Désaromatisation régiosélective d'arénols par l'utilisation de réactifs iodés hypervalents (application en vue de la synthèse de l'aquayamycine et analogues)

Les Angucyclines constituent une importante classe d'antibiotiques naturels présentant un large spectre d'activités biologiques. Leur architecture unique en fait des cibles très attractives pour les chimistes organiciens. La difficulté synthétique majeure réside actuellement dans l'introduction des fonctions hydroxyles en positions angulaires présentes dans les Angucyclines du type aquayamycine. En outre, ces composés cis-oxygénés à la jonction des cycles A et B possèdent des activités biologiques remarquables, notamment une activité anticancéreuse vis-à-vis de lignées de cellules leucémiques devenues résistantes aux traitements thérapeutiques classiques. Dans ce contexte, nous avons cherché à développer une nouvelle voie synthétique visant un accès rapide et efficace à ces composés. Deux nouvelles méthodologies basées sur l'utilisation d'une réaction de désaromatisation régiosélective oxydante d'arénols par l'utilisation de réactifs iodés hypervalents ont ainsi été testées. Nous avons pu, grâce à cette approche, préparer des analogues du système tricyclique ABC de l'aquayamycine présentant des cycles A à cinq chaînons ainsi que des intermédiaires avancés du type cyclohexa-2,4-diénones. Parallèlement à ces travaux, une nouvelle voie d'accès à des composés du type 1,4-naphtoquinones a été développéeBORDEAUX1-BU Sciences-Talence (335222101) / SudocSudocFranceF

Synthetic Anticancer Vaccine Candidates: Rational Design of Antigenic Peptide Mimetics That Activate Tumor-Specific T-Cells

International audienceA rational design approach was followed to develop peptidomimetic analogues of a cytotoxic T-cell epitope capable of stimulating T-cell responses as strong as or stronger (heteroclytic) than those of parental antigenic peptides. The work described herein focused on structural alterations of the central amino acids of the melanoma tumor-associated antigenic peptide Melan-A/MART-1 26-35 using nonpeptidic units. A screening was first realized in silico to select altered peptides potentially capable of fitting at the interface between the major histocompatibilty complex (MHC) class-I HLA-A2 molecule and T-cell receptors (TCRs). Two compounds appeared to be high-affinity ligands to the HLA-A2 molecule and stimulated several Melan-A/MART-1 specific T-cell clones. Most remarkably, one of them even managed to amplify the response of one clone. Together, these results indicate that central TCR-contact residues of antigenic peptides can be replaced by nonpeptidic motifs without loss of binding affinity to MHC class-I molecules and T-cell triggering capacity

Covalent modification of a melanoma-derived antigenic peptide with a natural quinone methide. Preliminary chemical, molecular modelling and immunological evaluation studies.

A ligand Fit shap-directed docking methodology was used to identify the best position at which the melanoma-derived MHC class-I-HLA-A2-binding antigenic peptide ELAGIGILTV could be modified by attaching a small molecule capable of fitting at the interface of complementary determining regional (CDR) loops of a T-cell receptor (TCR)whilie triggering T-cell responses

From Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A Virus

International audienceThe nucleoprotein (NP) of influenza A virus (IAV) required for IAV replication is a promising target for new antivirals. We previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here we designed and synthesized two new series of naproxen analogues called derivatives 2, 3, and 4 targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Derivative 2 presented improved antiviral effects in infected cells compared to that of naproxen and afforded a total protection of mice against a lethal viral challenge. Derivative 4 also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivatives 2 and 4 inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal interactions

From Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A Virus

The nucleoprotein (NP) of influenza A virus (IAV) required for IAV replication is a promising target for new antivirals. We previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here we designed and synthesized two new series of naproxen analogues called derivatives <b>2</b>, <b>3</b>, and <b>4</b> targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Derivative <b>2</b> presented improved antiviral effects in infected cells compared to that of naproxen and afforded a total protection of mice against a lethal viral challenge. Derivative <b>4</b> also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivatives <b>2</b> and <b>4</b> inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal interactions

From Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A Virus

The nucleoprotein (NP) of influenza A virus (IAV) required for IAV replication is a promising target for new antivirals. We previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here we designed and synthesized two new series of naproxen analogues called derivatives <b>2</b>, <b>3</b>, and <b>4</b> targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Derivative <b>2</b> presented improved antiviral effects in infected cells compared to that of naproxen and afforded a total protection of mice against a lethal viral challenge. Derivative <b>4</b> also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivatives <b>2</b> and <b>4</b> inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal interactions

From Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A Virus

The nucleoprotein (NP) of influenza A virus (IAV) required for IAV replication is a promising target for new antivirals. We previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here we designed and synthesized two new series of naproxen analogues called derivatives <b>2</b>, <b>3</b>, and <b>4</b> targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Derivative <b>2</b> presented improved antiviral effects in infected cells compared to that of naproxen and afforded a total protection of mice against a lethal viral challenge. Derivative <b>4</b> also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivatives <b>2</b> and <b>4</b> inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal interactions

From Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A Virus

The nucleoprotein (NP) of influenza A virus (IAV) required for IAV replication is a promising target for new antivirals. We previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here we designed and synthesized two new series of naproxen analogues called derivatives <b>2</b>, <b>3</b>, and <b>4</b> targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Derivative <b>2</b> presented improved antiviral effects in infected cells compared to that of naproxen and afforded a total protection of mice against a lethal viral challenge. Derivative <b>4</b> also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivatives <b>2</b> and <b>4</b> inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal interactions

From Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A Virus

The nucleoprotein (NP) of influenza A virus (IAV) required for IAV replication is a promising target for new antivirals. We previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here we designed and synthesized two new series of naproxen analogues called derivatives <b>2</b>, <b>3</b>, and <b>4</b> targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Derivative <b>2</b> presented improved antiviral effects in infected cells compared to that of naproxen and afforded a total protection of mice against a lethal viral challenge. Derivative <b>4</b> also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivatives <b>2</b> and <b>4</b> inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal interactions