A Practical Approach to New (5Z) 2-Alkylthio-5-arylmethylene- 1-methyl-1,5-dihydro-4H-imidazol-4-one Derivatives

International audienceA practical protocol for the preparation of (5Z)-2-alkylthio-5-arylmethylene-1-methyl-1,5-dihydro-4H-imidazol-4-one derivatives is reported. The new compounds were obtained in good yield and stereoselectivity in two steps, namely a solvent-free Knoevenagel condensation under microwave irradiation, followed by an S-alkylation reaction with various halogenoalkanes

Synthesis of new pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs as DYRK1A inhibitors

International audienceNew pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs were synthesized and their inhibitory activities against DYRK1A, CDK5/p25, GSK3α/β and p110-α isoform of PI3K evaluated using harmine as reference. Both furan-2-yl 10 and pyridin-4-yl 19 from the two different series, exhibited submicromolar IC50 against DYRK1A with no activities against the three other kinases. In addition, compound 10 exhibited antiproliferative activities in the Huh-7, Caco2 and MDA-MB-231 cell lines

Advances in tetrahydropyrido[1,2-a]isoindolone (valmerins) series: Potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors.

International audienceAn efficient synthetic strategy was developed to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSK3 as well as cellular effects on cancer cell lines were measured for each novel compound. Additionally docking studies were performed to support medicinal chemistry efforts. A strong GSK3/CDK5 dual inhibitor (38, IC50 GSK3/CDK5 32/84 nM) was obtained. A set of highly selective GSK3 inhibitors was synthesized by fine-tuning structural modifications (29 IC50 GSK3/CDK5 32/320 nM). Antiproliferative effects on cells were correlated with the in vitro kinase activities and the best effects were obtained with lung and colon cell lines

Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis.

BACKGROUND: Tuberculosis, which is caused by Mycobacterium tuberculosis, remains one of the leading causes of mortality worldwide. The C-type lectin DC-SIGN is known to be the major M. tuberculosis receptor on human dendritic cells. We reasoned that if DC-SIGN interacts with M. tuberculosis, as well as with other pathogens, variation in this gene might have a broad range of influence in the pathogenesis of a number of infectious diseases, including tuberculosis. METHODS AND FINDINGS: We tested whether polymorphisms in CD209, the gene encoding DC-SIGN, are associated with susceptibility to tuberculosis through sequencing and genotyping analyses in a South African cohort. After exclusion of significant population stratification in our cohort, we observed an association between two CD209 promoter variants (-871G and -336A) and decreased risk of developing tuberculosis. By looking at the geographical distribution of these variants, we observed that their allelic combination is mainly confined to Eurasian populations. CONCLUSIONS: Our observations suggest that the two -871G and -336A variants confer protection against tuberculosis. In addition, the geographic distribution of these two alleles, together with their phylogenetic status, suggest that they may have increased in frequency in non-African populations as a result of host genetic adaptation to a longer history of exposure to tuberculosis. Further characterization of the biological consequences of DC-SIGN variation in tuberculosis will be crucial to better appreciate the role of this lectin in interactions between the host immune system and the tubercle bacillus as well as other pathogens

DC-SIGN: a multi-task viral receptor

International audienceThe identification of DC‐SIGN, a lectin expressed at the surface of dendritic cells and macrophages, provides new insight into how viruses interact with their hosts. DC‐SIGN was initially described as a ligand for HIV envelope glycoproteins. This lectin does not play the usual role of a HIV receptor, since it does not allow viral infection in absence of CD4 and co‐receptor(s). However, DC‐SIGN promotes viral capture and transmission to permissive cells. From an immunological point of view, captured virions are processed and presented by MHC molecules, inducing the activation of immune responses. Besides HIV, several viruses (CMV, HCV, Dengue, Sindbis and Ebola viruses) and non viral pathogens also bind DC‐SIGN. This review focuses on our current knowledge of the virological and immunological roles of DC‐SIGN

Further investigation of Paprotrain: Towards the conception of selective and multi-targeted CNS kinase inhibitors

International audienceStarting from a known compound, identified as the first inhibitor of the kinesin MKLP-2 and named Paprotrain, we have investigated its reactivity to produce through photochemistry a potent nanomolar inhibitor of the kinase DYRK1A. Using similar and different chemical pathways, we have designed several families of compounds that have been screened on a panel of five protein kinases: CK1δ/ε, CDK5/p25, GSK3α/β, DYRK1A and CLK1, all involved in neurodegenerative disorders such as Alzheimer's disease. We have identified a first group of multi-targeted compounds, a second group of dual inhibitors of DYRK1A & CLK1 and a last group of selective inhibitors of CLK1. Then, our best submicromolar to nanomolar inhibitors were evaluated towards the closest members of the aforementioned kinases: DYRK1B and CLK4, as well as the subfamily CLK2-3. Several compounds appear to be particularly promising for the development of tools in the battle against Alzheimer's disease

Synthesis and biological evaluation of tetrahydro[1,4]diazepino[1,2-a]indol-1-ones as cyclin-dependent kinase inhibitors

International audienceNew series of 2,3,4,5-tetrahydro[1,4]diazepino[1,2a]indol-1-ones and 3,4,5,10-tetrahydro-2H-diazepino[3,4-b]indol-1-ones have been synthesized through an iodolactonisation/lactone-to-lactam rearrange-ment sequence. These compounds were evaluated as potential protein kinase inhibitors (CDK1, CDK5 andGSK-3). 11-Iodo-2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-one derivatives exhibited sub-micromolar inhibitory activity against cyclin-dependent kinases. Docking studies were realized todetermine the binding mode of the inhibitors into the ATP binding domain of the CDK5 catalytic site. Ourresult highlighted two weak Van-der-Waals bonding interactions established between the iodine atomand both phenyl group of Phe 80 and ammonium end of Lys 3

An efficient method for the preparation of new analogs of Leucettamine B under solvent-free microwave irradiation.

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Synthesis and biological evaluation of novel phenylcarbazoles as potential anticancer agents.

We here report the synthesis and biological evaluation of new phenylcarbazole derivatives designed as potential anticancer agents. Indole and hydroxyindole were used to generate three scaffolds that were successively exploited to introduce various substituents on the maleimide moiety. The synthesis includes a final intramolecular key Heck-type reaction, which was carried out with a triflate derivative or with a bromophenyl derivative. Each step was optimized and the complete chemical strategy is detailed. Several compounds showed a marked cytotoxicity against CEM human leukemia cells with IC(50) values in the 10-100 nM range. Precise structure-activity relationships were delineated. Cell cycle analysis, topoisomerase I inhibition, and interaction with DNA were evaluated, and inhibition of CDK activity was also investigated. Although binding of the drugs to DNA likely contributes to the cytotoxic action, the exact molecular targets of these molecules remain undiscovered. The efficient chemical routes reported here for the design of highly cytotoxic compounds provide novel opportunities to identify antitumor agents in the phenylcarbazole series