Isabelle Baussanne

Influence of chemical structure of amphiphilic β-cyclodextrins on their ability to form stable nanoparticles

The aim of the study was to establish a correlation between the chemical structure of amphiphilic beta-cyclodextrins (beta-CDa) and their ability to form stable nanospheres. Amphiphilic derivatives were obtained according to an optimized well-known three-step synthesis. The selective acylation of the secondary face of beta-CD being well controlled, several beta-CDa presenting different substitution degree were synthesized. The self-organization properties of the derivatives were evaluated. The peracylated beta-CD, i.e. bearing 14 alkyl chains on the secondary hydroxyl groups, does not yield stable nanosphere suspension, even in the presence of a non ionic surfactant in the aqueous phase. However, the presence of partially acylated derivatives within the beta-CDa allows self-assembly into stable nanosphere suspension.

Dependence of Concanavalin A Binding on Anomeric Configuration, Linkage Type, and Ligand Multiplicity for Thiourea-Bridged Mannopyranosyl–β-Cyclodextrin Conjugates

Concanavalin A (Con A), the mannose-specific lectin from Concanavalia ensiformis, has long been used as a model for carbohydrate ± protein interactions. Its commercial availability and the rather extensive structural knowledge currently available make it attractive for assessing and optimizing the functional parameters that affect its affinity for mannose neoglycoconjugates. Understanding these key elements may facilitate the development of new therapeutic strategies based on specific recognition events such as targeting of drugs. Con A binds a-D-mannopyranosides preferentially over the corresponding b anomers. The affinity for monosaccharide ligands is low; however, this is a rather common feature when considering protein ± carbohydrate interactions. Carbohydrate ± protein binding events usually involve several simultaneous contacts between carbohydrates that are clustered on cell surfaces and protein receptors that contain multiple carbohydrate-binding sites. Based on this concept, one could anticipate that multiplication of the saccharide epitope on the surface of the carrier may lead to a greater affinity than predicted from the sum of the constitutive one-to-one interactions Ðthe soThe authors are grateful to Sylvia Löbermann for expert technical assistance. This work received financial support by the Max-PlanckGesellschaft, Evotec Biosystems AG, BMBF together with Roche Diagnostics (grant 0311003), and the DFG (grant Ei 411/1-1), which is gratefully acknowledged.

Survey of recent literature related to the biologically active 4(3H)-quinazolinones containing fused heterocycles.

The present review focuses on the synthesis and biological evaluation of polycyclic 4(3H)-quinazolinones containing fused aromatic or heteroaromatic rings. The first part of the review is related to compounds with ring fused to the pyrimidine part of the quinazoline core. Most of the quinazolinone alkaloids belong to this class of molecules. The second part presents molecules bearing extra ring(s) fused to the benzo moiety of the quinazolinone skeleton. Their structural diversity opens new fields in the search of active molecules.

A peptide nucleic acid-aminosugar conjugate targeting transactivation response element of HIV-1 RNA genome shows a high bioavailability in human cells and strongly inhibits tat-mediated transactivation of HIV-1 transcription.

The 6-aminoglucosamine ring of the aminoglycoside antibiotic neomycin B (ring II) was conjugated to a 16-mer peptide nucleic acid (PNA) targeting HIV-1 TAR RNA. For this purpose, we prepared the aminoglucosamine monomer 15 and attached it to the protected PNA prior to its cleavage from the solid support. We found that the resulting PNA-aminoglucosamine conjugate is stable under acidic conditions, efficiently taken up by the human cells and fairly distributed in both cytosol and nucleus without endosomal entrapment because cotreatment with endosome-disrupting agent had no effect on its cellular distribution. The conjugate displayed very high target specificity in vitro and strongly inhibited Tat mediated transactivation of HIV-1 LTR transcription in a cell culture system. The unique properties of this new class of PNA conjugate suggest it to be a potential candidate for therapeutic application.

Synthesis and comparative lectin-binding affinity of mannosyl-coated β-cyclodextrin-dendrimer constructs

Targeted drug delivery systems have been built from β-cyclodextrin by monoconjugation with mannosyl-coated dendritic branches following an iterative thiourea-forming convergent strategy; the multivalent adducts showed high Concanavalin A lectin binding ability and intact inclusion capabilities.

Regioselective sulfonylation at O-2 of cyclomaltoheptaose with 1-(p-tolylsulfonyl)-(1H)-1,2,4-triazole.

2(I)-O-p-Tolylsulfonylcyclomaltoheptaose was obtained in 42% yield by reaction of 1-(p-tolylsulfonyl)-(1H)-1,2,4-triazole on NaH-deprotonated cyclomaltoheptaose in DMF and further converted into the corresponding mono-2(I),3(I)-manno-epoxide.

Investigation of the Pyridinium Ylide—Alkyne Cycloaddition as a Fluorogenic Coupling Reaction

The cycloaddition of pyridinium ylides with alkynes was investigated under mild conditions. A series of 13 pyridinium salts was prepared by alkylation of 4-substituted pyridines. Their reactivity with propiolic ester or amide in various reaction conditions (different temperatures, solvents, added bases) was studied, and 11 indolizines, with three points of structural variation, were, thus, isolated and characterized. The highest yields were obtained when electron-withdrawing groups were present on both the pyridinium ylide, generated in situ from the corresponding pyridinium salt, and the alkyne (X, Z = ester, amide, CN, carbonyl, etc.). Electron-withdrawing substituents, lowering the acid dissociation constant (pKa) of the pyridinium salts, allow the cycloaddition to proceed at pH 7.5 in aqueous buffers at room temperature.

Indolizine-Based Scaffolds as Efficient and Versatile Tools: Application to the Synthesis of Biotin-Tagged Antiangiogenic Drugs

We describe the design and optimization of polyfunctional scaffolds based on a fluorescent indolizine core derivatized with various orthogonal groups (amines, esters, oximes, alkynes, etc.). To show one application as tools in biology, the scaffold was used to prepare drug–biotin conjugates that were then immobilized onto avidin-agarose for affinity chromatography. More specifically, the antiangiogenic drug COB223, whose mechanism of action remained unclear, was chosen as a proof-of-concept drug. The drug-selective discrimination of proteins observed after elution of the cell lysates through the affinity columns, functionalized either with the biologically active COB223 or a structurally related inactive analogue (COB236), is a clear indication that the presence of the indolizine core does not limit drug–protein interaction and confirms the usefulness of the indolizine scaffold. Furthermore, the separation of COB223-interacting proteins from human placental extracts unveiled unanticipated protein targets belonging to the family of regulatory RNA-binding proteins, which opens the way to new hypotheses on the mode of action of this antiangiogenic drug.