Search results for "structure-activity relationship"
showing 10 items of 743 documents
1,5-Disubstituted 1,2,3-Triazoles as Amide Bond Isosteres Yield Novel Tumor-Targeting Minigastrin Analogs.
2021
[Image: see text] 1,5-Disubstituted 1,2,3-triazoles (1,5-Tz) are considered bioisosteres of cis-amide bonds. However, their use for enhancing the pharmacological properties of peptides or proteins is not yet well established. Aiming to illustrate their utility, we chose the peptide conjugate [Nle(15)]MG11 (DOTA-dGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH(2)) as a model compound since it is known that the cholecystokinin-2 receptor (CCK2R) is able to accommodate turn conformations. Analogs of [Nle(15)]MG11 incorporating 1,5-Tz in the backbone were synthesized and radiolabeled with lutetium-177, and their pharmacological properties (cell internalization, receptor binding affinity and specificity, pla…
Influence of Surface Charge and Polymer Coating on Internalization and Biodistribution of Polyethylene Glycol-Modified Iron Oxide Nanoparticles
2015
International audience; The aim of this study was to investigate the influence of the surface charge and coating of Superparamagnetic Iron Oxide Nanoparticles (SPIONs) on their in vitro and in vivo behaviors. Neutral and negatively-charged PEG-based SPIONs were synthesized and compared to Resovist (R), a carboxydextran-based SPION currently used in clinics. Their cytotoxicity, cell internalization, and potential as contrast agents for magnetic resonance imaging were assessed. Neutral pegylated SPIONs were internalized less readily by the reticuloendothelial system and showed a lower uptake by the liver, compared to negatively-charged SPIONs (with carboxydextran and PEG). These results sugge…
Synthesis of 131I-labeled glucose-conjugated inhibitors of O6-methylguanine-DNA methyltransferase (MGMT) and comparison with nonconjugated inhibitors…
2006
O 6 -Substituted guanine derivatives are powerful agents used for tumor cell sensitization by inhibition of the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT). To provide targeted accumulation of MGMT inhibitors in tumor tissue as well as tools for in vivo imaging, we synthesized iodinated C 8 -alkyl-linked glucose conjugates of 2-amino-6-(5-iodothenyl)-9H-purine (O 6 -(5-iodothenyl) guanine, ITG) and 2-amino-6-(3-iodobenzyloxy)-9H-purine (O 6 -(5-iodobenzyl) guanine, IBG). These compounds have MGMT inhibitor constants (IC 5 0 values) of 0.8 and 0.45 μM for ITGG and IBGG, respectively, as determined in HeLa S3 cells after 2-h incubation with inhibitor. To substantiate tha…
Phosphorylation of serine residues is fundamental for the calcium-binding ability of Orchestin, a soluble matrix protein from crustacean calcium stor…
2003
International audience; Orchestia cavimana is a terrestrial crustacean, which cyclically stores calcium in diverticula of the midgut, in the form of calcified amorphous concretions. These concretions are associated with a proteinaceous matrix, the main constituent of the soluble matrix is Orchestin, an acidic calcium-binding protein [Testenière et al., Biochem. J. 361 (2002) 327-335]. In the present paper, we clearly demonstrate that Orchestin is phosphorylated on serine and tyrosine residues, but that calcium binding only occurs via the phosphoserine residues. To our knowledge, this is the first example of an invertebrate mineralization for which a post-translational modification is clearl…
Structure-activity relationship of staurosporine analogs in regulating expression of endothelial nitric-oxide synthase gene.
2000
In human umbilical vein endothelial cells and in human umbilical vein endothelial cell-derived EA.hy 926 cells, staurosporine (Stsp) and its glycosidic indolocarbazole analogs 7-hydroxystaurosporine (UCN-01) and 4'-N-benzoyl staurosporine (CGP 41251) enhanced nitric-oxide synthase (NOS) III mRNA expression (analyzed by RNase protection assay), protein expression (determined by Western blot), and activity [measured by rat fetal lung fibroblast (RFL-6) reporter cell assay] in a concentration- and time-dependent manner. In contrast, the bisindolylmaleimide analogs GF 109203X, Ro 31-8220 and Go 6983 had no effect on NOS III expression, and Go 6976, a methyl- and cyanoalkyl-substituted nonglycos…
Oleanonic acid, a 3-oxotriterpene from Pistacia, inhibits leukotriene synthesis and has anti-inflammatory activity.
2001
One of the best known bioactive triterpenoids is oleanolic acid, a widespread 3-hydroxy-17-carboxy oleanane-type compound. In order to determine whether further oxidation of carbon 3 affects anti-inflammatory activity in mice, different tests were carried out on oleanolic acid and its 3-oxo-analogue oleanonic acid, which was obtained from Pistacia terebinthus galls. The last one showed activity on the ear oedema induced by 12-deoxyphorbol-13-phenylacetate (DPP), the dermatitis induced by multiple applications of 12-O-tetradecanoyl-13-acetate (TPA) and the paw oedemas induced by bradykinin and phospholipase A2. The production of leukotriene B4 from rat peritoneal leukocytes was reduced by ol…
Non-steroidal Anti-inflammatory Agents, Part 19:E-2-Pyrrolizin-5-yl Acrylic Acids as Potent Dual or Selective Inhibitors of Bovine Cyclooxygenase and…
1995
The pyrrolizinyl substituted acrylic acid derivatives represent another class of dual and selective inhibitors of cyclooxygenase and 5-lipoxygenase. By modifying their substitution pattern at the phenyl moiety of C-6 the balance between the activity against cyclooxygenase and against 5-lipoxygenase can be shifted. Structure-activity relationships are discussed. Compound 6k is the most potent and well-balanced dual inhibitor of both enzymes, while the highest selectivity of lipoxygenase inhibition was found for 6j. The activity and selectivity of compounds with an additional sulfur moiety depend on the oxidation status of this atom, giving an indication of the discussed coupling between pero…
COX-1/COX-2 inhibitors based on the methanone moiety
2002
This paper focuses on the synthesis and the in vitro testing of dual COX-1/COX-2 inhibitors. Starting from structures of non-steroidal anti-inflammatory drugs (NSAIDs) the diaryl methanone element was chosen as a lead. Modifications were carried out on this scaffold to obtain potent inhibitors of the COX enzymes. The N-(2-aroylphenyl)sulphonamides and -amides were studied in detail, and to consolidate the data evaluated the corresponding 3- and 4-regioisomers were also investigated. The potency and the enzyme selectivity were varied by structural modifications of the lead.
Development of an Easily Bioconjugatable Water-Soluble Single-Photon Emission-Computed Tomography/Optical Imaging Bimodal Imaging Probe Based on the …
2021
A water-soluble fluorescent aza-BODIPY platform (Wazaby) was prepared and functionalized by a polyazamacrocycle agent and a bioconjugable arm. The resulting fluorescent derivative was characterized and bioconjugated onto a trastuzumab monoclonal antibody as a vector. After bioconjugation, the imaging agent appeared to be stable in serum (>72 h at 37 °C) and specifically labeled HER-2-positive breast tumors slices. The bioconjugate was radiolabeled with [111In] indium and studied in vivo. The developed monomolecular multimodal imaging probe (MOMIP) is water-soluble and chemically and photochemically stable, emits in the near infrared (NIR) region (734 nm in aqueous media), and displays a goo…
Development of peptidomimetic boronates as proteasome inhibitors.
2013
Abstract Proteasome inhibition has emerged over the past decade as an effective therapeutic approach for the treatment of hematologic malignancies. It is a multicatalytic complex, whose proteolytic activity relies in three types of subunits: chymotrypsin-like (β5), trypsin-like (β2) and caspase-like (β1). Most important for the development of effective antitumor agents is the inhibition of the β5 subunits. In this context, the dipeptide boronate bortezomib (Velcade ® ) represents the first proteasome inhibitor approved by the FDA and the lead compound in drug discovery. This paper describes the synthesis and biological evaluation of a series of conformationally constrained pseudopeptide bor…