First Application of the Dakin-West Reaction to Fmoc Chemistry: Synthesis of the ketomethylene tripeptide Fmoc-Nα-Asp(tBu)-(R,S)Tyr(tBu)Ψ(CO-CH2)Gly-OH

International audienceA practical synthesis of a tripeptide containing a ketomethylene isostere, suitably protected for introduction in Fmoc SPPS, has been carried out for the first time in Fmoc chemistry by using a modified Dakin-West reaction

Isolement et identification des constituants de type taxane d'Austrotaxus spicata Compton (Taxacees). Hemisynthese d'analogues du taxol

SIGLEINIST T 75940 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Synthèse et étude biologique d'analogues di- et tripeptidiques de réversines susceptibles de moduler l'activité de deux protéines de transport (la glycoprotéine P et BCRP)

Cette thèse s'inscrit dans un ensemble de travaux menés au laboratoire de Chimie Thérapeutique de Lyon sur la mise au point d'analogues de di- ou tripeptides hydrophobes appelés réversines susceptibles de moduler la chimiorésistance des cellules tumorales liée à l'expression de protéines de transport appartenant à la famille ATP-Binding Cassette (ABC). Des analogues de ces réversines ont été synthétisés afin d'augmenter leur activité et leur biodisponibilité et de préciser les requis structuraux nécessaires à cette activité vis-à-vis de deux protéines de transport, la glycoprotéine P (P-gp) et la Breast Cancer Resistance Protein (BCRP). Dans un premier temps, afin d'évaluer l'influence de la liaison peptidique, nous avons synthétisé des analogues aminométhyléniques des réversines les plus actives ainsi que des dérivés cétométhyléniques d'une réversine de référence. Dans un second temps, nous avons entrepris la synthèse d'autres dérivés modifiés au niveau de la chaîne latérale du côté N-terminal d'une réversine de référence ainsi que des dérivés contraints de cette chaîne latérale afin d'explorer l'espace conformationnel dans cette région de liaison aux protéines de type ABC. Les activités biologiques des analogues synthétisés ont été évaluées sur les deux protéines de transport de type ABC, P-gp et BCRP. Les premiers résultats ont montré une sélectivité des produits vis-à-vis de la P-gp par rapport à BCRP ainsi que l'interaction de la chaîne latérale du côté N-terminal avec le site de liaison de la P-gp. Cette démarche a permis d'aboutir à des analogues plus actifs que les réversines de référence sur P-gp notamment ceux des dérivés contraintsThis thesis was carried out in the laboratory of Medicinal Chemistry in Lyon on the development of analogs of hydrophobic di- or tripeptides called reversins which may modulate the chemoresistance of tumor cells associated with the expression of proteins belonging to the "ATP-Binding cassette" (ABC) family. Some analogs of these reversins have been synthesized in order to increase their inhibitory activity and their bioavailability and to specify the necessary structural requirement for this activity towards two proteins, P-glycoprotein (P-gp) and the Breast Cancer Resistance Protein (BCRP). Firstly, in order to evaluate the peptide bond influence, we have synthesized aminomethylene analogs of the most active reversins as well as ketomethylene derivatives of a reference reversin. Secondly, we have undertaken the synthesis of derivatives modified at the N-terminal side chain of a reference reversin as well as constrained derivatives of this side chain to explore the conformational space in this region of ABC proteins binding. The biological activities of the synthesized analogs were evaluated on two ABC proteins, P-gp and BCRP. Initial results showed selectivity of the products towards P-gp compared to BCRP and the interaction of the N-terminal side chain with the P-gp binding site. This approach has resulted in analogs that are more active than the original reversins on P-gp especially the constrained derivativesLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Plantes de Nouvelle-Calédonie.114. Taxanes isolés des feuilles d'Austrotaxus spicata Compton (Taxacées)

International audienc

Un site de liaison peptidique accessoire avec effet allostérique sur la formation des complexes peptide–CMH-II

International audienc

Behaviour of Tetrabenazine in Acid Medium: Reassessment and Impact on Formulation

Thorough studies of previous analytical stress data of tetrabenazine, a dopamine depleting agent, showed a potential susceptibility to acidic conditions. Hence, the behavior of tetrabenazine acidic solutions was studied by LC-MS and NMR spectroscopy. Reverse-phase LC-MS analysis of tetrabenazine acidic aqueous solutions consistently showed a main lipophilic impurity in a proportion of 15 to 20%. NMR spectroscopy studies did not allow to completely ascertain its structure. However, we hypothesize an interconversion of trans-tetrabenazine with its unstable cis isomer via an open isoquinolinium intermediate. Evaluation of tetrabenazine integrity in orodispersible films was reassessed in light of these observations after formulation and during stability study. Even if interconversion of trans-tetrabenazine with its cis isomer was observed in orodispersible films containing tetrabenazine, this phenomenon seems not to have any consequences for the overall tetrabenazine bioavailability

ChemInform Abstract: Alkaloids from the Antarctic Sponge Kirkpatrickia varialosa. Part 1. Variolin B, a New Antitumor and Antiviral Compound.

International audienc

Synthesis of the TyrΨ[CH2CH2]gly carbapeptide analog of a MHC class II antigenic peptide

International audienc

Substitution of peptide bond 53-54 of HEL(52-61) with an ethylene bond rather than reduced peptide bond is tolerated by an MHC-II restricted T cell

International audienceTo probe the interactions between major histocompatibility class-II molecules and the amide bonds of the antigenic peptide main chain, we synthesized ethylenic and reduced analogues of HEL(52-61), an immunogenic peptide for murine major histocompatibility class-II IA k restricted T-cell clones. The synthesis of the corresponding ethylenic analogue of HEL(52-61) in position 53-54 was performed by coupling the Fmoc-protected tripeptide Asp-Tyr-psi [E, CH = CH]Gly with HEL(55-61). Biological tests showed that the ethylenic peptide was presented by major histocompatibility class-II IA kappa molecule and recognized by HEL(52-61)-specific T-cell clones. The corresponding reduced peptide of HEL(52-61) at position 53-54 neither stimulated T-cell clones nor competed with the natural peptide. These results show that, while reduced pseudopeptides might not be appropriate, ethylenic pseudopeptides may be used as probes to dissect the role of hydrogen bonding between the peptide main chain and MHC residues and also help in the design of more stable immunogenic peptides

4,5,7‐trisubstituted indeno[1,2‐ b ]indole inhibits CK2 activity in tumor cells equivalent to CX‐4945 and shows strong anti‐migratory effects

International audienceHighly pleiotropic and constitutively active protein kinase CK2 is a key target in cancer therapy, but only one small-molecule inhibitor has reached clinical trials - CX-4945. In this study we present the indeno[1,2-b]indole derivative 5-isopropyl-4-methoxy-7-methyl-5,6,7,8-tetrahydro-indeno[1,2-b]indole-9,10-dione (5a-2) that decreased the intracellular CK2 activity in A431, A549 and LNCaP tumor cell lines analogous to CX-4945 (>75% inhibition at 20 µM) and similarly blocked CK2-specific Akt phosphorylation in LNCaP cells. Cellular uptake analysis demonstrated higher intracellular concentrations of 5a-2 (408.3 nM) compared to CX-4945 (119.3 nM). This finding clarifies the comparable effects of both compounds on the intracellular CK2 activity despite their different inhibitory potency in vitro [IC50 = 25 nM (5a-2) and 3.7 nM (CX-4945)]. Examination of the effects of both CK2 inhibitors on cancer cells using live cell imaging revealed notable differences. Whereas CX-4945 showed a stronger pro-apoptotic effect on tumor cells, 5a-2 was more effective in inhibiting tumor cell migration. Our results showed that 49% of intracellular CX-4945 was localized in the nuclear fraction, whereas 71% of 5a-2 was detectable in the cytoplasm. The different subcellular distribution, and thus the site of CK2 inhibition, provide a possible explanation for the different cellular effects. Our study indicates that investigating CK2-inhibition-mediated cellular effects in relation to the subcellular sites of CK2 inhibition may help to improve our understanding of the preferential roles of CK2 within different cancer cell compartments