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The Hippo pathway represents a new opportunity for the treatment of cancer. Overexpression of Yes-associated protein (YAP) or transcriptional coactivator with PDZ-binding motif (TAZ) or TEAD has been demonstrated in cancers and YAP mediates resistance to cancer drugs. Since 2018, the potential of this pathway has been illustrated by numerous articles and patents and the first drugs entering in clinical trial phase 1.This review is limited to published patent applications that have disclosed direct small-molecule inhibitors of the YAP/TAZ-TEAD interaction.The YAP/TAZ-TEAD transcriptional complex is a promising target for the treatment of cancer. Approximately 30 international patents (used database: Sci-finder, query: TEAD; documents: patents; period: from 2017-January 2022) that disclose TEAD transcriptional inhibitors have been filled since 2018. The mechanism of action is not always described in the patents, we can divide the drugs into three different categories: (i) external TEAD ligands; (ii) non-covalent TEAD ligands of the palmitate pocket; (iii) covalent TEAD ligands, which bind into the palmitate pocket. The first molecules in clinical trial phase 1 are non-covalent TEAD ligands. The selective TEAD ligand have also been patented, published and selectivity could be of great interest for personalized medicine.

The risk of zoonotic coronavirus spillover into the human population, as highlighted by the SARS-CoV-2 pandemic, demands the development of pan-coronavirus antivirals. The efficacy of existing antiviral ribonucleoside/ribonucleotide analogs, such as remdesivir, is decreased by the viral proofreading exonuclease NSP14-NSP10 complex. Here, using a novel assay and in silico modeling and screening, we identified NSP14-NSP10 inhibitors that increase remdesivir’s potency. A model compound, sofalcone, both inhibits the exonuclease activity of SARS-CoV-2, SARS-CoV, and MERS-CoV in vitro, and synergistically enhances the antiviral effect of remdesivir, suppressing the replication of SARS-CoV-2 and the related human coronavirus OC43. The validation of top hits from our primary screenings using cellular systems provides proof-of-concept for the NSP14 complex as a therapeutic target.

Starting from our previously reported hit, a series of 1,5-diaryl-1,2,3-triazole-4-carbohydrazones were synthesized and evaluated as inhibitors of the YAP/TAZ-TEAD complex. Their binding to hTEAD2 was confirmed by nanodifferential scanning fluorimetry, and some of the compounds were also found to moderately disrupt the YAP-TEAD interaction, as assessed by a fluorescence polarization assay. A TEAD luciferase gene reporter assay performed in HEK293T cells and RTqPCR measurements in MDA-MB231 cells showed that these compounds inhibit YAP/TAZ-TEAD activity to cells in the micromolar range. In spite of the cytotoxic effects displayed by some of the compounds of this series, they are still good starting points and can be suitably modified into an effective and viable YAP-TEAD disruptor in the future.

International audience; Viral exoribonucleases are uncommon in the world of RNA viruses. To date, they have only been identified in the Arenaviridae and the Coronaviridae families. The exoribonucleases of these viruses play a crucial role in the pathogenicity and interplay with host innate immune response. Moreover, coronaviruses exoribonuclease is also involved in a proofreading mechanism ensuring the genetic stability of the viral genome. Because of their key roles in virus life cycle, they constitute attractive target for drug design.Here we developed a sensitive, robust and reliable fluorescence polarization assay to measure the exoribonuclease activity and its inhibition in vitro. The effectiveness of the method was validated on three different viral exoribonucleases, including SARS-CoV-2, Lymphocytic Choriomeningitis and Machupo viruses. We performed a screening of a focused library consisting of 113 metal chelators. Hit compounds were recovered with an IC50 at micromolar level. We confirmed 3 hits in SARS-CoV-2 infected Vero-E6 cells.

International audience; The Hippo pathway is involved in organ size control and tissue homeostasis by regulating cell growth, proliferation and apoptosis. It controls the phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) in order to control their nuclear import and their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several cancers making YAP/TAZ-TEAD interaction a new emerging anti-cancer target. We report the synthesis of a set of trisubstituted pyrazoles which bind to hTEAD2 at the interface 2 revealing for the first time a cryptic pocket created by the movement of the phenol ring of Y382. Compound 6 disrupts YAP/TAZ-TEAD interaction in HEK293T cells and inhibits TEAD target genes and cell proliferation in MDA-MB-231 cells. Compound 6 is therefore the first inhibitor of YAP/TAZ-TEAD targeting interface 2. This molecule could serve with other pan-TEAD inhibitors such as interface 3 ligands, for the delineation of the relative importance of VGLL vs YAP/TAZ in a given cellular model.

Transcriptional enhanced associate domain (TEAD) proteins are the downstream effectors of the Hippo signaling pathway that regulate cell proliferation and stem cell functions. TEADs are unable to activate transcription and require the help of coactivators such as YAP, TAZ, VgLL, and p160 proteins. The expression of TEAD family is up-regulated in many cancer types including gastric, colorectal, breast, and prostate cancers, which is correlated with poor survival in patients. Pharmacological modulators of TEADs could therefore find application in cancer treatment and regenerative medicine. In this review, we present the very recent available structures of TEADs with or without coactivators or inhibitors and discuss the potential therapeutic application of their ligands.

International audience; Herein, we report further insight into the biological activities displayed by the 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) scaffold. Previous studies have evidenced the marked fruitful effect of substitution of this two-metal binding pharmacophore at position 4 by phenyl and benzyl carboxamido chains. Strong human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors in the low nanomolar range with micromolar (even down to low nanomolar) anti-HIV activities were obtained. Keeping this essential 4-carboxamido function, we investigated the influence of the replacement of phenyl and benzyl groups by various alkyl chains. This study shows that the recurrent halogenobenzyl pharmacophore found in the INSTIs can be efficiently replaced by an n-alkyl group. With an optimal length of six carbons, we observed a biological profile and a high barrier to resistance equivalent to those of a previously reported hit compound bearing a 4-fluorobenzyl group.

International audience; Arenaviridae is a viral family whose members are associated with rodent-transmitted infections to humans responsible of severe diseases. The current lack of a vaccine and limited therapeutic options make the development of efficacious drugs of high priority. The cap-snatching mechanism of transcription of Arenavirus performed by the endonuclease domain of the L-protein is unique and essential, so we developed a drug design program targeting the endonuclease activity of the prototypic Lymphocytic ChorioMeningitis Virus. Since the endonuclease activity is metal ion dependent, we designed a library of compounds bearing chelating motifs (diketo acids, polyphenols, and N-hydroxyisoquinoline-1,3-diones) able to block the catalytic center through the chelation of the critical metal ions, resulting in a functional impairment. We pre-screened 59 compounds by Differential Scanning Fluorimetry. Then, we characterized the binding affinity by Microscale Thermophoresis and evaluated selected compounds in in vitro and in cellula assays. We found several potent binders and inhibitors of the endonuclease activity. This study validates the proof of concept that the endonuclease domain of Arenavirus can be used as a target for anti-arena-viral drug discovery and that both diketo acids and N-hydroxyisoquinoline-1,3-diones can be considered further as potential metal-chelating pharmacophores.

Integration of the viral genome into the host cell chromatin is a central step in the replication cycle of HIV. Blocking the viral integrase (IN) enzyme therefore provides an attractive therapeutic strategy, as evidenced by the recent clinical approval of three IN strand transfer inhibitors. Dolutegravir is a therapy that is unique in its ability to evade HIV drug resistance in treatment-naïve patients.This review starts by providing a brief summary of the history of HIV-1 IN inhibitors. The authors follow this with details of the discovery and preclinical and clinical developments of dolutegravir. Finally, the authors provide details of dolutegravir's post-launch including the launch of the combination pill of dolutegravir, abacavir and lamivudine in August 2014.The launch of raltegravir, the first IN inhibitor from MerckCo., has created new hopes for the patient. Indeed, pharmaceutical companies have not lost courage by attempting to address the major drawbacks of this first-in-class molecule. And while the drug elvitegravir has been inserted into a four-drug combination pill providing a once-daily dosing alternative, dolutegravir has demonstrated superiority in terms of its efficacy and resistance.

Nucleos(t)ide analog drugs profoundly suppress Hepatitis B virus (HBV) replication but rarely cure the infection, so therapy is usually life-long. The nucleos(t)ide analogs inhibit the viral DNA polymerase and often push HBV to the brink of extinction, so it may be possible to eradicate HBV by suppressing HBV replication further. The HBV ribonuclease H (RNaseH) is a logical new drug target because it is the second of only two viral enzymes essential for viral replication. We recently developed a low throughput screening pipeline for inhibitors of the HBV RNaseH and viral replication. Here, we screened a series of twenty-three nitrogen-based polyoxygenated heterocycles including sixteen 2-hydroxyisoquinoline-1,3(2 H ,4 H )-dione derivatives for anti-HBV RNaseH activity. Nine compounds inhibited the HBV RNaseH, but activity was marginal for eight of them. Compound #1 [2-hydroxyisoquinoline-1,3(2 H ,4 H )-dione, HID] was the best hit with an IC 50 of 28.1 μM and an EC 50 of 4.2 μM. It preferentially suppressed accumulation of the viral plus-polarity DNA strand in replication inhibition assays, indicating that replication was blocked due to suppression of HBV RNaseH activity. It had a CC 50 of 75 μM, yielding a therapeutic index of ∼18. The EC 50 value was 7-fold lower than the IC 50 , possibly due to cellular retention or metabolism of the compound, or higher affinity for the full-length enzyme than the recombinant form used for screening. These data indicate that the 2-hydroxyisoquinoline-1,3(2 H ,4 H )-diones will have different structure–activity relationships for the HBV and HIV RNaseHs. Therefore, HID compounds may provide a foundation for development of more effective RNaseH inhibitors of HBV replication.

Clinical HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) potently inhibit viral replication with a dramatic drop in viral load. However, the emergence of resistance to these drugs underscores the need to develop next-generation IN catalytic site inhibitors with improved resistance profiles. Here, we present a novel candidate IN inhibitor, MB-76, a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) derivative. MB-76 potently blocks HIV integration and is active against a panel of wild-type as well as raltegravir-resistant HIV-1 variants. The lack of cross-resistance with other INSTIs and the absence of resistance selection in cell culture indicate the potential of HID derivatives compared to previous INSTIs. A crystal structure of MB-76 bound to the wild-type prototype foamy virus intasome reveals an overall binding mode similar to that of INSTIs. Its compact scaffold displays all three Mg(2+) chelating oxygen atoms from a single ring, ensuring that the only direct contacts with IN are the invariant P214 and Q215 residues of PFV IN (P145 and Q146 for HIV-1 IN, respectively), which may partially explain the difficulty of selecting replicating resistant variants. Moreover, the extended, dolutegravir-like linker connecting the MB-76 metal chelating core and p-fluorobenzyl group can provide additional flexibility in the perturbed active sites of raltegravir-resistant INs. The compound identified represents a potential candidate for further (pre)clinical development as next-generation HIV IN catalytic site inhibitor.

We previously reported low sensitivity of the hepatitis B virus (HBV) ribonuclease H (RNaseH) enzyme to inhibition by N-hydroxyisoquinolinedione (HID) compounds. Subsequently, our biochemical RNaseH assay was found to have a high false negative rate for predicting HBV replication inhibition, leading to underestimation of the number of HIDs that inhibit HBV replication. Here, 39 HID compounds and structurally related polyoxygenated heterocycles (POH), N-hydroxypyridinediones (HPD), and flutimides were screened for inhibition of HBV replication in vitro. Inhibiting the HBV RNaseH preferentially blocks synthesis of the positive-polarity DNA strand and causes accumulation of RNA:DNA heteroduplexes. Eleven HIDs and one HPD preferentially inhibited HBV positive-polarity DNA strand accumulation. EC50s ranged from 0.69 μM to 19 μM with therapeutic indices from 2.4 to 71. Neither the HIDs nor the HPD had an effect on the ability of the polymerase to elongate DNA strands in capsids. HBV RNaseH inhibition by the HIDs was confirmed with an improved RNaseH assay and by detecting accumulation RNA:DNA heteroduplexes in HBV capsids from cells treated with a representative HID. Therefore, the HID scaffold is more promising for anti-HBV drug discovery than we originally reported, and the HPD scaffold may hold potential for antiviral development. The preliminary structure-activity relationship will guide optimization of the HID/HPDs as HBV inhibitors.

International audience; Porphyrin derivatives, in particular verteporfin (VP), a photosensitizer initially designed for cancer therapy, have been identified as inhibitors of the YAP–TEAD interaction and transcriptional activity. Herein we report the efficient convergent synthesis of the dipyrrin half of protoporphyrin IX dimethyl ester (PPIX‐DME), in which the sensitive vinyl group was created at the final stage by a dehydroiodination reaction. Two other dipyrrin derivatives were synthesized, including dipyrrin 19 [(Z)‐2‐((3,5‐dimethyl‐4‐vinyl‐2H‐pyrrol‐2‐ylidene)methyl)‐3,5‐dimethyl‐4‐vinyl‐1H‐pyrrole], containing two vinyl groups. We found that VP and dipyrrin 19 showed significant inhibitory effects on TEAD transcriptional activity in MDA‐MB‐231 human breast cancer cells, whereas other compounds did not show significant changes. In addition, we observed a marked decrease in both YAP and TAZ levels following VP treatment, whereas dipyrrin 19 treatment primarily decreased the levels of YAP and receptor kinase AXL, a downstream target of YAP. Together, our data suggest that, due to their chemical structures, porphyrin‐ and dipyrrin‐related derivatives can directly target YAP and/or TAZ proteins and inhibit TEAD transcriptional activity.

A series of 13 hydroxylated 2-arylnaphthalenes have been synthesized and evaluated as HIV-1 integrase inhibitors. 7-(3,4,5-Trihydroxyphenyl)naphthalene-1,2,3-triol 1c revealed chemical instability upon storage, leading to the isolation of a dimer 5c which was also tested. In the 2-arylnaphthalene series, all compounds were active against HIV-1 IN with IC50's within the 1–10 μM range, except for 1c and 5c which displayed submicromolar activity. Antiviral activity against HIV-1 replication was measured on 1b–c and 5c. Amongst the tested molecules, only 5c was found to present antiviral properties with a low cytotoxicity on two different cell lines.

Since the discovery of MK-0518 (raltegravir, the first FDA-approved integrase inhibitor) in October 2007, Merck Co. researchers have continued to patent original new heterocycles related to raltegravir as powerful strand transfer inhibitors. Among the most recent patented works hexahydrodiazocino-naphthyridinetriones present the particularity to possess two different sources of chirality, that is, an asymmetric carbon and a heterocyclic eight-membered ring presenting atropisomerism. The different synthesized isomers claimed in this patent are described and their biological properties commented on in relation to stereoisomerism.

A series of thirteen 4,5-diaryl-3-hydroxy-2(5H)-furanones were synthesized. They were evaluated for their antioxidant potencies and inhibitory properties of 5-lipoxygenase, cyclooxygenases, HIV-1 integrase and PC3 cell proliferation. New hits were discovered either in the anti-proliferation test or in the HIV anti-integrase test.

Rosmarinic acid was reacted with nitrite ions under acidic conditions to give 6'-nitro- and 6',6''-dinitrorosmarinic acids according to the reaction time. Both compounds were active as HIV-1 integrase inhibitors at the submicromolar level. They also inhibited the viral replication in MT-4 cells with modest and similar selectivity indexes. The nitration of rosmarinic acid strongly improves the anti-integrase inhibition and the antiviral activity without increasing the cellular toxicity.

Background: Verteporfin is a porphyrinic photosensitizer clinically used for the photodynamic treatment of age-related macular degeneration. It has been identified almost simultaneously as a YAP/TEAD and an autophagosome inhibitor. Over the last few years, YAP (TAZ), the downstream effectors of the Hippo pathway, have emerged as promising anticancer targets, as shown by several experimental lines of evidence, showing the overproduction of YAP in several cancers. However, YAP was also found to be closely connected to autophagy, mitochondria and reactive oxygen/nitrogen species. We herein, review the recent studies where VP was used without photoactivation as a YAP/TEAD inhibitor or protein oligomerization promoter, focusing on its effects on the YAP/TEAD gene targets and other biomarkers related to autophagy. Results: Since the identification of VP as YAP/TEAD inhibitor, several in vitro and in vivo studies have revealed the new potential of this molecule in different cancers, where YAP is overexpressed. However, detailed structural information about its interaction with YAP is still lacking. Concomitantly, VP was identified as autophagosome inhibitor by promoting oligomerization of p62. Moreover, VP proves to be tumor-selective proteotoxic (by oligomerization of p62, STAT3) in colorectal cancer. Knowledge on the biological properties of the only YAP inhibitor available to date is vital for its pharmacological use on cellular and animal models. Conclusion: VP is a multi-target drug interacting with several proteins implicated in major cellular processes. Although this does not impact its clinical use, VP does not seem to be the ideal drug for pharmacological inhibitions of YAP/TEAD.

Methoxylated phenylethanals were treated with concentrated hydrochloric acid in 1,4-dioxane to give methoxylated 2-phenylnaphthalenes or 1,2,9,10-tetrahydro-1,9-epoxydibenzo[ a , e ]cyclooctenes. Yields in 2-phenylnaphthalenes were quite good and 1,2,9,10-tetrahydro-1,9-epoxydibenzo[ a , e ]cyclooctenes could be easily isolated. 2-Phenylnaphthalenes were obtained by a tandem aldol condensation-intramolecular Friedel–Crafts cyclisation and 1,2,9,10-tetrahydro-1,9-epoxydibenzo[ a , e ]cyclooctenes by a O-condensation followed by a double intramolecular Friedel–Crafts alkylation.

Since 1996, highly active antiretroviral therapy (HAART) was designed to rapidly control HIV replication. It has had a significant impact on patient health and progression of AIDS in developed countries, but its success has not been complete. HAART strategy still suffers from issues of patient compliance, cost, deleterious side effects and emerging drug resistance. Therefore, expansion of novel anti-HIV drugs and targets will be critical in the coming years. In this context, discovering anti-HIV agents from natural sources and particularly from plants, may highlight the principle of a nutritional antioxidant antiretroviral diet. In this paper, we review the putative anti-HIV activity of simple caffeic acid derivatives, together with their antioxidant properties. Toxicity, metabolism and bioavailability, when known, will also be detailed. Well-known caffeic acid derivatives, such as chicoric, rosmarinic and lithospermic acids, may be designed as future leads multi-target anti-HIV compounds and the plants and vegetables containing them as potent nutritional therapeutic supplementation source. They are not expected to replace the actual antiretroviral therapy, but more likely, to complete and perhaps lighten it by adapted diet.

EPR spectroscopy of 3-hydroxyesculetin (1, solid and in solution) and of the radicals formed during the aerobic oxidation of alkaline solutions of 1 and related compounds was investigated. 1 in the solid state was studied by pulsed EPR experiments and showed a radical character. The aerobic oxidation of alkaline solutions of 1 was also followed by EPR spectroscopy. A ring contraction occurred leading to a 5,6-dihydroxybenzofuran-2-carboxylate radical. The autoxidation of an alkaline solution of (Z)-3-(3,4-dihydroxyphenyl)-2-hydroxypropenoic acid allowed the observation of a spectrum attributable to 5,6-dihydroxybenzofuran-3-one-2-carboxylate radical. The formation mechanisms of these radicals are discussed.

4-(4-Hydroxyphenyl)-5-(4-hydroxyphenylmethyl)-2-hydroxyfurane-2-one 1 was prepared by an acidic dimerisation of 4-hydroxyphenylpyruvic acid and some of its antioxidant and spectroscopic properties have been measured and compared to that of ascorbic acid. 1 is as good an antioxidant as ascorbic acid in the DPPH (2,2-diphenyl-1-picryl hydrazyl radical) test and the inhibition of hydroxyl radical and a powerful inhibitor of the Cu(2+) or AAPH (2,2'-azobis-(2-amidinopropane) dihydrochloride) induced oxidation of human LDL. 1 gives a stable radical characterised by its ESR spectrum similarly to ascorbic acid but in lower concentration and with a different reactivity towards nitroxides. Theoretical calculations allow us to propose the structure for the radical formed from 1, to explain its lower stability than ascorbyl radical and to evaluate the lipophilicity of 1.

International audience; We report herein further insight into the biological activities displayed by a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs). Substitution of the N-hydroxyimide two-metal binding pharmacophore at position 4 by carboxamido side chains was previously shown by us to be fruitful for this scaffold, since strong human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors in the low nanomolar range associated with low micromolar anti-HIV activities were obtained. We investigated the influence of substitution at position 7 on biological activity. Introduction of electron-withdrawing functional groups such as the nitro moiety at position 7 led to a noticeable improvement of antiviral activity, down to low nanomolar anti-HIV potencies, with advantageous therapeutic indexes going close to those of the clinically used raltegravir and retained potencies against a panel of IN mutants.

The chrome derivatives can be obtained in excellent yields, in three steps, using first the phase transfer catalysis for the synthesis of phenol ether followed by cyclization and the Perkin reaction

The prenylated cinnamic acids can be obtained in excellent yields, in two steps, using first a one-step conversion of corresponding bromobenzaldehydes to corresponding prenylated benzaldehydes

Fourteen catechol and bis-catechol derivatives have been synthesised and tested for their HIV-1 inhibitory activities. The six more active molecules have been tested for their antiviral activity and cytotoxicity. We have found that bis-catechols 1 and 2 are the most active HIV-1 integrase inhibitor whereas the best antiviral compound is 4.

An expeditious synthesis of polyhydroxylated 2-arylbenzo[ b ]furans is described. The key steps are the conversion of the corresponding polymethoxylated stilbenes into diarylethanoid molecules (epoxide or alcohol) that were demethylated and cyclised using boron tribromide to give the target polyhydroxylated 2-arylbenzo[ b ]furans.

( Z )-Mono, di or trimethoxyphenyl-2-hydroxypropenoic acids 1a–d gave mixtures of ( E ) and ( Z ) mono, di or trihydroxyphenyl-2-hydroxypropenoic acids 2a–d when treated with boron tribromide. The isomerisation proceeds during the work-up and depends on the duration of the hydrolysis and the number of oxygens on the aromatic ring. When the aromatic ring was substituted with a methoxy group at the ortho position, a cyclisation occurs, and 3-hydroxycoumarins 3 and benzofuran-2-carboxylic acids 4 can be obtained. 3-Hydroxycoumarin 3a can also be obtained almost quantitatively from the reaction of methyl 3-(2-methoxyphenyl)-2,3-epoxypropanoate with boron tribromide.

An expeditious synthesis of salvianolic acid F 2 is described in 10% overall yield. Tetramethyl salvianolic acid F 3 was obtained in six steps in 39% overall yield and was converted into the target molecule using boron tribromide in 26% yield.

Treatment of electron-rich aromatic derivatives with cerium (IV) ammonium nitrate coated on silica (CAN/Si02) affords nitro aromatic compounds. The scope and the limitation of this reaction are discussed.

Treatment of arylethanals 1 with boron tribromide give 2-phenylnaphthalenes 2 or 1,2,9,10-tetrahydro-1,9-epoxydibenzo[a,e]cyclooctenes 3 by a tandem aldol condensation-intramolecular Friedel-Crafts cyclization or a condensation at the O-position followed by a double Friedel-Crafts alkylation respectively. In all cases, a total demethylation of the methoxy groups occurs.

A successful synthesis of the acid part of salvianolic acid D is described (eight steps from isovanillin, 22% overall yield). The benzaldehyde key intermediate was obtained in six steps in 52% overall yield and was converted into the trimethylated precursor molecule using the Knoevenagel procedure. Finally, the acid part of salvianolic acid D was obtained by the exhaustive deprotection of the methyl groups with boron tribromide.

Treatment of phenylacetones 1 with boron tribromide gives the 1,3-dimethyl-2-phenylnaphtalenes 2 in good yields by a tandem aldol condensation-intramolecular Friedel-Crafts cyclization. In the cases of methoxyphenylacetones, a demethylation occurs leading to 1,3-dimethyl-2-hydroxyphenylnaphtols. © 1997 Published by Elsevier Science Ltd.

α-hydroxyesters 5a-g or diols 6a-g have been obtained in high yields by reduction of aromatic α-ketoesters 4 once or twice respectively by using NaBH 4 as the reducer under suitable conditions. The use of a solvent that does not interact with the reagent allowed the double reduction to occur with only a slight excess of borohydride in very mild conditions.

A series of 2-hydroxy-1,3-dioxoisoquinoline-4-carboxamides featuring an N-hydroxyimide chelating functionality was evaluated for their inhibitory properties against human immunodeficiency virus type 1 integrase (HIV-1 IN). Several derivatives displayed low nanomolar IC50 values comparable to that of the clinically used raltegravir. A marked effect of one compound on both primary IN-catalyzed reactions, strand transfer (ST), and 3′ processing (3′-P), emphasizes a novel IN inhibition mechanism establishing it as a potential new generation IN inhibitor. Substitution of the 2-hydroxyisoquinoline-1,3-dione scaffold at position 4 by carboxamido chains was beneficial for antiviral activity since reproducible low micromolar anti-HIV activities were obtained for the first time within this scaffold.

The nitration ipso to a carboxylic or formyl group of disubstituted and trisubstituted benzoic acids and benzaldehydes using nitric acid in acetic acid is described.

The oxidation behaviour of gentisic acid, from which a humic acid model was synthesized, was studied. Electrochemical investigation coupled with Electron Spin Resonance analysis revealed the complexity of the mechanism. Coupled chemical reactions appeared after the two electron oxidation, leading to trihydroxybenzoic acids, and to dimeric compounds. The presence of methylenic groups, particularly important to mimic the flexibility and aggregative properties of natural humic substance, was confirmed. Assuming a free radical mechanism for the chemical evolution of humic substances, metal ions could help the reaction process, leading to efficient spin-trapping matters to be considered in water treatments.

A series of nitrodihydroxybenzenes and nitrocaffeic acids were prepared and their hydroxyl radical (OH°) and superoxide anion (O 2− ) scavenging activities and xanthine oxidase inhibition activities were evaluated. 2-Nitrocaffeic acid is the more potent O 2− scavenger. 2- (and 5)-Nitrocaffeic acids are the more potent xanthine oxidase inhibitors.

The “Journées Franco-Belges de Pharmacochimie” is a recognized annual meeting in organic and medicinal chemistry known for the quality of scientific exchange and conviviality. Young researchers were encouraged to present their work and share ideas with senior scientists. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report.

A mild and efficient method for the synthesis of 3, 4-dihydroisoquinolinium salts, key intermediates for the preparation of isoquinoline alkaloids, by an oxidation of N-methyl-1, 2, 3, 4-tetrahydroisoquinolines using ceric ammonium nitrate (CAN) is described.

The oxidative cleavage of 2,5-dihydroxybenzoic acid (gentisic acid), presumably into maleylpyruvate in basic aqueous solution has been shown by ESR spectra of semiquinonic radicals bearing a methylenic group. One of these radicals has been unambiguously attributed to 2,4,5-trihydroxyphenylacetic acid semiquinonic radical. The formation of an hydroxylated homogentisic acid from gentisic acid (a metabolite of aspirin) is of particular importance in the treatment of alkaptonuria and related inflammatory arthritis.

The ability of hydroxylated metabolites of salicylic acid to scavenge reactive oxygen species and to inhibit arachidonic acid metabolism was investigated. The tested trihydroxybenzoic acids (THBAs) were potent scavengers of hydroxyl and superoxide anion radicals produced by Fenton reaction and xanthine/xanthine oxidase system or activated macrophages respectively. In the same tests, salicylic acid possessed moderate O2(-) and low OH'scavenging activities. Our results demonstrate that adding two hydroxyl groups to salicylic acid strongly increases the reactive oxygen species (ROS) scavenging activities. Adding two hydroxyl groups at position 4 and 5 (2,4,5-THBA) affords the most active ROS scavenging activity probably due to the ortho unsubstituted catechol moiety. In fact, we can consider that the ROS scavenging properties of salicylic acid are essentially due to its metabolic products such as 2,3- and 2,5-DHBAs, catechol and also to THBAs.

Les nitrocatechols et la nitrohydroquinone ont ete traitees par le borohydrure de sodium en solution basique oxygenee a des pH allant de 9 a 12 et leur spectre RPE a ete enregistre. Dans tous les cas le radical anion nitroaromatique est observe. A pH 12 un radical semiquinonique a ete observe dans le cas de la nitrohydroquinone et du 4-nitrocatechol

Caffeic acid derivatives are increasingly regarded as potential oncoprotective that could inhibit both the initiation and progression of cancer. Here we have synthesized seven 1-arylnaphthalene lignans and related compounds and tested their impact on breast cancer cell growth in tissue culture. The product of the oxidative dimerization of methyl caffeate, 1-phenylnaphthalene lignan, was found to induce a strong decrease in breast cancer cell number (IC(50) ~1 μM) and was selected for further investigation. Flow cytometry analysis revealed a decrease in cell proliferation and an increase in apoptosis in both MCF-7 and MDA-MB-231 breast cancer cell lines that are representative of the two main categories of breast tumors. The 3,4-dihydroxyphenyl group probably induced the biological activity, as the control compounds lacking it had no effect on breast cancer cells. Together, our data indicate that the oxidative dimerization product of methyl caffeate can inhibit breast cancer cell growth at a concentration adequate for pharmacological use.

We report herein the synthesis of a series of 3-hydroxyquinolin-2(1H)-one derivatives. Esters and amide groups were introduced at position 4 of the basis scaffold and some modulations of the benzenic moiety were performed. Most compounds presented selective inhibitory properties in the 10-20 μM range against HIV-1 reverse transcriptase associated ribonuclease H activity, without affecting the integrase and reverse transcriptase DNA polymerase activities. Unfortunately all tested compounds exhibited high cellular cytotoxicity in cell culture which limited their applications as antiviral agents.

N,N-Dimethylmethoxyphenylmethylamines were selectively converted to the corresponding methoxybenzaldehydes using Ceric Ammonium Nitrate (CAN) in acetonitrile/water.