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Exploring 1-adamantanamine as an alternative amine moiety for metabolically labile azepane ring in newly synthesized benzo[d]thiazol-2(3H)one σ receptor ligands.

ABSTRACT: In this work we report the structure-activity relationships, binding properties, and metabolic stability studies of a series of benzo[d]thiazol-2(3H)one as sigma receptors (σRs) ligands. Specifically, to improve the metabolic stability of the cyclic amine fragment of our lead compound (SN56), the metabolically unstable azepane ring was replaced with a 1-adatamantamine moiety. Within the synthesized analogs, compound 12 had low nanomolar affinity for the σ₁R (K _i = 7.2 nM) and moderate preference (61-fold) over the σ₂R. In vitro metabolic stability studies showed a slight improvement of the metabolic stability for 7-12, even though an extensive metabolism in rat liver microsomes is being observed. Furthermore, metabolic soft spot identification of 12 suggested that the N-methyl group of the adamantyl moiety is a major site of metabolism.

SUBMITTER: Intagliata S

PROVIDER: S-EPMC7880169 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Newly synthesized peripherally octa-substituted zinc phthalocyanines carrying halogen terminated phenoxy-phenoxy moiety: comparative photochemical and photophysical features.

Project description:This study reports the 3 new phthalonitrile derivatives, namely 4, 5 Bis-[4-(4-bromophenoxy) phenoxy] phthalonitrile ( 1 ), 4,5 Bis-[4-(4-chlorophenoxy) phenoxy]phthalonitrile ( 2 ), and 4, 5 Bis[4-(4-fluorophenoxy) phenoxy] phthalonitrile ( 3 ). Their octa-substituted zinc phthalocyanines ( 4 , 5 , 6 ) are reported for the first time in this study. The resulting compounds were characterized by utilizing some spectroscopic methods, such as UV-Vis, 1HNMR, FT-IR spectroscopy, as well as mass spectraand elemental analysis. To show photosynthesizer's potential, emission (F F ), singlet oxygen (1O2), and photodegradation quantum yields (F∆, Fd) of octa-peripherally phthalocyanines (Pcs) were performed in the solutions, such as biocompatible solvent DMSO (dimethyl sulfoxide) as well as DMF (dimethylformamide) and THF (tetrahydrofuran). Solvent and octa-peripherally binding effect of the halogen (Br, Cl, F) terminated phenoxy-phenoxy groups on phthalocyanine rings for photophysicochemical properties ( 4 , 5 , and 6 ) were compared with the tetra-peripherally and tetra nonperipherally substituted derivatives. The new dyes ( 4 to 6 ) may be evaluated in photodynamic therapy (PDT) of cancer as photosensitizers due to efficient 1O2 from 0.55 to 0.75.

| S-EPMC7765766 | biostudies-literature

Role of the viral hemagglutinin in the anti-influenza virus activity of newly synthesized polycyclic amine compounds.

Project description:We here report on the synthesis of new series of polycyclic amines initially designed as ring-rearranged analogs of amantadine and featuring pentacyclo, hexacyclo, and octacyclo rings. A secondary amine, 3-azahexacyclo[7.6.0.0¹,?.0?,¹².0?,¹?.0¹¹,¹?]pentadeca-7,13-diene, 3, effectively inhibited A/M2 proton channel function, and, moreover, possessed dual activity against an A/H3N2 virus carrying a wild-type A/M2 proton channel, as well as an amantadine-resistant A/H1N1 virus. Among the polycyclic amines that did not inhibit influenza A/M2 proton channel function, several showed low-micromolar activity against tested A/H1N1 strains (in particular, the A/PR/8/34 strain), but not A/H3N2 influenza viruses. A/PR/8/34 mutants selected for resistance to these compounds possessed mutations in the viral hemagglutinin that markedly increased the hemolysis pH. Our data suggest that A/H1N1 viruses such as the A/PR/8/34 strain are particularly sensitive to a subtle increase in the endosomal pH, as caused by the polycyclic amine compounds.

| S-EPMC7114147 | biostudies-literature

Metabolically Labile Fumarate Esters Impart Kinetic Selectivity to Irreversible Inhibitors.

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| S-EPMC5273863 | biostudies-literature

Importance of C(2) symmetry for the device performance of a newly synthesized family of fused-ring thiophenes.

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| S-EPMC2879658 | biostudies-literature

Quantitative analysis of newly synthesized proteins.

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| S-EPMC7422752 | biostudies-literature

Structure activity relationship study of benzo[d]thiazol-2(3H)one based ? receptor ligands.

Project description:Herein we report the SAR study which involved structural modifications to the linker length, aryl substitution and alkylamine ring size of the benzo[d]thiazol-2(3H)one based sigma receptor (?) ligands. Many compounds in this series displayed low nanomolar affinity for the ? receptor subtypes. In particular, 8a showed high affinity (?-1 Ki = 4.5 nM) for ?-1 receptors and moderately high selectivity (483-fold) over ?-2 receptors.

| S-EPMC3762478 | biostudies-literature

Access to benzo-fused nine-membered heterocyclic alkenes with a trifluoromethyl carbinol moiety via a double decarboxylative formal ring-expansion process under palladium catalysis.

Project description:Direct access to pharmaceutically attractive benzo-fused nine-membered heterocyclic alkenes 3 with a trifluoromethyl carbinol moiety was achieved via a palladium-catalyzed double-decarboxylative formal ring-expansion process from six-membered trifluoromethyl benzo[d][1,3]oxazinones 1 to nine-membered trifluoromethyl benzo[c][1,5]oxazonines 3 in the presence of vinylethylene carbonates 2. Generation of a Pd-?-allyl zwitterionic intermediate was proposed in the catalytic cycle. The trifluoromethyl group in the benzoxazinanones 1 plays an important role throughout the transformation. Diastereoselective chemical transformations of products 3 were also demonstrated.

| S-EPMC5915791 | biostudies-literature

Simple Syntheses of Two New Benzo-Fused Macrocycles Incorporating Chalcone Moiety.

Project description:Simple syntheses of the benzo-fused 26-membered macrocyclic bischalcone (19E,43E)-2.11.27.36-tetroxaheptacyclo[44.4.0.0(4,9).0(12,17).0(21,26).0(29,34).0(37,42)]pentaconta-1(46),4(9),5,7,12(17),13,15,19,21,23,25,29,31,33,37,39,41,43,47,49-icosaene-18,45-dione (3) and the benzo-fused 13-membered macrocyclic chalcone (19E)-2.11-dioxatetracyclo[19.4.0.0(4,9).0(12,17)]pentacosa-1(25),4(9),5,7,12(17),13,15,19,21,23-decaen-18-one (5) using very common starting materials and reagents are described. The compounds are new and they have been characterized from their analytical and spectral data.

| S-EPMC4897219 | biostudies-literature

Bioreducible and acid-labile poly(amido amine)s for efficient gene delivery.

Project description:Intracellular processes, including endosomal escape and intracellular release, are efficiency-determining steps in achieving successful gene delivery. It has been found that the presence of acid-labile units in polymers can facilitate endosomal escape and that the presence of reducible units in polymers can lead to intracellular release. In this study, poly(amido amine)s with both bioreducible and acid-labile properties were synthesized to improve gene delivery compared with single-responsive carriers. Transfection and cytotoxicity were evaluated in three cell lines. The complexes of DNA with dual-responsive polymers showed higher gene transfection efficiency than single-responsive polymers and polyethylenimine. At the same time, these polymers were tens of times less cytotoxic than polyethylenimine. Therefore, a polymer that is both reducible and acid-labile is a promising material for efficient and biocompatible gene delivery.

| S-EPMC3511192 | biostudies-literature

Vulnerability of newly synthesized proteins to proteostasis stress.

Project description:The capacity of the cell to produce, fold and degrade proteins relies on components of the proteostasis network. Multiple types of insults can impose a burden on this network, causing protein misfolding. Using thermal stress, a classic example of acute proteostatic stress, we demonstrate that ?5-10% of the soluble cytosolic and nuclear proteome in human HEK293 cells is vulnerable to misfolding when proteostatic function is overwhelmed. Inhibiting new protein synthesis for 30?min prior to heat-shock dramatically reduced the amount of heat-stress induced polyubiquitylation, and reduced the misfolding of proteins identified as vulnerable to thermal stress. Following prior studies in C. elegans in which mutant huntingtin (Q103) expression was shown to cause the secondary misfolding of cytosolic proteins, we also demonstrate that mutant huntingtin causes similar 'secondary' misfolding in human cells. Similar to thermal stress, inhibiting new protein synthesis reduced the impact of mutant huntingtin on proteostatic function. These findings suggest that newly made proteins are vulnerable to misfolding when proteostasis is disrupted by insults such as thermal stress and mutant protein aggregation.

| S-EPMC4893652 | biostudies-literature

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