Search results for "Structure-activity relationships"
showing 10 items of 12 documents
Synthesis and Structure-Activity Relationships of Amino Acid Conjugates of Cholanic Acid as Antagonists of the EphA2 Receptor
2013
The Eph–ephrin system plays a critical role in tumor growth and vascular functions during carcinogenesis. We had previously identified cholanic acid as a competitive and reversible EphA2 antagonist able to disrupt EphA2-ephrinA1 interaction and to inhibit EphA2 activation in prostate cancer cells. Herein, we report the synthesis and biological evaluation of a set of cholanic acid derivatives obtained by conjugation of its carboxyl group with a panel of naturally occurring amino acids with the aim to improve EphA2 receptor inhibition. Structure-activity relationships indicate that conjugation of cholanic acid with linear amino acids of small size leads to effective EphA2 antagonists whereas …
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…
Homology models of melatonin receptors: challenges and recent advances
2013
Melatonin exerts many of its actions through the activation of two G protein-coupled receptors (GPCRs), named MT1 and MT2. So far, a number of different MT1 and MT2 receptor homology models, built either from the prototypic structure of rhodopsin or from recently solved X-ray structures of druggable GPCRs, have been proposed. These receptor models differ in the binding modes hypothesized for melatonin and melatonergic ligands, with distinct patterns of ligand-receptor interactions and putative bioactive conformations of ligands. The receptor models will be described, and they will be discussed in light of the available information from mutagenesis experiments and ligand-based pharmacophore …
Synthesis and biological evaluation of papain-family cathepsin L-like cysteine protease inhibitors containing a 1,4-benzodiazepine scaffold as antipr…
2014
Novel papain-family cathepsin L-like cysteine protease inhibitors endowed with antitrypanosomal and antimalarial activity were developed, through an optimization study of previously developed inhibitors. In the present work, we studied the structure-activity relationships of these derivatives, with the aim to develop new analogues with a simplified and more synthetically accessible structure and with improved antiparasitic activity. The structure of the model compounds was significantly simplified by modifying or even eliminating the side chain appended at the C3 atom of the benzodiazepine scaffold. In addition, a simple methylene spacer of appropriate length was inserted between the benzod…
Structure-activity relationship of dopaminergic halogenated 1-benzyl-tetrahydroisoquinoline derivatives
2009
Two series of halogenated 1-benzyl-7-chloro-6-hydroxy-tetrahydroisoquinolines were prepared to explore the influence of each series on the affinity for dopamine receptors. All the compounds displayed a high affinity for D(1)-like and/or D(2)-like dopamine receptors in striatal membranes, although they were unable to inhibit [(3)H]-dopamine uptake in striatal synaptosomes. The halogen placed on the benzylic ring in 1-benzyl-THIQs, compounds of the series 1, 2'-bromobenzyl derivatives with K(i) values into the nanomolar range, and the series 2, 2',4'-dichlorobenzyl-THIQ homologues, proves to be an important factor to modulate affinity at dopamine receptor. (C) 2009 Elsevier Masson SAS. All ri…
Resveratrol-Related Dehydrodimers: Laccase-Mediated Biomimetic Synthesis and Antiproliferative Activity
2012
Seven resveratrol-related monomeric stilbenoids were submitted to biomimetic oxidative coupling in the presence of laccase from Trametes versicolor (TvL), and gave racemic dihydrobenzofuran dehydrodimers (±)-15 to (±)-21. These products, after spectral characterization, were submitted to an antiproliferative activity bioassay against SW480 human colon cancer cells. Five racemates were found to be active, and were resolved by chiral HPLC. The pure enantiomers were subjected to circular dichroism measurements to establish their absolute configurations at C-7 and C-8. These enantiomerically pure compounds were submitted to the antiproliferative activity assay towards SW480 cells, and were all …
Dopaminergic isoquinolines with hexahydrocyclopenta[ ij ]-isoquinolines as D 2 -like selective ligands
2016
Dopamine receptors (DR) ligands are potential drug candidates for treating neurological disorders including schizophrenia or Parkinson's disease. Three series of isoquinolines: (E)-1-styryl-1,2,3,4-tetrahydroisoquinolines (series 1), 7-phenyl-1,2,3,7,8,8a-hexahydrocyclopenta[ij]-IQs (HCPIQs) (series 2) and (E)-1-(prop-1-en-1-yl)-1,2,3,4- tetrahydroisoquinolines (series 3), were prepared to determine their affinity for both D1and D2-like DR. The effect of different substituents on the nitrogen atom (methyl or allyl), the dioxygenated function (methoxyl or catechol), the substituent at the β-position of the THIQ skeleton, and the presence or absence of the cyclopentane motif, were studied. We…
Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2
2020
Abstract Inhibition of coronavirus (CoV)‐encoded papain‐like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure‐activity relationships (SAR) of the noncovalent active‐site directed inhibitor (R)‐5‐amino‐2‐methyl‐N‐(1‐(naphthalen‐1‐yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS‐CoV PLpro. Moreover, we report the discovery of isoindolines as a new class of potent PLpro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS‐CoV‐2 replication in …
Synthesis and Spectral and Structural Characterization of a New Series of Bis-Strapped Chiral Porphyrins Derived from L-Proline
2001
International audience; New chiral porphyrins were obtained in reasonable yields in three steps, starting from the áâáâ atropisomer of mesotetrakis(o-aminophenyl)porphyrin (TAPP). These potential catalysts for the enantioselective epoxidation of alkenes were obtained by the reaction of different linkers on the same Lprolinoyl-picket porphyrin. Their 1H NMR spectral characteristics, as well as the crystal structure of one of them, clearly indicate that the orientation of the proline cycle depends on the linker used to tether the two pickets on each side of the porphyrin. The same linker is employed for both sides of the porphyrin; hence the resulting D2-symmetric superstructure.
Hepatoprotective effects of extracts, fractions and compounds from the stem bark of Pentaclethra macrophylla Benth: Evidence from in vitro and in viv…
2021
Abstract Aim To identify the bioactive hepatoprotective components of the ethanol extract of Pentaclethra macrophylla stem bark using in vitro and in vivo approaches. Methods The bioguided-fractionation of the ethanol extract was based on the substances’ capacity to prevent in vitro, the lipid peroxidation of hepatocytes’ membranes induced by hydrogen peroxide. For the in vivo hepatoprotective test, mice were treated orally with the ethyl acetate (EtOAc) fraction of the ethanol extract at doses of 50 and 75 mg/kg/day for one week and subjected to d -galactosamine/lipopolysaccharide (GaIN/LPS)-induced hepatotoxicity. Blood samples were collected for alanine aminotransferase (ALAT), aspartate…