produced known metabolites such as piericidins, avermectins or valinomycin. The one strain, CL307-24, and its insecticide products appeared novel and will be the topic of further study.

Actinomycetales↗
PubMed1985

Characterization and properties of very large inversions of the E. coli chromosome along the origin-to-terminus axis.

Suppression of a dnaA46 mutation by integration of plasmid R100.1 derivatives in the termination region of chromosome replication in E. coli results in medium dependence, the suppressed bacteria being sensitive to rich medium at 42 degrees C. Derivatives of such bacteria have been selected for growth at 42 degrees C in rich medium and we have analyzed representatives of the most frequently observed type: bacteria displaying, once cured of the suppressor plasmid, both rich-medium sensitivity and temperature sensitivity. We found, in all cases, that the chromosome had undergone a major inversion event between two inverted IS5's. One is located at 29.2 min on the chromosome map and the other at either one of two positions between 69 and 80 min. The consequences of such inversions for cell growth are discussed. Some of them result from the fact that the replication terminator T2 is located, in inverted chromosomes, close to oriC in the orientation which allows its functioning as a terminus (de Massy et al. in press). Our observations allow an estimation of the frequency of inversions arising from recombination between pairs of inverted chromosomal IS, which could be as high as 10(-2) per cell per generation. We also found that inversion reversal occurs frequently after Hfr conjugational transfer of one of the IS5's, in its wild-type location. This led us to propose a new mechanism of recombination, in which the incoming DNA strands serve as guides to favor recombination between the resident sequences.

Chromosome Mapping↗