Approche synthétique de diterpènes de la famille des cyathines, activateurs de la biosynthèse du facteur de croissance nerveuse

Les cyathines forment une famille de diterpènes présentant un squelette tricyclique décahydro[e]indène unique parmi les terpènes. Ces composés sont capables de stimuler la biosynthèse du facteur de croissance nerveuse et par conséquent pourraient être employés dans le traitement des maladies neuro-dégénératives comme la maladie d'Alzeihmer. Dans ce travail, nous décrivons une nouvelle voie d'accès à cette classe de molécules. Les deux étapes clé de la synthèse sont d'une part la préparation d'une sous-unité A dont la configuration absolue a éte établie en tirant parti de la réaction de Michael asymétrique impliquant les imines chirales. D'autre part, la construction du cycle B, qui a pu être réalisée par une réaction de Heck intramoléculaire permettant un contrôle anti entre les deux groupements angulaires en C6 et C9. Enfin le cycle C à 7 chaînons est élaboré par une réaction d'homologation de cycle à partir d'un système octahydro-cyclopenta[a]naphtalène.Cyathins are diterpenoid natural products which display an unusual tricyclic décahydro[e]indene skeleton. These compounds are strong stimulators of the nerve growth factor biosynthesis and have been expected as medicine for degenerative neuronal disorders such as Alzeihmer's disease. The present work describes a new access to these compounds. First of all, the formation of the A-subunit containing the stereo-defined C-9 angular methyl group which was controlled by using the deracemizing Michael addition involving the chiral imine derived from 2-methylcyclopentanone and (S)-1-phenylethylamine. In a second step, the crucial control of the relative anti configuration between the ring A and C was achieved with a high selectivity by an intramolecular Heck cyclization. Finally , the elaboration of the tricyclic [ABC] core was achieved by a one carbon expansion reaction of the six membered C-ring. This approach provided an highly advanced intermediate suitable for the synthesis of natural cyathin diterpenoids in 17 steps with an overall yield of 0.8%.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

DEVELOPPEMENT DE NOUVEAUX PROCESSUS SEQUENTIELS D'ANNELATION (APPLICATION A LA SYNTHESE D'ALCALOIDES DE TYPE ERYTHRINA (DOCTORAT : PHARMACOCHIMIE))

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Synthèse et activité biologique de nouvelles styrylquinoléines inhibitrices de l'intégrase du VIH-1

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Design of Rhenium Compounds in Targeted Anticancer Therapeutics

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Nanotechnologies for the treatment of colon cancer: from old drugs to new hope

International audienceColorectal cancer is a wide-reaching health problem due to its incidence and to the high mortality rates. Adjuvant chemotherapies have considerably improved the prognosis and/or the overall survival of patients with locally advanced and metastatic cancers. Nevertheless, their efficiency remains limited due to intrinsic and emerging multidrug resistance (MDR) of cancer cells, and to major adverse effects and dose limiting toxicities. The present review discusses the knowledge of clinically relevant mechanisms of resistance to cytotoxic and targeted therapies for the treatment of colorectal cancer, and focuses on the benefit of nanomedicine approach to circumvent these processes. Nanomedicaments should allow extensive cancer cell drug loading independent on cell surface transporters, -thus overwhelming drug metabolism and efflux-, but also alleviate side-effects related to tissue-dependent drug uptake. Finally, we provide an outline of preclinical and clinical studies of nanoparticles formulations for colorectal cancer treatment, and briefly discuss strategies to optimize the selective delivery of these nanomedicines to colorectal cancer cells

The rhenium(I)-diselenoether anticancer drug targets ROS, TGF-β1, VEGF-A, and IGF-1 in an in vitro experimental model of triple-negative breast cancers

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Gemcitabine Lipid Prodrugs: The Key Role of the Lipid Moiety on the Self-Assembly into Nanoparticles

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Photo-physics study of a styrylquinoline as inhibitor of Pim-1 kinase: Solvent and concentration effects

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Combinatorial Nanomedicine Made of Squalenoyl-Gemcitabine and Edelfosine for the Treatment of Osteosarcoma

International audienceDue to chemoresistance and a high propensity to form lung metastasis, survival rates in pediatric osteosarcoma (OS) are poor. With the aim to improve anticancer activity in pediatric OS, a multidrug nanomedicine was designed using the alkyl-lysophospholipid edelfosine (EF) co-assembled with squalenoyl–gemcitabine (SQ–Gem) to form nanoassemblies (NAs) of 50 nm. SQ–Gem/EF NAs modified the total Gem pool exposure in the blood stream in comparison with SQ–Gem NAs, which correlated with a better tolerability and a lower toxicity profile after multiple intravenous administrations in mice. For in vivo preclinical assessment in an orthotopic OS tumor model, P1.15 OS cells were intratibially injected in athymic nude mice. SQ–Gem/EF NAs considerably decreased the primary tumor growth kinetics and reduced the number of lung metastases. Our findings support the candidature of this anticancer nanomedicine as a potential pediatric OS therapy

A novel codrug made of the combination of ethionamide and its potentiating booster: synthesis, self-assembly into nanoparticles and antimycobacterial evaluation

International audienceEthionamide (ETH) is one of the most widely used second-line chemotherapeutic drugs for the treatment of multi-drug-resistant tuberculosis. The bioactivation and activity of ETH is dramatically potentiated by a family of molecules called "boosters" among which BDM43266 is one of the most potent. However, the co-administration of these active molecules is hampered by their low solubility in biological media and by the strong tendency of ETH to crystallize. A novel strategy that involves synthesizing a codrug able to self-associate into nanoparticles prone to be taken up by infected macrophages is proposed here. This codrug is designed by tethering N-hydroxymethyl derivatives of both ETH and its booster through a glutaric linker. This codrug self-assembles into nanoparticles of around 200 nm, stable upon extreme dilution without disaggregating as well as upon concentration. The nanoparticles of the codrug can be intranasally administered overcoming the unfavorable physico-chemical profiles of the parent drugs. Intrapulmonary delivery of the codrug nanoparticles to Mtb infected mice via the intranasal route at days 7, 9, 11, 14, 16 and 18 post-infection reduces the bacterial load in the lungs by a factor of 6