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Wong Y.-S.,University Grenoble Alpes | Wong Y.-S.,CNRS Molecular Pharmacochemistry Department
Medecine/Sciences | Year: 2015

Structural diversity oriented synthesis aims to fulfill the unoccupied tridimensional "chemical space" gap left by traditional chemical libra-ries. Through the development of novel synthetic strategies relying on divergent reactions, chemist is now able to realize in only two or three steps such library that ensures the access of a large number of products having a good quality in term of structural diversity. A few examples are presented to illustrate how this can be done in the context of increasing molecular complexity and diversity devoted to the discovery and optimization of bioactive compounds. © 2015 médecine/sciences-Inserm.


Haudecoeur R.,CNRS Molecular Pharmacochemistry Department | Peuchmaur M.,CNRS Molecular Pharmacochemistry Department | Ahmed-Belkacem A.,French Institute of Health and Medical Research | Pawlotsky J.-M.,French Institute of Health and Medical Research | And 2 more authors.
Medicinal Research Reviews | Year: 2013

Hepatitis C is a viral liver infection considered as the major cause of cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) possesses a single positive strand RNA genome encoding a polyprotein composed of approximatively 3000 amino acids. The polyprotein is cleaved at multiple sites by cellular and viral proteases to liberate structural and nonstructural (NS) proteins. NS5B, the RNA-dependent RNA polymerase (RdRp), which catalyzes the HCV RNA replication has emerged as an attractive target for the development of specifically targeted antiviral therapy for HCV (DAA, for direct-acting antivirals). In the last 10 years, a growing number of non-nucleoside compounds have been reported as RdRp inhibitors and few are undergoing clinical trials. Over the past 5 years, several reviews were published all describing potentially active molecules. To the best of our knowledge, only one review covers the structure-activity relationships.1 In this review, we will discuss the reported non-nucleoside molecules acting as RdRp inhibitors according to their chemical class especially focusing on structure-activity relationship aspects among each class of compounds. Thereafter, we will attempt to address the global structural requirements needed for the design of specific inhibitors of RdRp. © 2012 Wiley Periodicals, Inc.


Szakacs G.,Hungarian Academy of Sciences | Hall M.D.,U.S. National Institutes of Health | Gottesman M.M.,U.S. National Institutes of Health | Boumendjel A.,CNRS Molecular Pharmacochemistry Department | And 6 more authors.
Chemical Reviews | Year: 2014

The development of multidrug resistance (MDR) in patients suffering cancer remains a significant clinical challenge, with drug efflux by ABC (ATP-binding cassette) transporters contributing significantly. Theoretically, one could restore the efficacy of first-line drugs by circumventing these resistance mechanisms. However, cancer is a heterogeneous disease that can exhibit different characteristics from patient to patient or even within a single patient. Spatial and temporal heterogeneity is a result of continuous adaptation to selective pressures through sequential genetic changes that ultimately convert a normal cell into intractable cancer. Thus, cancer cells are moving targets, as individual cells in a tumor mass constantly adapt to local environmental challenges. Biological membranes represent a significant permeation barrier and thus play a critical role in the protection of pharmacokinetic compartments. Conversely, the activity of a drug ultimately depends on the ability of the compound to reach its target, which might reside in a well-protected pharmacological sanctuary.


Wong Y.-S.,CNRS Molecular Pharmacochemistry Department
Methods in Molecular Biology | Year: 2012

Recent advances and concepts for exploring chemical space are highlighted in this chapter and show how the synthetic chemical world meets the demand of making large and relevant collection of new molecules for analyzing the biological world more closely. © 2012 Springer Science+Business Media, LLC.


Haudecoeur R.,CNRS Molecular Pharmacochemistry Department | Boumendjel A.,CNRS Molecular Pharmacochemistry Department
Current Medicinal Chemistry | Year: 2012

The first review regarding the potential of aurones as promising drug candidates was reported in 2003. Since, considerable efforts have been made to explore the pharmacological and therapeutical activities of aurones. In this regard, many biological areas were concerned, including major pathological, such as cancer and neurodegenerative disorders. The aim of the present report is to highlight the progress made during the last ten years on the medicinal chemistry of aurones. A special focus will be made on the structure-activity relationship aspects among aurones and especially in case where aurones were found highly active than the corresponding flavones and chalcones. © 2012 Bentham Science Publishers.


Nicolle E.,CNRS Molecular Pharmacochemistry Department | Souard F.,CNRS Molecular Pharmacochemistry Department | Faure P.,French Institute of Health and Medical Research | Boumendjel A.,CNRS Molecular Pharmacochemistry Department
Current Medicinal Chemistry | Year: 2011

There is evidence that hyperglycemia results in the generation of reactive oxygen species, leading to oxidative stress in various tissues, including vascular system. An important link between oxidative stress, inflammatory response and insulin activity is now well established. The ability of antioxidants to protect against the deleterious effects of hyperglycemia and also to improve glucose metabolism and intake must be considered as leads of choice in diabetes treatment. In addition to their antioxidative activity, many flavonoids were demonstrated to act on biological targets involved in type 2 diabetes mellitus such as: glycosidase, glucose cotransporter or aldose reductase. In this context, flavonoids behaving as antioxidants were studied as potential drugs by acting as biological targets involved in diabetes development. In this review, we propose to shed light on antioxidants flavonoids investigated as antidiabetics. A special focus was made to address the structure-activity relationship related to the effect of these naturally occurring molecules on different targets involved in diabetes development. © 2011 Bentham Science Publishers Ltd.


Zhu Z.,CNRS Molecular Pharmacochemistry Department | Ravelet C.,CNRS Molecular Pharmacochemistry Department | Perrier S.,CNRS Molecular Pharmacochemistry Department | Guieu V.,CNRS Molecular Pharmacochemistry Department | And 2 more authors.
Analytical Chemistry | Year: 2012

Here, we describe a new fluorescence polarization aptamer assay (FPAA) strategy which is based on the use of the single-stranded DNA binding (SSB) protein from Escherichia coli as a strong FP signal enhancer tool. This approach relied on the unique ability of the SSB protein to bind the nucleic acid aptamer in its free state but not in its target-bound folded one. Such a feature was exploited by using the antiadenosine (Ade)-DNA aptamer (Apt-A) as a model functional nucleic acid. Two fluorophores (fluorescein and Texas Red) were introduced into different sites of Apt-A to design a dozen fluorescent tracers. In the absence of the Ade target, the binding of the labeled aptamers to SSB governed a very high fluorescence anisotropy increase (in the 0.1300.200 range) as the consequence of (i) the large global diffusion difference between the free and SSB-bound tracers and (ii) the restricted movement of the dye in the SSB-bound state. When the analyte was introduced into the reaction system, the formation of the folded tertiary structure of the Ade-Apt-A complex triggered the release of the labeled nucleic acids from the protein, leading to a strong decrease in the fluorescence anisotropy. The key factors involved in the fluorescence anisotropy change were considered through the development of a competitive displacement model, and the optimal tracer candidate was selected for the Ade assay under buffer and realistic (diluted human serum) conditions. The SSB-assisted principle was found to operate also with another aptamer system, i.e., the antiargininamide DNA aptamer, and a different biosensing configuration, i.e., the sandwich-like design, suggesting the broad usefulness of the present approach. This sensing platform allowed generation of a fluorescence anisotropy signal for aptamer probes which did not operate under the direct format and greatly improved the assay response relative to that of the most previously reported small target FPAA. © 2012 American Chemical Society.


Demeunynck M.,CNRS Molecular Pharmacochemistry Department | Baussanne I.,CNRS Molecular Pharmacochemistry Department
Current Medicinal Chemistry | Year: 2013

the present review focuses on the synthesis and biological evaluation of polycyclic 4(3H)-quinazolinones containing fused aromatic or heteroaromatic rings. The first part of the review is related to compounds with ring fused to the pyrimidine part of the quinazoline core. Most of the quinazolinone alkaloids belong to this class of molecules. The second part presents molecules bearing extra ring(s) fused to the benzo moiety of the quinazolinone skeleton. Their structural diversity opens new fields in the search of active molecules. © 2013 Bentham Science Publishers.


Genoux E.,CNRS Molecular Pharmacochemistry Department | Nicolle E.,CNRS Molecular Pharmacochemistry Department | Boumendjel A.,CNRS Molecular Pharmacochemistry Department
Current Organic Chemistry | Year: 2011

The cancer preventing effect of flavonoids is largely documented in literature. In addition to their nutritional value as cancer preventing agents, they have been studied as drug candidates in cancer treatment. Many mechanisms of action have been identified, including carcinogen inactivation, antiproliferation, cell cycle arrest, induction of apoptosis and differentiation, inhibition of angiogenesis, antioxidative activity and reversal of multidrug resistance. The diversity in the biological targets of flavonoids has led during the last twenty years to an extensive research toward medicinal chemistry of flavonoids with the aim to obtain anticancer drugs. Some anticancer agents derived from flavonoids are emerging as major anticancer drugs or chemosensitizers. This review will shed light on recent molecules obtained from efforts made on medicinal chemistry of flavonoids. A special focus will be made on flavonoid derivatives being studied in clinical trials. © 2011 Bentham Science Publishers Ltd.


Perez S.,CNRS Molecular Pharmacochemistry Department | Tvaroska I.,Slovak Academy of Sciences | Tvaroska I.,Constantine the Philosopher University
Advances in Carbohydrate Chemistry and Biochemistry | Year: 2014

The article reviews the significant contributions to, and the present status of, applications of computational methods for the characterization and prediction of protein-carbohydrate interactions. After a presentation of the specific features of carbohydrate modeling, along with a brief description of the experimental data and general features of carbohydrate-protein interactions, the survey provides a thorough coverage of the available computational methods and tools. At the quantum-mechanical level, the use of both molecular orbitals and density-functional theory is critically assessed. These are followed by a presentation and critical evaluation of the applications of semiempirical and empirical methods: QM/MM, molecular dynamics, free-energy calculations, metadynamics, molecular robotics, and others. The usefulness of molecular docking in structural glycobiology is evaluated by considering recent docking- validation studies on a range of protein targets. The range of applications of these theoretical methods provides insights into the structural, energetic, and mechanistic facets that occur in the course of the recognition processes. Selected examples are provided to exemplify the usefulness and the present limitations of these computational methods in their ability to assist in elucidation of the structural basis underlying the diverse function and biological roles of carbohydrates in their dialogue with proteins. These test cases cover the field of both carbohydrate biosynthesis and glycosyltransferases, as well as glycoside hydrolases. The phenomenon of (macro)molecular recognition is illustrated for the interactions of carbohydrates with such proteins as lectins, monoclonal antibodies, GAG-binding proteins, porins, and viruses. © 2014 Elsevier Inc.

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