Controlling passive diffusion through an amphiphilic membrane is a key factor for the development of future smart generations of drug delivery systems. It also plays a crucial role in understanding fundamental biological systems through the design of new artificial cell models. We report herein a new concept of bolalipids designed as key components for the control of the membrane's permeability.
View Article and Find Full Text PDFDiazirine is one of the smallest photo-sensitive moieties discovered to date. When incorporated in the structure of phospholipids, its minimal size has a low impact on the morphology of the resultant liposomes. A DMPC-diazirine analogue was designed and subsequently used to generate liposomes with a lower permeability and a lower phase-transition temperature compared to control DMPC liposomes.
View Article and Find Full Text PDFStructure-photosensitizing activity relationships for a series of flavin analogues were investigated with the final goal of identifying the most potent photosensitizer in these series. The main structural modifications involved the introduction of various halogen atoms in C- and/or C-positions on the isoalloxazine ring. These compounds were synthesized by reacting judiciously-functionalized anilines with alloxan.
View Article and Find Full Text PDFDue to their ability to easily absorb light and to generate highly reactive species, photosensitizers emerged as promising tools in a wide variety of physico-chemical and biological processes. Natural photosensitizers have the benefit of a life-compatible toxicological profile. Porphyrins and flavins are such examples that already proved their efficiency as photo-dynamic therapeutics.
View Article and Find Full Text PDFIn contrast to artificial molecules, natural photosensitizers have the benefit of excellent toxicity profiles and of life-compatible activating energy ranges. Flavins are such photosensitizers that were selected by nature in a plethora of light-triggered biochemical reactions. Flavin-rich nanoparticles could thus emerge as promising tools in photodynamic therapies and in active-targeting drug delivery.
View Article and Find Full Text PDFIdentification of a common Diels-Alder pattern in three classes of bioactive natural products led us to study the synthesis and cycloaddition of a new class of cyclic dienes readily available from β,γ-unsaturated lactams. A practical and readily scalable route to the parent p-methoxybenzyl-protected 6- and 7-membered β,γ-unsaturated lactams was developed. These were readily transformed into the corresponding O-silylated dienes, which were reacted with dimethyl and diethyl fumarate to yield stereoselectively highly functionalized bicyclic adducts.
View Article and Find Full Text PDFPure diastereomeric spirocyclic analogs of fluorocortivazol were conveniently prepared by a short and efficient synthetic sequence recently developed in our laboratory. The structures and conformations of several key products were confirmed by single crystal X-ray diffraction analysis. Conformational assignments were also supported by DFT calculations.
View Article and Find Full Text PDFPotent-selective peptidomimetic inhibitors of tissue transglutaminase (TG2) were developed through a combination of protein-ligand docking and molecular dynamic techniques. Derivatives of these inhibitors were made with the aim of specific TG2 targeting to the intra- and extracellular space. A cell-permeable fluorescently labeled derivative enabled detection of in situ cellular TG2 activity in human umbilical cord endothelial cells and TG2-transduced NIH3T3 cells, which could be enhanced by treatment of cells with ionomycin.
View Article and Find Full Text PDFAn asparagine or a histidine are present in a similar position in the outer pore region of SK2 and SK3 channels, respectively. Therefore, this structural difference was targeted in order to develop selective blockers of SK channel subtypes. Following docking investigations, based on theoretical models of truncated SK2 and SK3 channels, the benzyl side chain of N-methyl-laudanosine (NML) was functionalized in order to target this specific amino-acid residues.
View Article and Find Full Text PDFNew peptidic water-soluble inhibitors are reported. In addition to the carboxylate moiety, a new polar warhead was explored. Depending on the size of its substituents, the newly appended imidazolium scaffold designed to enhance the hydrophilic character of the inhibitors could induce a good inhibition for tissue transglutaminase (TG2) and blood coagulation factor XIIIa (FXIIIa).
View Article and Find Full Text PDFThis paper focuses on implementing a design space approach and on the critical process parameters (CPPs) to consider when applying the Quality by Design (QbD) concepts outlined in ICH Q8(R2), Q9 and Q10 to analytical method development and optimization for three chiral compounds developed as modulators of small conductance calcium-activated potassium (SK) channels. In this sense, an HPLC method using a polysaccharide-based stationary phase containing a cellulose tris (4-chloro-3-methylphenylcarbamate) chiral selector in polar organic solvent chromatography mode was considered. The effects of trifluoroacetic acid (TFA) and n-hexane concentration in an acetonitrile (MeCN) mobile phase were investigated under a wide range of column temperatures.
View Article and Find Full Text PDFA structure-activity relationship study of N-methyl-laudanosine, a SK channel blocker, has indicated that the 6,7-dimethoxy group could be successfully replaced by a hydrophobic moiety such as an isopropyl substituent in position 8 of the isoquinoline ring. In the present study, bis-(8-isopropyl-isoquinolinium) derivatives (2a-e) were synthesized and tested for their affinity for cloned SK2 and SK3 channels in comparison with their 6,7-dimethoxy analogues (4a-f). Several ligands were investigated, both in flexible (propyl, butyl and pentyl) and rigid (m- or p-xylyl) series, the m-xylyl derivative (2d) having the best profile in terms of affinity and selectivity for SK3/SK2 channels.
View Article and Find Full Text PDFStructure-activity relationships of a series of bis-arylic compounds, investigated as 5-HT(7)R ligands, are reported. The main structural modifications involved a central aryl moiety (phenyl, pyridine, diazine, triazine) and the nature and position of an amine-containing aliphatic chain. The affinity of the synthesized compounds (26 nM-10 microM) was systematically correlated with other previously reported series of bis-arylic ligands and rationalized by a ligand-based pharmacophore approach.
View Article and Find Full Text PDFThe synthesis of new N-homopiperazinyl-based ligands is reported. Various structural modifications along with the corresponding biological activities on 5-HT(1A)/5-HT(7) receptors give further insights into this class of serotoninergic ligands. Among the tested central heterocyles, the 7-azaindole gave the best results on the above-mentioned receptors.
View Article and Find Full Text PDFA new group of serotoninergic 5-HT(1A) or 5-HT(7) receptor ligands was identified. These compounds were designed and synthesized on a benzimidazolone scaffold and they enrich the well-known arylpiperazine class of 5-HT ligands. Diverse pharmacomodulations induced a shift in the affinity and selectivity profile with final identification of new potent hits.
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