Discovery of an L-like Configuration for 3'-Fluoro-5'-norcarbonucleoside Phosphonates as Potent Anti-HIV Agents.

Recently, we reported the racemic synthesis of 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates bearing adenine as the heterocyclic base. For this study, to evaluate the antiviral activity of each enantiomer, we synthesized both enantiomers, as well as their corresponding bis(POM) prodrugs. Anti-HIV-1 evaluation against the LAI strain and clinically NRTI-resistant HIV-1 strains are presented.

Incidence and risk factors of anastomotic complications after lung transplantation.

Background: Anastomotic complications are common after lung transplantation (1.4-33% of cases) and still associated with a high morbi-mortality.

Methods: The current study is a monocenter retrospective analysis of symptomatic anastomotic complications (SAC) occurring after lung transplantation between 2010 and 2016, using the macroscopic, diameter, and suture (M-D-S) classification from consensus of French experts in bronchoscopy.

Mononucleoside phosphorodithiolates as mononucleotide prodrugs.

The synthesis and in vitro anti-HIV activity of a novel series of pronucleotides are reported. These prodrugs were characterized by a phosphorodithiolate structure, incorporating two O-pivaloyl-2-oxyethyl substituents as biolabile phosphate protections. The compounds were obtained following an original one-pot three-step procedure, involving the formation of a phosphorodithioite intermediate which is in situ oxidized.

An original pronucleotide strategy for the simultaneous delivery of two bioactive drugs.

The synthesis and in vitro anti-HIV activity of a novel series of phosphoramidate pronucleotides including a S-pivaloyl-2-thioethyl (tBuSATE) group as biolabile phosphate protecting group are reported. Such constructs, obtained through different phosphorus chemistries, are characterized by the association of two different anti-HIV nucleoside analogues linked to the phosphorus atom respectively by the sugar residue and the exocyclic amino function of the nucleobase. In vitro, comparative anti-HIV evaluation demonstrates that such original prodrugs are able to allow the efficient intracellular combination release of a 5'-mononucleotide as well as another nucleoside analogue.

Celsior crystalloid cardioplegia versus standard hyperkalemic normothermic blood cardioplegia: Analysis of myocardial protection in elective mitral valve repair.

Introduction: With the increase and refinement of video assisted mitral valve surgery, cristalloïd cardioplegia started regaining popularity. The aim of our study was to evaluate the effectiveness of Celsior, a crystalloid cardioplegic solution, on myocardial protection in elective surgical mitral valve repair in comparison to blood based hyperkalemic cardioplegia.

Methods: In this observational retrospective study, all consecutive elective isolated surgical mitral valve repair where Celsior or normothermic hyperkalemic blood cardioplegia were used were included.

A heart transplant after total artificial heart support: initial and long-term results.

Objectives: At our centre, the SynCardia temporary Total Artificial Heart (TAH-t) (SynCardia Systems, LLC, Tucson, AZ, USA) is used to provide long-term support for patients with biventricular failure as a bridge to a transplant. However, a heart transplant (HT) after such support remains challenging. The aim of this retrospective study was to assess the immediate and long-term results following an HT in the cohort of patients who had a TAH-t implant.

Synthesis and Antiviral Evaluation of 3'-Fluoro-5'-norcarbocyclic Nucleoside Phosphonates Bearing Uracil and Cytosine as Potential Antiviral Agents.

Carbocyclic nucleoside analogues are an essential class of antiviral agents and are commonly used in the treatment of viral diseases (hepatitis B, AIDS). Recently, we reported the racemic synthesis and the anti-human immunodeficiency virus activities (HIV) of 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates bearing purines as heterocyclic base. Based on these results, the corresponding racemic norcarbocyclic nucleoside phosphonates bearing pyrimidine bases were synthesized.

β-Hydroxy- and β-Aminophosphonate Acyclonucleosides as Potent Inhibitors of Growth.

Malaria is an infectious disease caused by a parasite of the genus , and the emergence of parasites resistant to all current antimalarial drugs highlights the urgency of having new classes of molecules. We developed an effective method for the synthesis of a series of β-modified acyclonucleoside phosphonate (ANP) derivatives, using commercially available and inexpensive materials (i.e.

Synthesis and Antiviral Evaluation of 3'-Fluoro-4'-modified-5'-norcarbocyclic Nucleoside Phosphonates.

The synthesis and anti-HIV evaluation of hitherto unknown 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates bearing adenine with modifications at the 4' position (ethynyl, vinyl, ethyl, hydroxymethyl) is described. One of the synthesized compounds was found to be an inhibitor of HIV-1 replication, but with moderate efficiency relative to (R)-9-(2-phosphonylmethoxypropyl)adenine ((R)-PMPA, tenofovir), with no concomitant cytotoxicity.

Contribution of the precursors and interplay of the pathways in the phospholipid metabolism of the malaria parasite.

The malaria parasite, , develops and multiplies in the human erythrocyte. It needs to synthesize considerable amounts of phospholipids (PLs), principally phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS). Several metabolic pathways coexist for their de novo biosynthesis, involving a dozen enzymes.

Synthesis of 3'-halo-5'-norcarbocyclic nucleoside phosphonates as potent anti-HIV agents.

The synthesis and the antiviral evaluation of 3'-halo (iodo and fluoro) 5'-norcarbocyclic nucleoside phosphonates is described. No antiviral activity was observed against Zika virus, Dengue virus 2, HSV-1, HSV-2 and Chikungunya virus. In contrast, some of the synthesized compounds are potent inhibitors of the replication of HIV-1, comparatively to (R)-PMPA, with no concomitant cytotoxicity.

Synthesis and substrate properties towards HIV-1 reverse transcriptase of new diphosphate analogues of 9-[(2-phosphonomethoxy)ethyl]adenine.

Background The replacement of β,γ-pyrophosphate by β,γ-phosphonate moieties within the triphosphate chain of 5'-triphosphate nucleoside analogues was previously studied for various antiviral nucleoside analogues such as AZT and 2',3'-dideoxynucleosides. Thus, it has been shown that these chemical modifications could preserve, in some cases, the terminating substrate properties of the triphosphate analogue for HIV-RT. Herein, we aimed to study such 5'-triphosphate mimics based on the scaffold of the well-known antiviral agent 9-[(2-phosphonomethoxy)ethyl]adenine (PMEA, Adefovir).

Revaluation of biomass-derived furfuryl alcohol derivatives for the synthesis of carbocyclic nucleoside phosphonate analogues.

The racemic synthesis of new carbocyclic nucleoside methylphosphonate analogues bearing purine bases (adenine and guanine) was accomplished using bio-sourced furfuryl alcohol derivatives. All compounds were prepared using a Mitsunobu coupling between the heterocyclic base and an appropriate carbocyclic precursor. After deprotection, the compounds were evaluated for their activity against a large number of viruses.

Evidence that oxidative dephosphorylation by the nonheme Fe(II), α-ketoglutarate:UMP oxygenase occurs by stereospecific hydroxylation.

LipL and Cpr19 are nonheme, mononuclear Fe(II)-dependent, α-ketoglutarate (αKG):UMP oxygenases that catalyze the formation of CO , succinate, phosphate, and uridine-5'-aldehyde, the last of which is a biosynthetic precursor for several nucleoside antibiotics that inhibit bacterial translocase I (MraY). To better understand the chemistry underlying this unusual oxidative dephosphorylation and establish a mechanistic framework for LipL and Cpr19, we report herein the synthesis of two biochemical probes-[1',3',4',5',5'- H]UMP and the phosphonate derivative of UMP-and their activity with both enzymes. The results are consistent with a reaction coordinate that proceeds through the loss of one H atom of [1',3',4',5',5'- H]UMP and stereospecific hydroxylation geminal to the phosphoester to form a cryptic intermediate, (5'R)-5'-hydroxy-UMP.

Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation.

A series of seventeen β-hydroxyphosphonate ribonucleoside analogues containing 4-substituted-1,2,3-triazoles was synthesized and fully characterized. Such compounds were designed as potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), an enzyme involved in the regulation of purine nucleotide pools. NMR and molecular modelling studies showed that a few derivatives adopted similar structural features to IMP or GMP.

Recent Trends in Nucleotide Synthesis.

Focusing on the recent literature (since 2000), this review outlines the main synthetic approaches for the preparation of 5'-mono-, 5'-di-, and 5'-triphosphorylated nucleosides, also known as nucleotides, as well as several derivatives, namely, cyclic nucleotides and dinucleotides, dinucleoside 5',5'-polyphosphates, sugar nucleotides, and nucleolipids. Endogenous nucleotides and their analogues can be obtained enzymatically, which is often restricted to natural substrates, or chemically. In chemical synthesis, protected or unprotected nucleosides can be used as the starting material, depending on the nature of the reagents selected from P(III) or P(V) species.

Identification of Noncompetitive Inhibitors of Cytosolic 5'-Nucleotidase II Using a Fragment-Based Approach.

We used a combined approach based on fragment-based drug design (FBDD) and in silico methods to design potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), which has been recognized as an important therapeutic target in hematological cancers. Two subgroups of small compounds (including adenine and biaryl moieties) were identified as cN-II binders and a fragment growing strategy guided by molecular docking was considered. Five compounds induced a strong inhibition of the 5'-nucleotidase activity in vitro, and the most potent ones were characterized as noncompetitive inhibitors.

Determination of the enzymatic activity of cytosolic 5'-nucleotidase cN-II in cancer cells: development of a simple analytical method and related cell line models.

The cytosolic 5'-nucleotidase (cN-II) has been shown to be involved in the response of cancer cells to cytotoxic agents, and the quantification of its activity in biological samples is of great interest. In this context, we developed and validated an analytical method for determination of cN-II activity in cultured cancer cells. This non-radioactive method, using a Hypercarb column as stationary phase, was validated with a lower limit of quantification of 0.

Early structural valve deterioration of Mitroflow aortic bioprosthesis: mode, incidence, and impact on outcome in a large cohort of patients.

Background: Structural valve deterioration (SVD) is a major flaw of bioprostheses. Early SVD has been suspected in the last models of Mitroflow bioprosthesis. We sought to assess the incidence, mode, and impact of SVD on outcome in a large series of Mitroflow aortic valve replacement.

²⁰¹Tl⁺-labelled Prussian blue nanoparticles as contrast agents for SPECT scintigraphy.

Prussian blue (PB) and its analogues on the nanometric scale are exciting nano-objects that combine the advantages of molecular-based materials and nanochemistry. Herein, we demonstrate that ultra-small PB nanoparticles of 2-3 nm can be easily labelled with radioactive (201)Tl(+) to obtain new nanoprobes as radiotracers for 201-thallium-based imaging.

Exploring prodrug approaches for albitiazolium and its analogues.

Choline analogues such as bis-thiazolium salts are thought to inhibit choline transport into Plasmodium-infected erythrocytes, thus preventing parasite PC biosynthesis, and also to interact with plasmodial haemoglobin degradation in the food vacuole. This new and multiple mode of action is a major asset of these new class of antimalarials, as they could help delay resistance development. We synthesized and designed various sets of analogues, notably prodrugs, since the oral bioavailability of bis-thiazolium salts is relatively low.

Synthesis of {[5-(adenin-9-yl)-2-furyl]methoxy}methyl phosphonic acid and evaluations against human adenylate kinases.

AMP mimics constitute an important class of therapeutic derivatives to treat diseases where the pool of ATP is involved. A new phosphonate derivative of 9-(5-hydroxymethylfuran-2-yl)adenine was synthesized in a multi-step sequence from commercially available adenosine. Its ability to behave as a substrate of human adenylate kinases 1 and 2 was assessed.

Structure-activity relationships of β-hydroxyphosphonate nucleoside analogues as cytosolic 5'-nucleotidase II potential inhibitors: synthesis, in vitro evaluation and molecular modeling studies.

The cytosolic 5'-nucleotidase II (cN-II) has been proposed as an attractive molecular target for the development of novel drugs circumventing resistance to cytotoxic nucleoside analogues currently used for treating leukemia and other malignant hemopathies. In the present work, synthesis of β-hydroxyphosphonate nucleoside analogues incorporating modifications either on the sugar residue or the nucleobase, and their in vitro evaluation towards the purified enzyme were carried out in order to determine their potency towards the inhibition of cN-II. In addition to the biochemical investigations, molecular modeling studies revealed important structural features for binding affinities towards the target enzyme.

[Creation of software to help cardiac surgeons: CordaBase].

Background: The writing of surgical and hospitalization reports is time-consuming and does not necessarily enable the increment of a statistical database, tool that is indispensable nowadays to evaluate unit activity or to carry out scientific studies. In order to prevent this double data capture, a computer tool, named CordaBase, has been developed by surgeons and set up in a cardiac surgery unit.

Materials And Methods: CordaBase is an interactive software that stores medical data.

[Helical tomotherapy in the treatment of malignant pleural mesothelioma: The impact of low doses on pulmonary and oesophageal toxicity].

Purpose: To evaluate the adjuvant treatment of malignant pleural mesothelioma by helical tomotherapy and the impact of low doses on esophageal and pulmonary toxicity.

Patients And Methods: Between June 2007 and May 2011, 29 patients diagnosed with malignant pleural mesothelioma received adjuvant radiotherapy by helical tomotherapy. The median age was 63 years (34-72).