Synthesis and biological evaluation of O-alkylated tropolones and related alpha-ketohydroxy derivatives as ribonucleotide reductase inhibitors.

A series of O-alkylated tropolones and related alpha-ketohydroxy compounds were evaluated for their biological activities and were shown to present an expected ribonucleotide reductase inhibition and cytotoxicity against some cancer cell lines but no antitubulin activity. Pharmacomodulation studies were realised to understand and enhance the observed activities. These original benzylic, heterocyclic and allylic compounds have been synthesised by a phase-transfer catalysed O-alkylation developed in our laboratories.

Synthesis and in vitro antibacterial activity of catechol-spiramycin conjugates.

The first synthesis of siderophore conjugates of two macrolide antibiotics, spiramycin 1 and neospiramycin 2, which are unable to penetrate the outer membrane of gram-negative bacteria are described. These novel conjugates were prepared by regioselective acylation of a hydroxyl function of 1 and 2 with a dihydroxybenzoic Fe(III) complexing ligand linked via a carboxyl group containing spacer to the macrolide antibiotics. The preliminary biological evaluation of these novel conjugates under standard and iron depleted conditions has shown that their antibacterial activity was comparable to that of spiramycin 1 and neospiramycin 2.

Recent developments in streptogramin research.

The streptogramins are a class of antibiotics remarkable for their antibacterial activity and their unique mechanism of action. These antibiotics are produced naturally, but the therapeutic use of the natural compounds is limited because they do not dissolve in water. New semisynthetic derivatives, in particular the injectable streptogramin quinupristin/dalfopristin, offer promise for treating the rising number of infections that are caused by multiply resistant bacteria. The streptogramins consist of two structurally unrelated compounds, group A and group B. The group A compounds are polyunsaturated macrolactones: the group B compounds are cyclic hexadepsipeptides. Modifications of the group B components have been mainly performed on the 3-hydroxypicolinoyl, the 4-dimethylaminophenylalanine and the 4-oxo pipecolinic residues. Semi-synthesis on this third residue led to the water-soluble derivative quinupristin. Water-soluble group A derivatives were obtained by Michael addition of aminothiols to the dehydroproline ring of pristinamycin IIA. Followed by oxidation of the intermediate sulfide into the sulfone derivatives (i.e., dalfopristin). Water-soluble derivatives (both group A and group B) can now be obtained at the industrial scale. Modified group B compounds are now also being produced by mutasynthesis, via disruption of the papA gene. Mutasynthesis has proved particularly useful for producing PIB, the group B component of the oral streptogramin RPR 106972. The streptogramins inhibit bacterial growth by disrupting the translation of mRNA into protein. Both the group A and group B compounds bind to the peptidyltransferase domain of the bacterial ribosome. The group A compounds interfere with the elongation of the polypeptide chain by preventing the binding of aa-tRNA to the ribosome and the formation of peptide bonds, while the B compounds stimulate the dissociation of the peptidyl-tRNA and may also interfere with the release of the completed polypeptide by blocking its access to the channel through which it normally leaves the ribosome. The synergy between the group A and group B compounds appears to result from an enhanced affinity of the group B compounds for the ribosome. Apparently, the group A compound induces a conformational change such that B compound binds with greater affinity. The natural streptogramins are produced as mixtures of the group A and B compounds, the combination of which is a more potent antibacterial agent than either type of compound alone. Whereas the type A or type B compound alone has, in vitro and in animal models of infection, a moderate bacteriostatic activity, the combination of the two has strong bacteriostatic activity and often bactericidal activity. Minimal inhibitory concentrations of quinupristin/dalfopristin range from 0.20 to 1 mg/l for Streptococcus pneumonae, from 0.25 to 2 mg/l for Staphylococcus aureus and from 0.50 to 4 for Enterococcus faecium, the principal target organisms of this drug. Quinupristin/dalfopristin also has activity against mycoplasmas, Neisseria gonorrhoeae, Haemophilus influenz, Legionella spp. and Moraxella catarrhalis. Bacteria develop resistance to the streptogramms by ribosomal modification, by producing inactivating enzymes, or by causing an efflux of the antibiotic. Dimethylation of an adenine residue in rRNA, a reaction that is catalyzed by a methylase encoded by the erm gene class, affects the binding of group B compounds (as well as the macrolides and lincosamides; hence, MLSB resistance), but group A and B compounds usually maintain their synergy and their bactericidal effect against MLSB-resistant strains. erm genes are widespread both geographically and throughout numerous bacterial genera. Several types of enzymes (acetyltransferases, hydrolases) have been identified that inactivate the group A or the group B compounds. Genes involved in streptogramin efflux have so far been found only in staphylococci, particularly in coagulase-negative species

Unusual transformation of the 3-hydroxy-picolinoyl residue of pristinamycin IA.

Pristinamycin IA was modified in a two-step procedure to give original derivatives possessing a tricyclic nucleus (8a, 8b, 8c) or a substituted pyrrole ring (10a, 10b) in place of the natural exocyclic 3-hydroxy-picolinoyl residue. This transformation involved firstly preparation of pyridinium betaines 5 from pristinamycin IA and secondly a 1-3 dipolar cycloaddition between 5 and N-substituted maleimides or diethyl acetylenedicarboxylate. The compounds obtained were evaluated as antibacterial agents alone and in association with pristinamycin IIA.

Antimicrobial activity against Staphylococcus aureus of semisynthetic injectable streptogramins: RP 59500 and related compounds.

Pristinamycin displays unique antibacterial properties due to the synergy between its two components, pristinamycin I and pristinamycin II. Because this antibiotic is not water-soluble, its administration is restricted to the oral route, and its therapeutic potential is thereby limited. Novel water-soluble derivatives of the naturally-occurring antibiotic pristinamycin were obtained by modifications of its two major components. The modifications included regioselective and stereoselective substitution alpha to the carbonyl group in the 4-oxo-pipecolic acid residue of pristinamycin IA (PIA) and stereoselective conjugate addition to the double bond of the dehydroproline ring in pristinamycin IIA (PIIA). We report here the in-vitro and in-vivo activities of some representative water-soluble derivatives of pristinamycin IA and pristinamycin IIA against Staphylococcus aureus reference strains, sensitive or resistant to methicillin and/or macrolides.

[Surgical treatment of congenital aortic valve constriction with associated obstructive cardiomyopathy. Perioperative left intraventricular gradient treated with beta blockers. Apropos of a case]. / Traitement chirurgical d'un rétrécissement aortique valvulaire congénital avec myocardiopathie obstructive associée. Gradient intra-ventriculaire gauche peropératoire traité par bêta-bloquers. A propos d'un cas.

The authors report a case of congenital valvular aortic stenosis associated with echocardiographic and angiographic appearances of hypertrophic obstructive cardiomyopathy. After valvular replacement and partial myotomy a high intraventricular pressure gradient (125 mmHg) with low intra aortic pressure was recorded. High dose intravenous propranolol (25 mg in 2 hours) reduced this gradient to 50 mmHg allowing cardiopulmonary bypass to be discontinued. This clinical combination is associated with a risk of aggravation of the intra-ventricular obstructive phenomenon when the obstacle to left ventricular ejection is relieved: surgical myotomy was performed in similar, previously published cases. High doses betablocker therapy can be performed in similar, previously published cases. High dose betablocker therapy can be useful in this association and it may also be instituted when right intraventricular pressure gradient increase after relief of pulmonary valvular stenosis.