Publications by authors named "Rachid Benhida"

58 Publications

Ultrasound-assisted one-pot three-component synthesis of new isoxazolines bearing sulfonamides and their evaluation against hematological malignancies.

Ultrason Sonochem 2021 Oct 9;78:105748. Epub 2021 Sep 9.

Equipe de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23, Faculty of Science, B.P. 1014, Geophysics, Natural Patrimony and Green Chemistry (GEOPAC) Research Center, Mohammed V University in Rabat, Morocco; Chemical & Biochemical Sciences Green-Process Engineering (CBS) Mohammed VI Polytechnic University, Lot 660, Hay Moulay Rachid, Benguerir, Morocco. Electronic address:

In the present study, following a one-pot two-step protocol, we have synthesized novel sulfonamides-isoxazolines hybrids (3a-r) via a highly regioselective 1,3-dipolar cycloaddition. The present methodology capitalized on trichloroisocyanuric acid (TCCA) as a safe and ecological oxidant and chlorinating agent for the in-situ conversion of aldehydes to nitrile oxides in the presence of hydroxylamine hydrochloride, under ultrasound activation. These nitrile oxides could be engaged in 1,3-dipolar cycloaddition reactions with various alkene to afford the targeted sulfonamides-isoxazolines hybrids (3a-r). The latter were assessed for their antineoplastic activity against model leukemia cell lines (Chronic Myeloid Leukemia, K562 and Promyelocytic Leukemia, HL-60).
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http://dx.doi.org/10.1016/j.ultsonch.2021.105748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436160PMC
October 2021

In vivo monitoring of the therapeutic efficacy of a CXCR1/2 inhibitor with 18F-FDG PET/CT imaging in experimental head and neck carcinoma: A feasibility study.

Biochem Biophys Rep 2021 Sep 12;27:101098. Epub 2021 Aug 12.

Département de Biologie Médicale, Centre Scientifique de Monaco, Monaco.

The chemokine receptors CXCR1/2 play a key role in the aggressiveness of several types of cancers including head and neck squamous cell carcinomas (HNSCCs). In HNSCCs, CXCR1/2 signaling promotes cell proliferation and angiogenesis leading to tumor growth and metastasis. The competitive inhibitor of CXCR1/2, C29, inhibits the growth of experimental HNSCCs in mice. However, a non-invasive tool to monitor treatment response is essential to implement the use of C29 in clinical practices. F-FDG PET/CT is a gold-standard tool for the staging and the post-therapy follow-up of HNSCCs patients. Our study aimed to perform the first i monitoring of C29 efficacy by non-invasive F-FDG PET/CT imaging. Mice bearing experimental HNSCCs (CAL33) were injected with F-FDG (T0) and thereafter treated (n = 7 mice, 9 tumors, 50 mg/kg by gavage) or not (n = 7 mice, 10 tumors) with C29 for 4 consecutive days. Final F-FDG-tumor uptake was determined at day 4 (TF). The average relative change (TF-T0) in F-FDG tumor uptake was +25.85 ± 10.93 % in the control group -5.72 ± 10.07 % in the C29-treated group (p < 0.01). These results were consistent with the decrease of the tumor burden and with the decrease of tumor proliferating Ki67+ cells. These results paved the way for the use of F-FDG to monitor tumor response following C29 treatment.
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http://dx.doi.org/10.1016/j.bbrep.2021.101098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374394PMC
September 2021

A simple and fast spectroscopy-based technique for Covid-19 diagnosis.

Sci Rep 2021 08 18;11(1):16740. Epub 2021 Aug 18.

Anoual Laboratory, Boulevard d'Alexandrie, 20360, Casablanca, Morocco.

The coronavirus pandemic, which appeared in Wuhan, China, in December 2019, rapidly spread all over the world in only a few weeks. Faster testing techniques requiring less resources are key in managing the pandemic, either to enable larger scale testing or even just provide developing countries with limited resources, particularly in Africa, means to perform tests to manage the crisis. Here, we report an unprecedented, rapid, reagent-free and easy-to-use screening spectroscopic method for the detection of SARS-CoV-2 on RNA extracts. This method, validated on clinical samples collected from 280 patients with quantitative predictive scores on both positive and negative samples, is based on a multivariate analysis of FTIR spectra of RNA extracts. This technique, in agreement with RT-PCR, achieves 97.8% accuracy, 97% sensitivity and 98.3% specificity while reducing the testing time post RNA extraction from hours to minutes. Furthermore, this technique can be used in several laboratories with limited resources.
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http://dx.doi.org/10.1038/s41598-021-95568-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373901PMC
August 2021

Biguanides drugs: Past success stories and promising future for drug discovery.

Eur J Med Chem 2021 Nov 29;224:113726. Epub 2021 Jul 29.

Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272, 28 Avenue Valrose, 06108, Nice, France; Department of Chemical and Biochemical Sciences, Green Process Engineering, CBS, Mohamed VI Polytechnic University, UM6P, 43150 Ben Guerir, Morocco.

Biguanides have attracted much attention a century ago and showed resurgent interest in recent years after a long period of dormancy. They constitute an important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases. Therapeutic indications of biguanides include antidiabetic, antimalarial, antiviral, antiplaque, and bactericidal applications. This review presents an extensive overview of the biological activity of biguanides and different mechanisms of action of currently marketed biguanide-containing drugs, as well as their pharmacological properties when applicable. We highlight the recent developments in research on biguanide compounds, with a primary focus on studies on metformin in the field of oncology. We aim to provide a critical overview of all main bioactive biguanide compounds and discuss future perspectives for the design of new drugs based on the biguanide fragment.
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http://dx.doi.org/10.1016/j.ejmech.2021.113726DOI Listing
November 2021

Dual Covalent Inhibition of PKM and IMPDH Targets Metabolism in Cutaneous Metastatic Melanoma.

Cancer Res 2021 07 7;81(14):3806-3821. Epub 2021 Jun 7.

Université Côte d'azur, Nice, France.

Overcoming acquired drug resistance is a primary challenge in cancer treatment. Notably, more than 50% of patients with BRAF cutaneous metastatic melanoma (CMM) eventually develop resistance to BRAF inhibitors. Resistant cells undergo metabolic reprogramming that profoundly influences therapeutic response and promotes tumor progression. Uncovering metabolic vulnerabilities could help suppress CMM tumor growth and overcome drug resistance. Here we identified a drug, HA344, that concomitantly targets two distinct metabolic hubs in cancer cells. HA344 inhibited the final and rate-limiting step of glycolysis through its covalent binding to the pyruvate kinase M2 (PKM2) enzyme, and it concurrently blocked the activity of inosine monophosphate dehydrogenase, the rate-limiting enzyme of guanylate synthesis. As a consequence, HA344 efficiently targeted vemurafenib-sensitive and vemurafenib-resistant CMM cells and impaired CMM xenograft tumor growth in mice. In addition, HA344 acted synergistically with BRAF inhibitors on CMM cell lines . Thus, the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers. SIGNIFICANCE: Glycolytic and purine synthesis pathways are often deregulated in therapy-resistant tumors and can be targeted by the covalent inhibitor described in this study, suggesting its broad application for overcoming resistance in cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2114DOI Listing
July 2021

Development and evaluation of fused benzazole analogs of anti-melanoma agent HA15.

Future Med Chem 2021 07 7;13(14):1157-1173. Epub 2021 Jun 7.

Institut de Chimie de Nice CRNS UMR7272, Université Côte d'Azur, 28 Avenue Valrose, Nice, 06108, France.

In line with our recent discovery of an efficient anticancer thiazolebenzenesulfonamide framework HA15 () based on a remarkable endoplasmic reticulum stress inducement mode of action, we report herein a series of innovative constrained HA15 analogs, featuring four types of bicylic derivatives. The structure-activity relationship analysis, using a cell line assay, led us to identify a novel version of HA15: a new benzothiazole derivative () exhibiting important anti-melanoma effect against sensitive and resistant melanoma cells. Meanwhile, compound induced a significant tumor growth inhibition with no apparent signs of toxicity. These results consistently open new directions to improve and develop more powerful anticancer therapeutics harboring this type of fused framework.
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http://dx.doi.org/10.4155/fmc-2021-0001DOI Listing
July 2021

Synthetic accesses to biguanide compounds.

Beilstein J Org Chem 2021 5;17:1001-1040. Epub 2021 May 5.

Institut de Chimie de Nice UMR7272, Parc Valrose, Université Côte d'Azur, Nice, France.

Biguanide is a unique chemical function, which has attracted much attention a century ago and is showing resurgent interest in recent years after a long period of dormancy. This class of compounds has found broad applications such as reaction catalysts, organic strong bases, ligands for metal complexation, or versatile starting materials in organic synthesis for the preparation of nitrogen-containing heterocycles. Moreover, biguanides demonstrate a wide range of biological activities and some representatives are worldwide known such as metformin, the first-line treatment against type II diabetes, or chlorhexidine, the gold standard disinfectant and antiseptic. Although scarcely represented, the number of "success stories" with biguanide-containing compounds highlights their value and their unexploited potential as future drugs in various therapeutic fields or as efficient metal ligands. This review provides an extensive and critical overview of the synthetic accesses to biguanide compounds, as well as their comparative advantages and limitations. It also underlines the need of developing new synthetic methodologies to reach a wider variety of biguanides and to overcome the underrepresentation of these compounds.
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http://dx.doi.org/10.3762/bjoc.17.82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111433PMC
May 2021

Discovery of a new molecule inducing melanoma cell death: dual AMPK/MELK targeting for novel melanoma therapies.

Cell Death Dis 2021 01 11;12(1):64. Epub 2021 Jan 11.

INSERM, U1065, Equipe 12, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de saint Antoine de Ginestière, 06204, Nice cedex 3, France.

In the search of biguanide-derived molecules against melanoma, we have discovered and developed a series of bioactive products and identified the promising new compound CRO15. This molecule exerted anti-melanoma effects on cells lines and cells isolated from patients including the ones derived from tumors resistant to BRAF inhibitors. Moreover, CRO15 was able to decrease viability of cells lines from a broad range of cancer types. This compound acts by two distinct mechanisms. First by activating the AMPK pathway induced by a mitochondrial disorder. Second by inhibition of MELK kinase activity, which induces cell cycle arrest and activation of DNA damage repair pathways by p53 and REDD1 activation. All of these mechanisms activate autophagic and apoptotic processes resulting in melanoma cell death. The strong efficacy of CRO15 to reduce the growth of melanoma xenograft sensitive or resistant to BRAF inhibitors opens interesting perspective.
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http://dx.doi.org/10.1038/s41419-020-03344-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801734PMC
January 2021

Synthesis and biological evaluation of 3-amino-1,2,4-triazole derivatives as potential anticancer compounds.

Bioorg Chem 2020 11 8;104:104271. Epub 2020 Sep 8.

Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272, 28 Avenue Valrose, 06108 Nice, France; Mohamed VI Polytechnic University, UM6P, 43150, Ben Guerir, Morocco. Electronic address:

Two series of compounds carrying 3-amino-1,2,4-triazole scaffold were synthesized and evaluated for their anticancer activity against a panel of cancer cell lines using XTT assay. The 1,2,4-triazole synthesis was revisited for the first series of pyridyl derivatives. The biological results revealed the efficiency of the 3-amino-1,2,4-triazole core that could not be replaced and a clear beneficial effect of a 3-bromophenylamino moiety in position 3 of the triazole for both series (compounds 2.6 and 4.6) on several cell lines tested. Moreover, our results point out an antiangiogenic activity of these compounds. Overall, the 5-aryl-3-phenylamino-1,2,4-triazole structure has promising dual anticancer activity.
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http://dx.doi.org/10.1016/j.bioorg.2020.104271DOI Listing
November 2020

SARS-CoV-2 Genome Sequence from Morocco, Obtained Using Ion AmpliSeq Technology.

Microbiol Resour Announc 2020 Jul 30;9(31). Epub 2020 Jul 30.

Molecular Biology Department, ANOUAL Laboratory, Casablanca, Morocco.

This study describes a genome sequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sampled from a male patient with SARS-CoV-2 who was likely infected in Casablanca, Morocco.
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http://dx.doi.org/10.1128/MRA.00690-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393964PMC
July 2020

Sulfonylguanidine Derivatives as Potential Antimelanoma Agents.

ChemMedChem 2020 07 12;15(13):1113-1117. Epub 2020 May 12.

Institut de Chimie de Nice CRNS UMR7272, Université Côte d'Azur, 28 Avenue Valrose, 06108, Nice, France.

Sulfonylguanidines are interesting bioactive compounds with a broad range of applications in the treatment of different pathologies. 2-Aminobenzazole-based structures are well employed in the development of new anticancer drugs. Two series of novel N-benzazol-2-yl-N'-sulfonyl guanidine derivatives were synthesized with the sulfonylguanidine in either an extra- or intracyclic frame. They were evaluated for their antiproliferative activity against malignant melanoma tumor cells, thus allowing structure-activity relationships to be defined. Additionally, NCI-60 screening was performed for the best analogue to study its efficiency against a panel of other cancer cell lines. The stability profile of this promising compound was then validated. During the synthetic process, an unexpected new deamidination of the sulfonylguanidine towards sulfonamide function was also identified.
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http://dx.doi.org/10.1002/cmdc.202000218DOI Listing
July 2020

Probing of Nucleic Acid Structures, Dynamics, and Interactions With Environment-Sensitive Fluorescent Labels.

Front Chem 2020 28;8:112. Epub 2020 Feb 28.

Université Côte d'Azur, CNRS, Institut de Chimie de Nice, UMR 7272 - Parc Valrose, Nice, France.

Fluorescence labeling and probing are fundamental techniques for nucleic acid analysis and quantification. However, new fluorescent probes and approaches are urgently needed in order to accurately determine structural and conformational dynamics of DNA and RNA at the level of single nucleobases/base pairs, and to probe the interactions between nucleic acids with proteins. This review describes the means by which to achieve these goals using nucleobase replacement or modification with advanced fluorescent dyes that respond by the changing of their fluorescence parameters to their local environment (altered polarity, hydration, flipping dynamics, and formation/breaking of hydrogen bonds).
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http://dx.doi.org/10.3389/fchem.2020.00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059644PMC
February 2020

Synthesis, 3D-structure and stability analyses of NRPa-308, a new promising anti-cancer agent.

Bioorg Med Chem Lett 2019 12 16;29(24):126710. Epub 2019 Oct 16.

Université de Paris, CiTCoM, UMR 8038 CNRS, Faculté de Pharmacie, F-75006 Paris, France. Electronic address:

We report herein the synthesis of a newly described anti-cancer agent, NRPa-308. This compound antagonizes Neuropilin-1, a multi-partners transmembrane receptor overexpressed in numerous tumors, and thereby validated as promising target in oncology. The preparation of NRPa-308 proved challenging because of the orthogonality of the amide and sulphonamide bonds formation. Nevertheless, we succeeded a gram scale synthesis, according to an expeditious three steps route, without intermediate purification. This latter point is of utmost interest in reducing the ecologic impact and production costs in the perspective of further scale-up processes. The purity of NRPa-308 has been attested by means of conventional structural analyses and its crystallisation allowed a structural assessment by X-Ray diffraction. We also reported the remarkable chemical stability of this molecule in acidic, neutral and basic aqueous media. Eventually, we observed for the first time the accumulation of NRPa-308 in two types of human breast cancer cells MDA-MB231 and BT549.
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http://dx.doi.org/10.1016/j.bmcl.2019.126710DOI Listing
December 2019

GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism.

Cancer Cell 2019 09 22;36(3):268-287.e10. Epub 2019 Aug 22.

CRCT, INSERM U1037 - Université Paul Sabatier - CNRS ERL5294, Université de Toulouse, Laboratoire d'Excellence TOUCAN, Programme Hospitalo-Universitaire en Cancérologie CAPTOR, Toulouse, France; IUCT, 31037 Toulouse, France.

GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.
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http://dx.doi.org/10.1016/j.ccell.2019.07.008DOI Listing
September 2019

New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments.

Theranostics 2019 9;9(18):5332-5346. Epub 2019 Jul 9.

Centre Scientifique de Monaco, Biomedical Department, Principality of Monaco.

Clear cell Renal Cell (RCC) and Head and Neck Squamous Cell Carcinomas (HNSCC) are characterized by a pro-angiogenic/pro-inflammatory context. Despite conventional or targeted therapies, metastatic RCC and HNSCC remain incurable. Alternative treatments to reference therapies (sunitinib, a multi tyrosine kinase inhibitor for RCC or cisplatin for HNSCC) are urgently needed on relapse. Here, we described the relevance of targeting the ELR+CXCL cytokines receptors, CXCR1/2, for the treatment of these two cancer types. : The relevance to patient treatment was evaluated by correlating the ELRCXCL/CXCR1/2 levels to survival using online available data. We report herein the synthesis of new pharmacological inhibitors of CXCR1/2 with anti-proliferation/survival activity. The latter was evaluated with the XTT assay with leukemic, breast, RCC and HNSCC cell lines. Their relevance as an alternative treatment was tested on sunitinib- and cisplatin- resistant cells. The most efficient compound was then tested in a mouse model of RCC and HNSCC. : RCC and HNSCC expressed the highest amounts of CXCR1/2 of all cancers. High levels of ELRCXCL cytokines (CXCL1, 2, 3, 5, 6, 7, 8) correlated to shorter survival. Among the 33 synthesized and tested molecules, compound C29 reduced ELRCXCL/CXCR1/2-dependent proliferation and migration of endothelial cells. C29 exerted an anti-proliferation/survival activity on a panel of cancer cells including naive and resistant RCC and HNSCC cells. C29 reduced the growth of experimental RCC and HNSCC tumors by decreasing tumor cell proliferation, angiogenesis and ELR/CXCL-mediated inflammation. : Our study highlights the relevance of new CXCR1/2 inhibitors for the treatment of RCC or HNSCC as first-line treatment or at relapse on reference therapies.
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http://dx.doi.org/10.7150/thno.34681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691587PMC
August 2020

Functionalized C-nucleosides as remarkable RNA binders: targeting of prokaryotic ribosomal A-site RNA.

Chem Commun (Camb) 2019 Aug;55(70):10432-10435

Université Côte d'Azur, CNRS, Institute of Chemistry of Nice (ICN), Nice, France.

RNA represents an extremely promising and yet challenging therapeutic target. Here, we report the design of a series of C-nucleosides as original RNA binders. Some of them bind strongly and selectively to A-site prokaryotic ribosomal RNA.
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http://dx.doi.org/10.1039/c9cc04915kDOI Listing
August 2019

Concise synthesis and antibacterial evaluation of novel 3-(1,4-disubstituted-1,2,3-triazolyl)uridine nucleosides.

Arch Pharm (Weinheim) 2018 Nov 1;351(11):e1800204. Epub 2018 Oct 1.

Equipe de Chimie des Plantes et de Synthèse Organique et Bioorganique, Faculty of Science, Geophysics, Natural Patrimony and Green Chemistry (GEOPAC) Research Center, Mohammed V University in Rabat, Rabat, Morocco.

We report herein a simple and efficient synthesis of a new series of antibacterial uridine nucleosides. The strategy involved a sequential silylation/N-glycosylation/N-propargylation procedure of uracil 1 for preparing the dipolarophile 5 in good yield. A series of novel uridine-[1,2,3]triazole nucleosides 6a-j were efficiently synthesized via the copper-catalyzed azide-alkyne cycloaddition (CuAAC) from dipolarophile 5 with different selected azides. The reactions were carried out under both conventional and ultrasonic irradiation conditions. In general, improvements were observed when reactions were carried out under sonication. Their antibacterial potential has been evaluated by means of a micro-dilution assay against either Gram-positive or Gram-negative bacteria. Compounds 6i and 6j have shown significant bactericidal activity against Staphylococcus aureus (MIC = 10 and 6 μM, respectively), and 6h against Escherichia coli (MIC = 8 μM). Moreover, antibacterial kinetic assays showed that 6i and 6j significantly reduced the S. aureus growth rate at the MIC concentration, after 6 h, compared to their deprotected analogs, 6k and 6l, respectively. Compound 6h also significantly reduced the growth of E. coli. These antibacterial effects may be related to the penetrating properties of these compounds, as revealed by the leakage of nucleic acids from the sensitive strains.
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http://dx.doi.org/10.1002/ardp.201800204DOI Listing
November 2018

Photoactivatable oligonucleotide probes to trap single-stranded DNA binding proteins: Updating the potential of 4-thiothymidine from a comparative study.

Biochimie 2018 Nov 29;154:164-175. Epub 2018 Aug 29.

Sorbonne Université, École normale supérieure, PSL University, CNRS, Laboratoire des biomolécules, LBM, 75005 Paris, France; Institut de Chimie Moléculaire et des Matériaux d'Orsay, Univ. Paris-Sud, CNRS, Université Paris-Saclay, F-91405, Orsay, France. Electronic address:

Photoaffinity labeling (PAL) in combination with recent developments in mass spectrometry is a powerful tool for studying nucleic acid-protein interactions, enabling crosslinking of both partners through covalent bond formation. Such a strategy requires a preliminary study of the most judicious photoreactive group to crosslink efficiently with the target protein. In this study, we report a survey of three different photoreactive nucleobases (including a guanine functionalized with a benzophenone or a diazirine and the zero-length agent 4-thiothymine) incorporated in 30-mer oligonucleotides (ODN) containing a biotin moiety for selective trapping and enrichment of single-stranded DNA binding proteins (SSB). First, the conditions and efficiency of the photochemical reaction with a purified protein using human replication protein A as the relevant model was studied. Secondly, the ability of the probe as bait to photocrosslink and enrich SSB in cell lysate was addressed. Among the different ODN probes studied, we showed that 4-thiothymine was the most relevant: i) it allows efficient and specific trapping of SSB in whole cell extracts in a similar extent as the widely used diazirine, ii) it features the advantages of a zero-length agent thus retaining the physicochemical properties of the ODN bait; iii) ODN including this photochemical agent are easily accessible. In combination with mass spectrometry, the probes incorporating this nucleobase are powerful tools for PAL strategies and can be added in the toolbox of the traditional photocrosslinkers for studying DNA-protein interactions.
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http://dx.doi.org/10.1016/j.biochi.2018.08.007DOI Listing
November 2018

Development of highly sensitive fluorescent probes for the detection of β-galactosidase activity - application to the real-time monitoring of senescence in live cells.

Analyst 2018 May;143(11):2680-2688

Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR7272, Nice, France.

We report the development of four novel fluorescent probes to monitor the activity of the β-galactosidase enzyme (β-gal), in vitro and in living cells. The fluorophores are based on a 6-amino-styryl-benzothiazole push-pull core and display a strong ICT emission. The probes encompass the fluorescent motif that is connected to a β-d-galactopyranoside moiety through a self-immolative benzyl carbamate linker (βGal-1-4). The screening of four different fluorophores enabled us to access new light-up and two-band ratiometric reporters. The four probes, βGal-1-4, exhibited an extremely fast response and over 200-fold fluorescence enhancement (βGal-1) following the enzymatic cleavage of the β-d-galactopyranoside unit. This rapid and extremely sensitive response allowed the detection of senescence-associated β-galactosidase (SA-β-gal) activity; a widely used biomarker of senescence. More importantly, βGal-1 also enabled us to monitor, in real-time, the emergence of senescence in live cells, i.e. the phenotypic transformation from normal to senescent cell. These findings underpin the fact that βGal-1 may find useful applications in biomedical research. Importantly, βGal-1 is suitable for epifluorescence and confocal microscopies, and flow cytometry techniques, which are among the most common analytical tools in biology.
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http://dx.doi.org/10.1039/c8an00516hDOI Listing
May 2018

Modular synthesis of new C-aryl-nucleosides and their anti-CML activity.

Bioorg Med Chem Lett 2018 06 24;28(10):1931-1936. Epub 2018 Mar 24.

Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272, 06108 Nice, France; Mohamed VI Polytechnic University, UM6P, 43150 Ben Guerir, Morocco. Electronic address:

The C-aryl-ribosyles are of utmost interest for the development of antiviral and anticancer agents. Even if several synthetic pathways have been disclosed for the preparation of these nucleosides, a direct, few steps and modular approaches are still lacking. In line with our previous efforts, we report herein a one step - eco-friendly β-ribosylation of aryles and heteroaryles through a direct Friedel-Craft ribosylation mediated by bismuth triflate, Bi(OTf). The resulting carbohydrates have been functionalized by cross-coupling reactions, leading to a series of new C-aryl-nucleosides (32 compounds). Among them, we observed that 5d exerts promising anti-proliferative effects against two human Chronic Myeloid Leukemia (CML) cell lines, both sensitive (K562-S) or resistant (K562-R) to imatinib, the "gold standard of care" used in this pathology. Moreover, we demonstrated that 5d kills CML cells by a non-conventional mechanism of cell death.
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http://dx.doi.org/10.1016/j.bmcl.2018.03.063DOI Listing
June 2018

The GRP78/BiP inhibitor HA15 synergizes with mitotane action against adrenocortical carcinoma cells through convergent activation of ER stress pathways.

Mol Cell Endocrinol 2018 10 20;474:57-64. Epub 2018 Feb 20.

Université Côte d'Azur, Valbonne, 06560, France; CNRS UMR 7275, Sophia Antipolis, Valbonne, 06560, France; NEOGENEX CNRS International Associated Laboratory, Valbonne, 06560, France; Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, 06560, France. Electronic address:

Many types of cancer cells present constitutively activated ER stress pathways because of their significant burden of misfolded proteins coded by mutated and rearranged genes. Further increase of ER stress by pharmacological intervention may shift the balance towards cell death and can be exploited therapeutically. Recent studies have shown that an important component in the mechanism of action of mitotane, the only approved drug for the medical treatment of adrenocortical carcinoma (ACC), is represented by activation of ER stress through inhibition of the SOAT1 enzyme and accumulation of toxic lipids. Here we show that HA15, a novel inhibitor of the essential ER chaperone GRP78/BiP, inhibits ACC H295R cell proliferation and steroidogenesis and is able to synergize with mitotane action. These results suggest that convergent activation of ER stress pathways by drugs acting via different mechanisms represents a valuable therapeutic option for ACC.
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http://dx.doi.org/10.1016/j.mce.2018.02.010DOI Listing
October 2018

NRPa-308, a new neuropilin-1 antagonist, exerts in vitro anti-angiogenic and anti-proliferative effects and in vivo anti-cancer effects in a mouse xenograft model.

Cancer Lett 2018 02 28;414:88-98. Epub 2017 Oct 28.

INSERM U648, Laboratory of Molecular and Cellular Pharmacochemistry, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270, Paris cedex 06, France; Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, 75270, Paris cedex 06, France; Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272, 06108, Nice, France. Electronic address:

Neuropilin-1 (NRP-1) is an extra-cellular receptor for the main Vascular Endothelial Growth Factor over-expressed in tumour tissues, VEGF-A. Consequently, NRP-1 is involved in angiogenesis and in tumour growth, and its over-expression is related to a clinical poor prognosis. NRP-1 appears as a major target in oncology, which remains poorly exploited. Herein, we report a new series of 18 small-sized fully organic VEGF-A/NRP-1 antagonists (NRPas). These compounds share an original scaffold, including two linkers (sulphonamide and amide) and three aromatic cores. Among them, 2a (renamed NRPa-308) emerges as a promising "hit". In vitro,2a exerts not only potent anti-angiogenic activity, but also significant effects on cell viability of large panel of human solid and haematological cancer cell lines. Importantly, 2a is less cytotoxic on healthy tissues than the marketed anti-angiogenic drug sunitinib. Lastly, in a mouse xenograft model (human MDA-MB-231 breast cancer cells), 2a improves the median survival and reduces the tumour growth, but does not exert visible acute toxicity. Altogether, these results highlight its huge potential for a further "hit-to-lead" optimization, leading to new anti-cancer drugs.
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http://dx.doi.org/10.1016/j.canlet.2017.10.039DOI Listing
February 2018

Ultrasound-assisted facile one-pot sequential synthesis of novel sulfonamide-isoxazoles using cerium (IV) ammonium nitrate (CAN) as an efficient oxidant in aqueous medium.

Ultrason Sonochem 2018 Jan 11;40(Pt A):289-297. Epub 2017 Jul 11.

Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23, Université Mohammed V, Faculté des Sciences, B.P. 1014 Rabat, Morocco. Electronic address:

A series of novel 3,5-disubstituted isoxazoles have been synthesized, using a new, green, and versatile "one-pot three-steps" methodology. The key step is an oxidative 1,3-dipolar cycloaddition under ultrasonic irradiation, occurring in aqueous media, and mediated by cerium (IV) ammonium nitrate (CAN). CAN is a one-electron oxidant, highly soluble in water, slightly toxic and inexpensive, that allows the in situ conversion of the intermediate aldoximes into nitrile oxide. The syntheses are highly regioselective, as illustrated by the structures of the final compounds, which have been fully assessed by spectral analyses (H and C NMR, MS). This study illustrates the potency of the ultrasound activation to synthesize a set of highly functionalized heterocycles, with potential applications in biology, in short reaction times and following an eco-friendly process.
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http://dx.doi.org/10.1016/j.ultsonch.2017.07.019DOI Listing
January 2018

Structure activity relationship and optimization of N-(3-(2-aminothiazol-4-yl)aryl)benzenesulfonamides as anti-cancer compounds against sensitive and resistant cells.

Bioorg Med Chem Lett 2017 05 23;27(10):2192-2196. Epub 2017 Mar 23.

Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR7272, 06108 Nice, France. Electronic address:

We recently described a new family of bioactive molecules with interesting anti-cancer activities: the N-(4-(3-aminophenyl)thiazol-2-yl)acetamides. The lead compound of the series (1) displays significant anti-proliferative and cytotoxic activities against a panel of cancer cell lines, either sensitive or resistant to standard treatments. This molecule also shows a good pharmacological profile and high in vivo potency towards mice xenografts, without signs of toxicity on the animals. In the present article, we disclose the structure-activity relationships of this lead compound, which have provided clear information about the replacement of the acetamide function and the substitution pattern of the benzenesulfonamide ring. An improved high-yielding synthetic procedure towards these compounds has also been developed. Our drug design resulted in potency enhancement of 1, our new optimized lead compound being 19. These findings are of great interest to further improve this scaffold for the development of future clinical candidates.
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http://dx.doi.org/10.1016/j.bmcl.2017.03.054DOI Listing
May 2017

Synthesis and anti-cancer activities of new sulfonamides 4-substituted-triazolyl nucleosides.

Bioorg Med Chem Lett 2017 05 9;27(9):1989-1992. Epub 2017 Mar 9.

Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272, 06108 Nice, France. Electronic address:

Nucleoside analogues are among the most known drugs commonly used in antiviral and anticancer chemotherapies. Among them, those featuring a five-membered ring nucleobase are of utmost interest such as the anti-cancer agent AICAR or the anti-viral drug ribavirin. Despite its low activity in vitro in different cell lines, AICAR is under clinical development for several pathologies, thanks to its original mode of action. Indeed, AICAR induced autophagy cell death and is able, following this mechanism, to circumvent resistance to apoptotic drugs including kinase inhibitors currently on the market. To improve the activity of AICAR, we report herein an efficient synthesis of new series of sulfonamide-4-substituted-1,2,3-triazolyl nucleosides using a Cu-catalyzed 1,3-dipolar cycloaddition. All these molecules have been fully characterized and evaluated against two aggressive tumor cell lines, RCC4 and MDA-MB-231. Among them, nucleoside analogue 5i belonging to the ribose series was found to be 19 to 66-fold more active than AICAR. Western blot analyses on RCC4 cells showed that 5i displayed an interesting mode of action by inducing both apoptosis and autophagy cell death, making therefore this class of molecules highly promising for further hit-to-lead optimization.
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http://dx.doi.org/10.1016/j.bmcl.2017.03.018DOI Listing
May 2017

Assessment of new triplet forming artificial nucleobases as RNA ligands directed towards HCV IRES IIId loop.

Bioorg Med Chem Lett 2017 04 24;27(8):1780-1783. Epub 2017 Feb 24.

Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR7272, 06108 Nice, France. Electronic address:

We report the synthesis of two new artificial nucleobase scaffolds, 1 and 2, featuring adequate hydrogen bonding donors and acceptors for the molecular recognition of U:A and C:G base pairs, respectively. The tethering of these structures to various amino acids and the assessment of these artificial nucleobase-amino acid conjugates as RNA ligands against a model of HCV IRES IIId domain are also reported. Compound 1e displayed the highest affinity (K twice lower than neomycin - control). Moreover, it appears that this interaction is enthalpically and entropically favored.
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http://dx.doi.org/10.1016/j.bmcl.2017.02.061DOI Listing
April 2017

Targeting BIP to induce Endoplasmic Reticulum stress and cancer cell death.

Oncoscience 2016 9;3(11-12):306-307. Epub 2016 Dec 9.

INSERM U1065 team 1, Université de Nice Cote d'Azur et Centre Méditerranéen de Médecine Moléculaire, Nice, France.

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http://dx.doi.org/10.18632/oncoscience.330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5235914PMC
December 2016

In Vitro and in Vivo Evaluation of Fully Substituted (5-(3-Ethoxy-3-oxopropynyl)-4-(ethoxycarbonyl)-1,2,3-triazolyl-glycosides as Original Nucleoside Analogues to Circumvent Resistance in Myeloid Malignancies.

J Med Chem 2017 02 2;60(4):1523-1533. Epub 2017 Feb 2.

Institut de Chimie de Nice UMR7272, Université Côte d'Azur, CNRS , 06108 Nice, France.

A series of nucleoside analogues bearing a 1,4,5-trisubstituted-1,2,3-triazole aglycone was synthesized using a straightforward click/electrophilic addition or click/oxidative coupling tandem procedures. SAR analysis, using cell culture assays, led to the discovery of a series of compounds belonging to the 5-alkynyl-1,2,3-triazole family that exhibits potent antileukemic effects on several hematologic malignancies including chronic myeloid leukemia (CML) and myelodysplastic syndromes (MDS) either sensitive or resistant to their respective therapy. Compound 4a also proved efficient in vivo on mice xenografted with SKM1-R MDS cell line. Additionally, some insights in its mode of action revealed that this compound induced cell death by caspase and autophagy induction.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01803DOI Listing
February 2017

ATM, ATR, CHK1, CHK2 and WEE1 inhibitors in cancer and cancer stem cells.

Medchemcomm 2017 Feb 30;8(2):295-319. Epub 2016 Nov 30.

Université Côte d'Azur , CNRS , Institut de Chimie de Nice , UMR7272 - Parc Valrose , 06108 Nice Cedex 2 , France . Email: ; ; Tel: +33 4 92076143.

DNA inevitably undergoes a high number of damages throughout the cell cycle. To preserve the integrity of the genome, cells have developed a complex enzymatic machinery aimed at sensing and repairing DNA lesions, pausing the cell cycle to provide more time to repair, or induce apoptosis if damages are too severe. This so-called DNA-damage response (DDR) is yet considered as a major source of resistance to DNA-damaging treatments in oncology. Recently, it has been hypothesized that cancer stem cells (CSC), a sub-population of cancer cells particularly resistant and with tumour-initiating ability, allow tumour re-growth and cancer relapse. Therefore, DDR appears as a relevant target to sensitize cancer cells and cancer stem cells to classical radio- and chemotherapies as well as to overcome resistances. Moreover, the concept of synthetic lethality could be particularly efficiently exploited in DDR. Five kinases play pivotal roles in the DDR: ATM, ATR, CHK1, CHK2 and WEE1. Herein, we review the drugs targeting these proteins and the inhibitors used in the specific case of CSC. We also suggest molecules that may be of interest for preclinical and clinical researchers studying checkpoint inhibition to sensitize cancer and cancer stem cells to DNA-damaging treatments.
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http://dx.doi.org/10.1039/c6md00439cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072143PMC
February 2017

Hypoxia inducible factor down-regulation, cancer and cancer stem cells (CSCs): ongoing success stories.

Medchemcomm 2017 Jan 19;8(1):21-52. Epub 2016 Oct 19.

Université Côte d'Azur , CNRS , Institut de Chimie de Nice UMR 7272 - 06108 Nice , France . Email: ; Email: ; ; Tel: +33 4 92076143.

In cancers, hypoxia inducible factor 1 (HIF-1) is an over-expressed transcription factor, which regulates a large set of genes involved in tumour vascularization, metastases, and cancer stem cells (CSCs) formation and self-renewal. This protein has been identified as a relevant target in oncology and several HIF-1 modulators are now marketed or in advanced clinical trials. The purpose of this review is to summarize the advances in the understanding of its regulation and its inhibition, from the medicinal chemist point of view. To this end, we selected in the recent literature relevant examples of "hit" compounds, including small-sized organic molecules, pseudopeptides and nano-drugs, exhibiting and/or both anti-HIF-1 and anti-tumour activities. Whenever possible, a particular emphasis has been dedicated to compounds that selectively target CSCs.
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http://dx.doi.org/10.1039/c6md00432fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071925PMC
January 2017
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