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The Institut de Chimie des Substances Naturelles (ICSN): Past and Present

2018; Wiley; Volume: 2018; Issue: 42 Linguagem: Inglês

10.1002/ejoc.201801558

1434-193X

Angéla Marinetti,

History and advancements in chemistry

This guest editorial sketches the history of the Institut de Chimie des Substances Naturelles (ICSN, Gif-sur-Yvette, France) and presents the research topics currently developed at the Institute. The “Institut de Chimie des Substances Naturelles” (Gif-sur-Yvette, France) was created by the CNRS1 in 1959, under the scientific input of Prof. Edgar Lederer and Maurice-Marie Janot, with the aim to promote the Chemistry of Natural Products in France through both research and training programs. Indeed, this area was not covered by academic research programs that were mainly devoted, at that time, to fundamental organic synthesis. The Institute was structured initially into two separate sections around the research activities of its founders: the chemistry of alkaloids and antibiotics, on one hand, and the chemistry of natural products of microbial, plant, and animal origins, on the other. Since the foundation of the ICSN answered to a deliberate commitment and scientific policy of the CNRS, the Institute received strong support in terms of human resources. In 1960, the Institute's 114 research scientists, engineers, and technicians represented more than 10 % of all the chemists hired by the CNRS at the national level. The permanent staff of the Institute increased regularly in number, and over 170 scientific employees were hired by both the CNRS and INSERM2 in the eighties when the ICSN attained prominent international renown. From the seventies onwards, the Institute was directed or co-directed by Pierre Potier (from 1974 to 2000), Sir Derek Barton (from 1977 to 1986), and Guy Ourisson (from 1985 to 1989), then followed by Jean-Yves Lallemand, David Crich, and Max Malacria during the 2001–2014 period. At the interface between chemistry and biology, research at the ICSN focused mainly on natural products of biological relevance, and as potential sources of new drugs, in strong connection with French industrial partners (Roussel-Uclaf, Pierre Fabre, Sanofi, Servier, and others). In pioneering actions, research antennas were established over the years in Noumea (New Caledonia) and French Guyana in order to gain easier access to extended world biodiversity. For the same purpose, collaborative networks have been established with academic research laboratories notably in Malaysia and Vietnam. Research on bioactive molecules culminated in the discovery of two anticancer drugs of natural origin (Figure 1), Navelbine® from Catharanthus roseus (1978, for treatment of lung and breast cancers, marketed in 1989) and Taxotere® from Taxus baccata (1986, for breast and lung cancer).3 Both drugs were discovered, patented, and developed by the Pierre Potier team,4 in partnership with the Laboratoires Pierre Fabre and Rhône-Poulenc (now Sanofi) companies, respectively. They afforded huge financial benefits to both the CNRS and the cooperating companies: to get an idea of how successful these drugs were, we can recall that Taxotere® alone had an annual turnover of over 1.7 billion Euros in 2004. A third natural substance, the marine metabolite Girolline (Girodazole®) attained clinical trials. The challenges of investigating nature and biodiversity represent today, more than ever, major societal issues within the context of sustainable development. The increased recognition of the pivotal role of biodiversity for human health and well-being encourages sheltering biodiversity from threats of overexploitation and human economic development. In this context, in-depth knowledge of natural ecosystems remains a global strategic issue. It represents a focused mission of the ICSN, which has developed unique expertise in this area, together with expertise in the valorization of bioresources (marine organisms, plants, and microorganisms) as therapeutics and cosmetics. Nevertheless, modern natural products chemistry could not expand and evolve without interdisciplinary approaches including acquisition and exploitation of big data combined with metabolomics, bioinformatic methods and analytical tools, advanced synthetic and theoretical methods, chemistry oriented to drug discovery in selected therapeutic areas, knowledge of biosynthetic pathways, chemical biology, genomics, and chemical ecology. Today, therefore, the ICSN pursues research activities inspired by natural substances and oriented toward their biomedical applications but also develops recognized expertise in the above complementary areas. It is consequently organized into four research departments: “Natural Products and Medicinal Chemistry”, “Organic Synthesis and Catalytic Methods”, “Chemical Biology”, and “Analytical and Structural Chemistry and Biology”. At the same time, multidisciplinary projects at the interface of chemistry and biology are implemented as transversal, inter-department programs. The ICSN benefits today from its long-established expertise in the isolation and characterization of bioactive natural products and has the complete know-how needed to develop new drugs based on these natural compounds. Scientific missions are organized worldwide for sourcing and taking inventories of biodiversity in under-explored areas of the planet. These missions are conducted within the framework of cooperation networks and technological development projects, with total respect of the Nagoya protocol on access and benefit sharing. As mentioned, an ICSN antenna, the “Laboratoire des Plantes Médicinales”, is located in the New Caledonian biodiversity “Hot Spot” (Noumea). Moreover, two Associated International Laboratories (LIA) managed by M. Litaudon, F. Roussi, and A. Al-Mourabit are currently operating. The first involves the Institute of Marine Biochemistry (IMBC) of the Academy of Sciences and Technology of Vietnam (Hanoi) and the second the Department of Chemistry, Faculty of Sciences of the University of Malaya (Kuala Lumpur). The collection of organisms and microorganisms of marine origin is being improved in terms of sourcing and preservation of natural ecosystems thanks to the SOMARTEX technology (Self Operating MARine Trapping Extractor). The device principle is the extraction of molecules produced by invertebrate holobionts in their natural habitat at any location and depth without the necessity of harvesting the organisms. The SOMARTEX as well as the UNIFERTEX (UNIversal FERmenTor EXpert) technologies developed by J. Ouazzani (CNRS patents) have been validated and exploited within the collaborative EU Horizon 2020 TASCMAR project (“Tools And Strategies to access original bioactive compounds by Cultivating MARine invertebrates and associated symbionts”) which brings together 120 researchers from 8 European countries (http://www.tascmar.eu/). The ICSN extract library, the largest collection of natural extracts in the French public domain, gathers and indexes more than 14,000 extracts from over 7,000 endemic and indigenous plants, microbial strains and marine organisms. Selection of relevant botanical families and access to biodiversity-rich areas ensures great structural diversity and almost unlimited bioactivity potential. A database allows the management of the collection of microplates and data related to HTS phenotypic or target-based screenings. With respect to classical bio-guided approaches, the identification of new bioactive leads from complex matrices is accelerated today by bioinformatics and molecular network strategies. For instance, processing large sets of extracts by LC/MS-MS and implementation of biological activity filters enable instantaneous data mining and visualization of molecular networks of relevant clusters. ICSN teams currently apply and develop this recent approach as well as fast dereplication methods by supercritical chromatography. Medicinal chemistry programs tackle some of the World Health Organization's priority targets such as antibiotic resistance, which today attains highly preoccupying levels worldwide, and tropical diseases that are largely neglected because of their low strategic interest for private companies. Central Nervous System diseases and cancer are also among the therapeutic areas historically investigated at the ICSN. Studies of the receptor–ligand interactions using molecular modeling contribute to optimization of bioactivity. Most notably, identification of Paprotrain as a selective inhibitor of the MKLP2 kinesin with antitumor activity led to the creation of the Biokinesis start-up in 2012 (C. Guillou). The medicinal chemistry programs are based on both natural and synthetic bioactive compounds. They are implemented mainly within the framework of external collaborations with biologists and clinicians and are financially supported by Technology Transfer Agencies (SATT). At the same time, research programs in structural chemistry and biology aim at a better understanding of the relationship between the structure, dynamics, and function of relevant target proteins and their interactions with drugs. More specific interest relates to proteins presenting high intrinsic disorder that are involved in cancer, neurodegenerative diseases, or viral infections. In particular, these proteins are investigated by means of high-field NMR methods that are easily accessible since the ICSN operates one of the major High-Field French national NMR facilities that houses a 950 MHz instrument (http://www.ir-rmn.fr/en/). Furthermore, novel bioinformatics and computational methods are being developed particularly aimed at a better understanding of antibiotic resistance processes essential to the design of new antibiotics. Another facet of phytochemistry currently investigated at the ICSN relates to mechanisms of plant growth with relevance to agrochemistry. Special attention is payed to strigolactones, the most recently discovered class of plant hormones known for their role in the rhizosphere. Notably, the design of profluorescent probes enables a better understanding of strigolactone perception mechanisms and plant architecture control. Also, expeditious syntheses of glycolipidic plant growth promoters, as well as the biochemical identification of their receptors, are being actively investigated. Research programs in synthetic organic chemistry include the development of catalytic methods with special emphasis on processes allowing stereochemical control through enantioselective reactions. Rhodium-promoted nitrene transfers, visible light photoredox catalysis for new functionalization processes, uses of hypervalent iodine in tandem catalytic reactions, and gold-promoted cycloisomerizations are a few representative examples of organometallic catalysis studies carried out at the ICSN. In parallel, highly efficient enantioselective organocatalytic methods based on chiral phosphoric acids, such as difunctionalization of unsaturated ubstrates, as well as on trivalent phosphines for [3+2] cyclizations, are developed. The design of innovative organic photocatalysts and organoiodines, chiral phosphorus ligands and organocatalysts are also important areas of research. Moreover, methods in carbohydrate chemistry, including glycosylation strategies, as well as organic reactions involving elemental sulfur are actively developed. The new synthetic methods are challenged by their applications to either the synthesis of complex molecules, for example total synthesis of natural or bioactive compounds, or the development of diversity-oriented synthetic procedures, cascade, and multicomponent reactions. Generally speaking, focused objectives are environmentally friendly synthetic methods based on sustainable energy, direct CH functionalization, abundant resources (e.g., sulfur), and efficient tandem processes. In the field of chemical biology, research conducted at the ICSN involves the design of new probes for the study of biological events (smart probes for multimodal Magnetic Resonance (MRI)/Optical Imaging) as well as new strategies for metabolic glycan labeling. The metabolic labeling of bacterial lipopolysaccharides has led notably to the development of a rapid identification method for pathogenic Legionella pneumophila and resulted in the creation of the Click4Tag start-up company (B. Vauzeilles with S. Dukan, Marseille). Biological research at the ICSN includes studies on the adaptive response of mammalian cells towards environmental signals and stresses, focusing on reversible post-translational modifications of protein sensors of redox signals and related biorelevant Fe-S proteins. Advanced analysis and biological screening platforms provide support to both ICSN groups and external academic and private laboratories, bringing expertise and facilities in the areas of HPLC–Mass spectrometry, NMR spectroscopy, elemental analysis, X-ray diffraction, qPCR (quantitative Polymerase Chain Reaction), TSA (Thermal Shift Assays), and HTS bioactivity screening. The ICSN's areas of expertise are labeled and structured at a national level by three “Excellence Laboratories” in which the Institute is involved: LabEx CEBA “CEnter for the study of Biodiversity in Amazonia”, LabEx LERMIT “Laboratory of Excellence in Research on Medication and Innovative Therapeutics”, and LabEx CHARM3AT “Chemistry of Multifunctional Molecular Architectures and MATerials” (Figure 2). At the local level, the ICSN is part of the emerging Paris-Saclay University bringing together 15 institutions: three universities, five major engineering and business schools, and seven research organizations including CNRS, CEA,5 INRA,6 and INSERM.2 These institutions decided to work on a common project and merged in 2015, pooling educational courses and research in order to face the challenges of global competition in these important domains. Offering training programs and research of highest international standards as well as fostering innovation and technology transfer by gathering academics and private research laboratories on the same campus are the declared ambitions of the Paris-Saclay project. The University, covering a broad range of disciplines including Life Sciences, Chemistry, Mathematics, Information Science and Technology, Physics, and Geosciences, among others, counts today over 65,000 students, 5000 PhD students, and 300 research laboratories. It represents over 15 % of the research workforce in France. This stimulating environment will broaden and strengthen the scientific bases of the ICSN in the near future while offering a clear opportunity to assert its central role in the field of natural products chemistry. All members of the ICSN who have contributed to this paper and especially the ICSN Management Committee members Ali Al-Mourabit, Géraldine Masson, Carine Van Heijenoort, Boris Vauzeilles, and Philippe Durand are warmly acknowledged.