Le Gentiopicroside (GPS) est un secoiridoïde isolé de Gentiana lutea qui est appelé Qin Jiao en chinois. C'est l'une des plantes médicinales les plus couramment utilisée en Chine. Le GPS a des activités biologiques et pharmacologiques allant des propriétés antiviral, anti-inflammatoire, analgésique, anti-hépatotoxique et cholérétiques. Toutefois, la modification structurelle et la synthèse totale du GPS est toujours un défi pour les chimistes organiciens.Dans ce mémoire, nous avons traité la conception, la synthèse et l'évaluation pharmacologique d'une série de composés dérivés du GPS comme inhibiteurs potentiels du virus de l'hépatite C (HCV). Certaines fonctions communes dans la conception de médicaments, tels que des halogènes, du soufre, de l'azoture et un groupe amino, ont été introduites au fragment sucre du GPS. Dans le même temps, nous avons étudié trois approches pour synthétiser la partie aglycone du GPS, deux d'entre elles sont basées sur des cycloadditions [3+3] inter- ou intramoléculaire organocatalyzées à partir des aldéhydes insaturés B et D. La troisième est basée sur le réarrangement d'énol-esters α,β-insaturés F, catalysé par un N-hétérocyclique carbène (NHC). L'intermédiaire commun pour ces approches est un ester insaturé A qui a été préparé en quatre étapes à partir de D-(-)-mannitol et de méthylcrotonate commerciaux. La cycloaddition [3+3] entre l'énal 54 et l'énol stabilisé 59 ne fournit pas le cyclo-adduit attendu même si sur un modèle de réaction les 3,4-dihydropyranne 68 et pyranone 69 ont été formées. Le traitement de l'énol-ester 77 avec un NHC donne un accès à un précurseur potentiel dans la synthèse totale du GPS. / Gentiopicroside (GPS) is a secoiridoid compound isolated from Gentiana lutea which is called Qin Jiao in Chinese. It is one of the most common herbal medicines used in China. The biological and pharmacological activities of GPS contain antiviral, anti-inflammatory, analgesia, antihepatotoxic and choleretic activities. GPS is involved in ongoing phase III clinical trials as the first class new drug. However, the structural modifications and total synthesis of GPS is still a challenge for organic chemists.In this thesis we have processed the design, synthesis and pharmacological evaluation of a series of GPS derivatives as potential hepatitis C virus (HCV) entry inhibitors. Some common functional elements in drug design, such as halogen, sulfur, azide and amino group, have been successfully introduced on the sugar moiety of GPS. In the mean time, we studied three approaches to synthesize the aglycone part of GPS. Two of them are based on organocatalyzed inter- or intramolecular [3+3] cycloadditions from unsaturated aldehydes B and D. The third one was based on an NHC-catalysed rearrangement of α,β-unsaturated enol-esters F. The common key intermediate for these approaches was the unsaturated ester A which was prepared in four steps from commercially available D-(-)-manitol and methylcrotonate. The formal [3+3] cycloaddition between enal 54 and the stabilized enol 59 did not provide the expected cyclo-adduct even if on a model reaction 3,4-dihydropyran 68 and pyranone 69 were formed. The α-substituted position of enal 54 could explain this default in reactivity under proline organocatalysis. The treatment of enol-ester 77 with N-Heterocyclic-Carbene gave an access to the advanced precursor 78 potentially useful in the total synthesis of GPS.

Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease that although systemic, mainly affects the synovium of the joints. Currently, remission is the goal of RA treatment. Research efforts are however targeted towards finding a cure. Radix Gentiana macrophylla Pall. (秦艽, Pinyin: Qinjiao) has been used for a long time in several prescriptions in the Chinese herbal medicinal tradition to treat, among others, rheumatic conditions. In this study, compounds from Radix G. macrophylla Pall. were extracted by maceration, isolated by NP-SPE followed by RP-HPLC-UV, identified by LRESIMS(+), 1D and 2D-NMR and finally prepared for in vitro screening (NF-κB downregulation activity). The method used was adapted from the NCI Program for Natural Product Discovery (NPNPD). This resulted in the identification of six known compounds. The secoiridoid aglycone (-)-swermusic acid B, known only in Swertia mussotii Franch., was however for the first time isolated from a Gentiana species.