Biomedical subjects
Publications and source records attributed to G Gosselin.
Two unnatural L-oligodeoxyribonucleotides, namely alpha- and beta-L-dT8pO(CH2)3OH, have been synthesized. These oligomers are resistant towards nuclease degradation. They do not show any UV detectable base pairing with beta-D-dA8 and poly rA.
1-(2-Azido-2,3-dideoxy-beta-D-erythro-pentofuranosyl)thymine (2'-N3ddThd) was synthesized from 1-(5-O-trityl-2,3-anhydro-beta-D-lyxofuranosyl)thymine by two different procedures. Method A prepared the title compound by opening of the oxirane ring with LiEt3BH followed by mesylation of the 2'-hydroxyl function, introduction of the 2'-azido substituent and deblocking of the 5'-function. In method B nucleophilic opening of 3'-deoxy-5'-O-(tert-butyldimethylsilyl)-5-methyl-2,2'-anhydrouridine+ ++ was carried out with sodium azide in hexamethylphosphoramide in the presence of benzoic acid. Single X-ray crystallographic studies indicated a solid state conformation (3T2), which was opposite to that of the A form of AZT (2T3) but closely resembled that of 1-(2-fluoro-2,3-dideoxy-beta-D-erythropentofuranosyl)thymine (2'-FddThd) (3T2) and of 3'-azido-2',3'-dideoxy-2,6-diaminopurine riboside (3'-N3ddDAP) (3T2). Whereas the latter displayed significant inhibitory activity against human immunodeficiency virus (HIV) replication, 2'-FddThd and 2'-N3ddThd were essentially inactive.
The 5'----5' dinucleoside methylphosphonates of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (DDC) were prepared and evaluated for their inhibitory properties against different viruses, including human immunodeficiency virus (HIV). The synthesis of the compounds was achieved by reaction of AZT or N4-(4-monomethoxytrityl)-2',3'-dideoxycytidine with in situ prepared methylphosphonic bis (triazolide), followed in the latter case by an acidic treatment. The two title compounds showed in vitro anti-HIV activity, that was 200- to 450-fold less pronounced that that shown by the corresponding monomeric nucleosides AZT and DDC. The decreased antiviral activity may be ascribed to nuclease resistance of the methylphosphonate linkage.
Two cases of coronary artery right ventricular fistula were diagnosed during the yearly check-up of 38 of the 66 cardiac transplant patients of the Montreal Heart Institute between September 1982 and April 1989. In one case, the fistula involved the right anterior ventricular branch of the right coronary artery and in the other case, a septal branch of the left anterior descending artery. Histological examination of the biopsy fragments obtained before diagnosis of the fistula showed the presence of small calibre arteries, which was not the case in 10 control transplant patients. A review of the literature indicates that the risks of endomyocardial biopsy are minimal (less than or equal to 0.5%). However, the possibility of a coronary artery right ventricular fistula should be added to the list of known complications. The resulting shunt is negligible and has no haemodynamic consequences.
Homozygous familial hypercholesterolemia (HFH) is characterized by a very shortened lifespan, mainly due to cardiac events, and by resistance to conventional lipid lowering therapies. Two patients are described for whom a combination of portacaval shunt and mammary coronary bypass graft were done with good long term success. A review of the actual forms of treatment of HFH is made. To the authors' knowledge, there is no report in the literature of this double surgical approach.
A series of oligopeptides have been synthesized that are structurally related to the natural agent netropsin. The binding constants to double-stranded polynucleotides as well as the cytostatic activity against both murine human tumor cell lines and the in vitro activity against a range of DNA and RNA viruses have been determined for these novel compounds and some of their synthetic precursors. 1-Methyl-5-nitropyrrole-2-carboxylic acid methyl ester (4), N-[[1-methyl-4-(1-methyl-4-nitropyrrole-2-carboxamido)pyrrol-2- yl]carbonyl]-L-alanine tert-butyl ester (28), and N-[[1-methyl-4-(1-methyl-4-nitropyrrole-2-carboxamido)pyrrol-2- yl]carbonyl]-L-alanyl-L-alanine tert-butyl ester (29) showed modest inhibitory effect on tumor cell proliferation (CD50 = 26-85 micrograms/mL). Of all the compounds that were evaluated, 28 proved the most potent antiviral agent. It was inhibitory to parainfluenza-3 virus and Coxsackie virus B4 in Vero cells at a concentration of 20 micrograms/mL.
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The 3'----5',3'----3' and 5'----5' dinucleoside monophosphates and methylphosphonates of 9-beta-D-arabinofuranosyladenine, as well as its 5'-(hydrogen phosphonate) and 5'-(methyl methylphosphonate) derivatives have been the subject of a systematic synthesis and examination of their biological, i.e. antiviral and cytostatic, properties. First the properly protected monomeric building blocks were prepared and then condensed to give fully protected intermediates. These latter were then deblocked to afford the unprotected compounds, which were fully characterized. Only the 3'----5' phosphodiester isomers 13 and 16 and, to a lesser extent, the 5'-(hydrogen phosphonate) derivative 21 showed marked biological activity.
Originally described in Japan, 'apical hypertrophic cardiomyopathy' has now been reported in many other countries. A series of eight patients who present with the classic 'spade-like' left ventricular angiographic pattern are reported; five of them also had hypertension. Thus, this angiographic pattern may not be specific for apical hypertrophic cardiomyopathy and may be seen in acquired heart disease.
Several arabinosyl-, xylosyl-, lyxosyl, 5'-deoxy-, acyclo-, 2,2'-anhydro-, 2,3'-anhydro-2'-deoxy-, 2,5'-anhydro-, 6,5'-cyclo-, and carbocyclic analogues of uridine with various 5-substitutions (fluoro, methyl, bromo, ethyl, benzyl, or benzyloxybenzyl) have been tested and compared with their corresponding ribo- and 2'-deoxyribosides for their potency to inhibit uridine phosphorylase (UrdPase) from both mouse and human livers. The effect of the alpha- and beta-configurations of the glycosidic bond was also tested. Xylo-, lyxo-, 2,3'-anhydro-2'-deoxy-, 6,5'-cyclo-, and carbocyclic uridines did not bind to the enzyme. Ribosides bound better than the corresponding 2'-deoxyribosides, which were better than the 5'-deoxyribosides. 2'-alpha-Deoxyribosides bound to the enzyme, albeit less tightly than the corresponding beta-anomers. The acyclo- and 2,2'-anhydrouridines were all potent inhibitors with the 2,2'-anhydro- derivatives being the most potent. 2,5'-Anhydrouridine bound to UrdPase less effectively than 2,2'-anhydrouridine and acyclouridine. Arabinosyl uracil was at best a very poor inhibitor but binds better if a benzyl group is added at the 5-position of the pyrimidine ring. This binding was enhanced further by adding a 5-benzyloxybenzyl group. A similar enhancement of the binding with increased hydrophobicity at the 5-position of the pyrimidine ring was observed with ribosides, alpha- and beta-anomers of the 2'-deoxyribosides, acyclonucleosides, and 2,2'-anhydronucleosides. The inhibitory potencies of these compounds with UrdPase from human liver roughly parallel those obtained with UrdPase from mouse liver. It is concluded that the presence of a N-glycosidic bond as well as a properly oriented 3'-hydroxyl group are prerequisites for a nucleoside ligand to bind to UrdPase. On the other hand, the presence of a 2'- or 5'-hydroxyl group or an N-glycosidic bond in the beta-configuration enhances but is not essential for binding. Furthermore, the potency of the binding of 2,2'-anhydrouridines (fixed syn-isomers) in contrast to the complete lack of binding of the 6,5'-cyclouridines (fixed anti-isomers) to UrdPase indicates that the binding of ligands to this enzyme is in the syn-conformation around the N-glycosidic bond.
A series of 9-beta-D-xylofuranosyladenine (xyloA or xyloadenosine) substituted analogs of 2-5A core trimer and tetramer were examined for their ability to be degraded by the 2',5'-phosphodiesterase activity of cytoplasmic extracts of mouse L cells. Two distinct groups of xyloA-substituted analogs could be readily discriminated. The first group contained xyloadenosine at the 2'-termini and included A2'p5'A2'p5'(xyloA) and A2'p5'A2'p5'A2'p5'(xyloA). These oligomers behaved as did their parent oligoadenylates in that they were equally sensitive to degradation by the 2',5'-phosphodiesterase activity. The second group of oligonucleotides bore a xyloadenosine residue in the penultimate nucleotide residues of the oligomers and included A2'p5'(xyloA)2'p5'(xyloA), (xyloA)2'p5'(xyloA)2'p5'(xyloA), A2'p5'A2'p5'(xyloA)2'p5'(xyloA) and (xyloA)2'p5' (xyloA)2'p5'(xyloA)2'p5'(xyloA). This group was quite resistant to 2',5'-phosphodiesterase activity. In all, the findings demonstrate that the ribo configuration 3'-hydroxyl group in the penultimate nucleotide of the oligonucleotide substrate is a prerequisite for the 2',5'-phosphodiesterase activity.
Reversed-phase high-performance liquid chromatography using a C18 column was applied to the analysis of reconstituted mixtures of previously synthesized alpha, beta D-xylo- and D-lyxofuranonucleosides as well as a number of commercially available D-ribo- and D-arabinofuranonucleosides. From a detailed study of various parameters (size of support particles, nature and pH of the mobile phase, temperature), optimized conditions were established. Correlations between the retention times and structures of the bases, the orientations of the secondary hydroxyl groups of the sugar moiety and the anomeric configurations of the nucleosides are also reported.
This report presents the design and methodological features of a double-blind, randomized, placebo-controlled, trial in 383 patients with coronary artery disease. The study's principal objective is to determine whether chronic treatment with a calcium entry blocker can retard the progression of coronary artery disease. The study population consists of patients with coronary artery disease and a baseline coronary arteriogram that qualifies them as being at high risk for disease progression. After satisfying all entry criteria, patients were randomized to receive either the calcium entry blocker nicardipine or placebo. All indicated concomitant medications except calcium entry blockers are permitted. Patients are being followed clinically for 24 months before undergoing a second coronary arteriogram. The effect of the treatments on a variety of clinical and angiographic parameters will be determined.
The alpha- and beta-D-lyxofuranosyl analogues of the naturally occurring nucleosides have been synthesized and their antiviral properties examined. The alpha anomers were prepared by glycosylation of purine and pyrimidine aglycons with tetra-O-acetyl-alpha-D-lyxofuranose, followed by removal of the blocking groups. The beta anomers were obtained by sequential oxidation and reduction of 3',5'-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-beta-D-x ylofuranosyl nucleosides. The lyxofuranosyl nucleosides were tested for their activity against a variety of RNA and DNA viruses and for inhibition of cell growth. One compound, 9-alpha-D-lyxofuranosyladenine, showed activity against herpes simplex virus types 1 and 2 both in vitro and in vivo.
The non-exchangeable 1H-NMR signals of the branch core trinucleotide of the lariat branch site (A2'p5'G3'p5'C, 1) and its derivatives 2 and 3 are completely assigned using one- and two-dimensional NMR techniques including NOE, COSY, NOESY, 1H-1H INADEQUATE and 2D-J-resolved spectroscopy. From the vicinal coupling constants in the individual ribose rings, NOE data and T1 measurements, the following properties of the trimers are deduced. (i) The unique stacking behavior of the trimers is S2'N3'N, and the sugar rings exist predominantly in the N-conformation (3'-endo-2'-exo). (ii) The sugar-base orientations appear to be anti. (iii) The branched trimers exist in solution as single-stranded right-handed conformations resembling A-RNA with stacking between the adenine and guanine residues in aqueous solution at 21 degrees C and pH 7.2. (iv) The calculated values for the torsion angles epsilon t and gamma+ for the trimers are 201-203 degrees and 71-86%, respectively, while the percent beta t values are higher for the guanine (87-92%) than the cytosine residues (73-77%). The computer generated depiction of the triribonucleotide 1 is also shown. These subtle structural features may act as recognition signals for this critical lariat branch site which is essential for the second step in yeast mRNA splicing.
The alpha- and beta-D-xylofuranosyl analogues of the naturally occurring nucleosides, as well as other D-xylofuranosyl derivatives, have been the subject of a systematic synthesis and examination of their biological, i.e. antiviral antimetabolic, and cytostatic properties. The beta anomers were prepared by glycosylation of purine and pyrimidine aglycons with peracylated 1-O-acetyl-alpha-D-xylofuranoses, followed by removal of the blocking groups. The alpha anomers were obtained by a multistep synthesis with use of 2-amino- or 2-mercapto-alpha-D-xylofuran[1',2':4,5]-2-oxazoline as starting material. The xylofuranosyl nucleosides were tested for their activity against a variety of RNA and DNA viruses and for inhibition of cell growth and macromolecule synthesis. Three compounds, 9-(beta-D-xylofuranosyl)adenine, 9-(beta-D-xylofuranosyl)guanine, and 1-(beta-D-xylofuranosyl)cytosine, showed marked biological activity.
Between April 1983 and November 1985, 14 patients have undergone a heart transplant, or 10 men and 4 women, aged from 17 to 55 years. The surgical indication was a cardiomyopathy in terminal evolutive phase, of which the etiology was ischemia in 8 cases, congestion in 5 cases and rheumatism in one case. There was one operative death (7.1%) from acute rejection and a late death secondary to chronic rejection. The actuarial rate of survival at one and 2 years was 81.9%. Post-operative complications, most frequent at an early stage, were arterial hypertension (9 cases), rejection (8 cases) and renal insufficiency (6 cases). During an average post-operative evolution of 13 months, 17 rejection episodes occurred in 10 patients (71.4%) and 5 patients (35.7%) presented with 7 infectious episodes, one of them severe. Cyclosporin's toxicity appeared in the immediate post-operative period by an always reversible increase of the bilirubin and creatinin levels. On a long term, all patients present with arterial hypertension, accompanied by a moderate renal insufficiency (creatinin between 2.2 and 2.4 mg%). Among the survivors, 9 patients (75%) remain completely asymptomatic and have resumed normal physical activities. Cardiac transplantation has therefore become a valid therapeutic alternative, able to greatly improve survival and the functional condition of patients with terminal cardiomyopathy.
The homogeneous poly(A)-specific 2',3'-exoribonuclease from calf thymus gland, which cleaves both 3',5'- and 2',5'-linked oligoriboadenylates, does not degrade (xyloA2'p)2 xyloA, the xylofuranosyladenosine analogue of the 2-5A core. This oligonucleotide, which is supposed to enter intact cells rapidly, was found to possess an increased stability and an enhanced antiherpesvirus activity compared to the natural (A2'p)2A (Eppstein, D.A., Barnett, J.W., Marsh, Y.V., Gosselin, G. and Imbach, J.-L. (1983) Nature 302, 723-724). The poly(A) anabolic enzyme, poly(A) polymerase (Mn2+-dependent), from the same source, which is initiated by (A3'p)2A and its higher oligomers, does not accept 2-5A core and its xyloadenosine analogue as primer. Both oligonucleotides exert no influence on endoribonuclease IV and on the integrity of the poly(A)-ribonucleoprotein complex.