ABSTRACT
Ajoene is an organosulfur compound found in crushed garlic that exerts its anti-cancer activity by S-thiolating cysteine residues on proteins. Its development is hampered due to limited bioavailability, so in this study, we synthesised analogues of ajoene to probe the significance of the ajoene vinyl disulfide/sulfoxide core with respect to cytotoxicity and blood stability. Polar side groups were also incorporated to improve aqueous solubility. It was found that derivatives containing a vinyl disulfide functional group (4-7, as in ajoene), were more cytotoxic compared to analogues in which the double bond was removed, although the latter showed superior blood stability. It was also found that the allyl-S sulfur of the disulfide was more electrophilic to S-thiolysis based on the global electrophilicity index (ω) and the condensed electrophilic Fukui function f k + ${{ f}_{\rm{k}}^{\rm{ + }} }$ . S-Thiolysis was found to be exergonic for the vinyl disulfides based on entropy and enthalpy computations with a deprotonated thiolate. Derivatisation to the dihydro (10, 12) and deoxydihydroajoenes (9, 11) produced analogues that were slightly less potent but with greatly improved blood stability. Taken together, the deoxydihydroajoenes present themselves as good candidates for further therapeutic development.
Subject(s)
Antineoplastic Agents , Drug Screening Assays, Antitumor , Humans , Structure-Activity Relationship , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Molecular Structure , Sulfoxides/chemistry , Sulfoxides/pharmacology , Sulfoxides/chemical synthesis , Dose-Response Relationship, Drug , Cell Proliferation/drug effects , Cell Survival/drug effects , Disulfides/chemistry , Disulfides/pharmacology , Disulfides/chemical synthesis , Cell Line, TumorABSTRACT
Isothiocyanates (ITCs) show strong activity against numerous human tumors. Five structurally diverse ITCs were tested in vivo using the zebrafish embryos 6 and 48 h post-fertilization (hpf). The survival rate, hatching time, and gross morphological changes were assessed 24, 48, and 72 h after treatment with all compounds in various doses (1-10 µM). As a result, we selected a phosphonate analog of sulforaphane (P-ITC; 1-3 µM) as a non-toxic treatment for zebrafish embryos, both 6 and 48 hpf. Furthermore, the in vivo anti-cancerogenic studies with selected 3 µM P-ITC were performed using a set of cell lines derived from the brain (U87), cervical (HeLa), and breast (MDA-MB-231) tumors. For the experiment, cells were labeled using red fluorescence dye Dil (1,1'-Dioctadecyl-3,3,3',3'-Tetramethylindocarbocyanine, 10 µg/mL) and injected into the hindbrain ventricle, yolk sac region and Cuvier duct of zebrafish embryos. The tumor size measurement after 48 h of treatment demonstrated the significant inhibition of cancer cell growth in all tested cases by P-ITC compared to the non-treated controls. Our studies provided evidence for P-ITC anti-cancerogenic properties with versatile activity against different cancer types. Additionally, P-ITC demonstrated the safety of use in the living organism at various stages of embryogenesis.
Subject(s)
Antineoplastic Agents/pharmacology , Isothiocyanates/pharmacology , Organophosphonates/pharmacology , Sulfoxides/pharmacology , Xenograft Model Antitumor Assays , Zebrafish/physiology , Animals , Cell Line, Tumor , Embryo, Nonmammalian/drug effects , Embryo, Nonmammalian/metabolism , Humans , Isothiocyanates/chemical synthesis , Isothiocyanates/chemistry , Microwaves , Organophosphonates/chemical synthesis , Organophosphonates/chemistry , Signal Transduction/drug effects , Sulfoxides/chemical synthesis , Sulfoxides/chemistry , Zebrafish/embryologyABSTRACT
With unique chemical and biological activity, sulfoximines have attracted enormous attention in the past decades, whereas limited reports exist for their synthesis via asymmetric catalysis. We report the synthesis of chiral sulfoximines through the desymmetrizing N-oxidation of pyridyl sulfoximines using an aspartic acid-containing peptide catalyst. Various mono- and bis-pyridyl sulfoximine oxides are obtained with up to 99:1 er. The directing group introduced on the substrate highly enhances the enantioinduction and could be easily removed to give the free N-H sulfoximines. Additionally, peptides with methyl ester and the methyl amide C-terminal protecting group give the opposite enantiomers of the product. A binding model is proposed to explain this phenomenon.
Subject(s)
Aspartic Acid/chemistry , Peptides/chemistry , Sulfoxides/chemical synthesis , Catalysis , Molecular Structure , Stereoisomerism , Sulfoxides/chemistryABSTRACT
The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of sulfoxide derivatives were prepared and their antiproliferative activity evaluated in vitro against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP and VCap). Bicalutamide and enzalutamide were used as positive controls. Compound 28 displayed significant enhancement in anticancer activity across the four PC cell lines with IC50 = 9.09 - 31.11 µM compared to the positive controls: bicalutamide (IC50 = 45.20 -51.61 µM) and enzalutamide (IC50 = 11.47 - 53.04 µM). Sulfoxide derivatives of bicalutamide were prepared efficiently from the corresponding sulfides using only one equivalent of mCPBA, limiting the reaction time to 15-30 min and maintaining the temperature at 0 °C. Interestingly, three pairs of sulfoxide diastereomers were separated and NMR comparison of their diastereotopic methylene (CH2) group is presented. X-ray diffraction crystal structure analysis provided relative configuration assignment at the chiral sulfur and carbon centres. Molecular modelling study of the four diastereoisomers of compound 28 is described.
Subject(s)
Anilides/pharmacology , Antineoplastic Agents/pharmacology , Nitriles/pharmacology , Prostatic Neoplasms/drug therapy , Sulfoxides/pharmacology , Tosyl Compounds/pharmacology , Anilides/chemical synthesis , Anilides/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Male , Models, Molecular , Molecular Structure , Nitriles/chemical synthesis , Nitriles/chemistry , Prostatic Neoplasms/pathology , Structure-Activity Relationship , Sulfoxides/chemical synthesis , Sulfoxides/chemistry , Tosyl Compounds/chemical synthesis , Tosyl Compounds/chemistryABSTRACT
Asymmetric epoxidation catalyzed with styrene monooxygenase (SMO) is a powerful enzymatic process producing enantiopure styrene epoxide derivatives. To establish a more diversified reservoir of SMOs, a new SMO from Bradyrhizobium sp. ORS 375, named BrSMO, was mined from the database and characterized. BrSMO was constituted of an epoxygenase component of 415 amino acid residues and an NADH-dependent flavin reductase component of 175 residues. BrSMO catalyzed the epoxidation of styrene and 7 more styrene derivatives, yielding the corresponding (S)-epoxides with excellent enantiomeric excesses (95- > 99% ee), with the highest activity achieved for styrene. BrSMO also catalyzed the asymmetric sulfoxidation of 7 sulfides, producing the corresponding (R)-sulfoxides (20-90% ee) with good yields.
Subject(s)
Bacterial Proteins/chemistry , Bradyrhizobium/enzymology , Oxygenases/chemistry , Sulfoxides/chemical synthesis , Catalysis , Sulfoxides/chemistryABSTRACT
A simple, efficient, and selective oxidation under flow conditions of sulfides into their corresponding sulfoxides and sulfones is reported herein, using as a catalyst perselenic acid generated in situ by the oxidation of selenium (IV) oxide in a diluted aqueous solution of hydrogen peroxide as the final oxidant. The scope of the proposed methodology was investigated using aryl alkyl sulfides, aryl vinyl sulfides, and dialkyl sulfides as substrates, evidencing, in general, a good applicability. The scaled-up synthesis of (methylsulfonyl)benzene was also demonstrated, leading to its gram-scale preparation.
Subject(s)
Sulfides/chemistry , Sulfones/chemical synthesis , Sulfoxides/chemical synthesis , Catalysis , Hydrogen Peroxide/chemistry , Molecular Structure , Oxidation-Reduction , Selenium Oxides/chemistry , Sulfones/chemistry , Sulfoxides/chemistryABSTRACT
Covering: January 2013 to September 2018Sulfur-containing natural products are a large class of significant functional molecules. Many of these compounds exhibit potent biological activities and pharmacological properties; in fact, some of them have been developed into important drugs. The total synthesis of sulfur-containing natural products is a subject that has long attracted significant attention from synthetic organic chemists; to achieve this goal, various methods have been developed over the past years. This review surveys total syntheses of sulfur-containing natural products that introduce sulfur atoms using different sulfurization agents to construct related sulfur-containing moieties.
Subject(s)
Biological Products/chemical synthesis , Sulfur/chemistry , Alkaloids/chemical synthesis , Alkaloids/chemistry , Biological Products/chemistry , Carbolines/chemical synthesis , Carbolines/chemistry , Disaccharides/chemical synthesis , Disaccharides/chemistry , Disulfides/chemistry , Enediynes/chemical synthesis , Enediynes/chemistry , Ferrichrome/analogs & derivatives , Ferrichrome/chemical synthesis , Ferrichrome/chemistry , Indole Alkaloids/chemical synthesis , Indole Alkaloids/chemistry , Indoles/chemical synthesis , Indoles/chemistry , Isothiocyanates/chemical synthesis , Isothiocyanates/chemistry , Molecular Structure , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/chemistry , Piperazines/chemistry , Sulfates/chemistry , Sulfoxides/chemical synthesis , Sulfoxides/chemistry , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
Innovation in drug discovery critically depends on the development of new bioisosteric groups. Chiral sulfoximines, which contain a tetrasubstituted sulfur atom that bears one nitrogen, one oxygen, and two different carbon substituents, represent an emerging chiral bioisostere in medicinal chemistry. Chiral sulfoximines are conventionally prepared by a stereospecific nitrene transfer reaction to chiral sulfoxides; however, the number of readily available chiral sulfoxides remains limited. Herein, we report the asymmetric synthesis of a class of hitherto difficult-to-access chiral sulfoximines with two structurally similar alkyl chains. Our synthetic approach is based on the sulfur-selective alkylation of easily accessible chiral sulfinamides with commercially available reagents under simple and safe conditions. This stereospecific S-alkylation offers a general and scalable approach to the asymmetric synthesis of chiral sulfoximines, which represent important substructures in bioactive molecules.
Subject(s)
Amides/chemistry , Imines/chemistry , Sulfoxides/chemical synthesis , Alkylation , Catalysis , Molecular Structure , Solvents/chemistry , Stereoisomerism , Temperature , Time FactorsABSTRACT
A novel series of 1,5-diarylpyrrol-3-sulfur derivatives (10-12) was synthesized and characterized by NMR and mass spectroscopy and x-ray diffraction. The biological activity of these compounds was evaluated in in vitro and in vivo tests to assess their COX-2 inhibitory activity along with anti-inflammatory and antinociceptive effect. Results showed that the bioisosteric transformation of previously reported alkoxyethyl ethers (9a-c) into the corresponding alkyl thioethers (10a-c) still leads to selective and active compounds being the COX-2 inhibitory activity for most of them in the low nanomolar range. The oxidation products of 10a,b were also investigated and both couple of sulfoxides (11a,b) and sulfones (12a,b) showed an appreciable COX-2 inhibitory activity. Molecular modeling studies were performed to investigate the binding mode of the representative compounds 10b, 11b, and 12b into COX-2 enzyme and to explore the potential site of metabolism of 10a and 10b due to the different in vivo efficacy. Among the developed compounds, compound 10b showed a significant in vivo anti-inflammatory and antinociceptive activity paving the way to develop novel anti-inflammatory drugs.
Subject(s)
Cyclooxygenase 2 Inhibitors/therapeutic use , Pyrroles/therapeutic use , Sulfides/therapeutic use , Sulfones/therapeutic use , Sulfoxides/therapeutic use , Analgesics/chemical synthesis , Analgesics/metabolism , Analgesics/therapeutic use , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/therapeutic use , Carrageenan , Cell Line , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/metabolism , Drug Design , Humans , Inflammation/chemically induced , Inflammation/drug therapy , Male , Mice , Molecular Docking Simulation , Molecular Structure , Protein Binding , Pyrroles/chemical synthesis , Pyrroles/metabolism , Rats, Sprague-Dawley , Rats, Wistar , Structure-Activity Relationship , Sulfides/chemical synthesis , Sulfides/metabolism , Sulfones/chemical synthesis , Sulfones/metabolism , Sulfoxides/chemical synthesis , Sulfoxides/metabolismABSTRACT
BACKGROUND: Malaria, caused by the deadly Plasmodium falciparum strain, claims the lives of millions of people annually. The emergence of drug-resistant strains of P. falciparum to the artemisinin-based combination therapy (ACT), the last line of defense against malaria, is worrisome and urges for the development of new chemo-types with a new mode of action. In the search of new antimalarial agents, hybrids of triazoles and other known antimalarial drugs have been reported to possess better activity than either of the parent compounds administered individually. Despite their better activity, no hybrid antimalarial drugs have been developed so far. OBJECTIVE: In the hope of developing new antimalarial prototypes, we propose the design, synthesis and antimalarial evaluation of novel sulfoximine-triazole hybrids owing to their interesting biological and physiological properties. METHODS: The sulfoximine part of the hybrid will be synthesized via imidation of the corresponding sulfoxide. Propargylation of the NH moiety of the sulfoximine followed by copper-catalyzed click chemistry with benzyl azide was envisaged to provide the target sulfoximine-triazole hybrids. RESULTS: Five novel sulfoximine-triazole hybrids possessing various substituents on the sulfoximine moiety have been successfully synthesized and evaluated for their antiplasmodial and cytotoxicity activities. The results revealed that the co-presence of the sulfoximine and triazole moieties along with a lipophilic alkyl substituent on the sulfur atom impart significant activity. CONCLUSION: Sulfoximine-triazole hybrids could be used as a prototype for the synthesis of new derivatives with better antiplasmodial activities.
Subject(s)
Antimalarials/pharmacology , Imines/pharmacology , Sulfoxides/pharmacology , Triazoles/pharmacology , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antimalarials/toxicity , Drug Design , HeLa Cells , Humans , Imines/chemical synthesis , Imines/chemistry , Imines/toxicity , Molecular Structure , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Sulfoxides/chemical synthesis , Sulfoxides/chemistry , Sulfoxides/toxicity , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/toxicityABSTRACT
The in vivo antimalarial efficacies of two phosphatidylinositol 4-kinase (PI4K) inhibitors, a 3,5-diaryl-2-aminopyrazine sulfoxide and its corresponding sulfone metabolite, were evaluated in the NOD-scid IL2Rγnull (NSG) murine malaria disease model of Plasmodium falciparum infection. We hypothesized that the sulfoxide would serve as a more soluble prodrug for the sulfone, which would lead to improved drug exposure with oral dosing. Both compounds had similar efficacy (90% effective dose [ED90], 0.1 mg kg-1 of body weight) across a quadruple-dose regimen. Pharmacokinetic profiling revealed rapid sulfoxide clearance via conversion to sulfone, with sulfone identified as the major active metabolite. When the sulfoxide was dosed, the exposure of the sulfone achieved was as much as 2.9-fold higher than when the sulfone was directly dosed, thereby demonstrating that the sulfoxide served as an effective prodrug for the treatment of malaria.
Subject(s)
Antimalarials/pharmacology , Malaria, Falciparum/drug therapy , Parasitemia/drug therapy , Prodrugs/pharmacology , Pyrazines/pharmacology , Sulfones/pharmacology , Sulfoxides/pharmacology , 1-Phosphatidylinositol 4-Kinase/antagonists & inhibitors , 1-Phosphatidylinositol 4-Kinase/genetics , 1-Phosphatidylinositol 4-Kinase/metabolism , Animals , Antimalarials/blood , Antimalarials/chemical synthesis , Antimalarials/pharmacokinetics , Biotransformation , Disease Models, Animal , Dose-Response Relationship, Drug , Erythrocytes/drug effects , Erythrocytes/metabolism , Erythrocytes/parasitology , Gene Expression , Humans , Malaria, Falciparum/metabolism , Malaria, Falciparum/parasitology , Malaria, Falciparum/pathology , Male , Mice , Mice, Inbred NOD , Mice, SCID , Parasitemia/pathology , Plasmodium falciparum/drug effects , Plasmodium falciparum/enzymology , Plasmodium falciparum/growth & development , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Pyrazines/blood , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Sulfones/blood , Sulfones/chemical synthesis , Sulfones/pharmacokinetics , Sulfoxides/blood , Sulfoxides/chemical synthesis , Sulfoxides/pharmacokinetics , Treatment OutcomeABSTRACT
The design and synthesis of three novel polycyclic scaffolds containing sulfoximines are presented in this work, which exemplify that sulfoximines represent a real opportunity for the discovery of new drug candidates. Additionally, the structures present at least two points of diversification and contain a high level of sp3-character, hence being very interesting 3D scaffolds. The compounds synthesized were added to the compound collection of the European Lead Factory.
Subject(s)
Polycyclic Compounds/chemical synthesis , Small Molecule Libraries/chemical synthesis , Sulfoxides/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Cycloaddition Reaction , Drug Discovery , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Spiro Compounds/chemical synthesis , StereoisomerismABSTRACT
Cross-linking mass spectrometry (XL-MS) has become an emerging technology for defining protein-protein interactions (PPIs) and elucidating architectures of large protein complexes. Up to now, the most widely used cross-linking reagents target lysines. Although such reagents have been successfully applied to map PPIs at the proteome-wide scale, comprehensive PPI profiling would require additional cross-linking chemistries. Cysteine is one of the most reactive amino acids and an attractive target for cross-linking owing to its unique role in protein structures. Although sulfhydryl-reactive cross-linkers are commercially available, their applications in XL-MS studies remain sparse, likely due to the difficulty in identifying cysteine cross-linked peptides. Previously, we developed a new class of sulfoxide-containing MS-cleavable cross-linkers to enable fast and accurate identification of cross-linked peptides using multistage tandem mass spectrometry (MS n). Here, we present the development of a new sulfoxide-containing MS-cleavable homobifunctional cysteine-reactive cross-linker, bismaleimide sulfoxide (BMSO). We demonstrate that BMSO-cross-linked peptides display the same characteristic fragmentation pattern during collision-induced dissociation (CID) as other sulfoxide-containing MS-cleavable cross-linked peptides, thus permitting their simplified analysis and unambiguous identification by MS n. Additionally, we show that BMSO can complement amine- and acidic-residue-reactive reagents for mapping protein-interaction regions. Collectively, this work not only enlarges the toolbox of MS-cleavable cross-linkers with diverse chemistries, but more importantly expands our capacity and capability of studying PPIs in general.
Subject(s)
Cross-Linking Reagents/chemistry , Cysteine/chemistry , Protein Interaction Mapping , Serum Albumin, Bovine/chemistry , Sulfoxides/chemistry , Animals , Cattle , Molecular Structure , Protein Binding , Sulfoxides/chemical synthesis , Tandem Mass SpectrometryABSTRACT
Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model.
Subject(s)
Imines/pharmacology , Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors , Sulfonamides/pharmacology , Sulfoxides/pharmacology , Animals , Drug Inverse Agonism , Female , Humans , Imines/chemical synthesis , Imines/chemistry , Ligands , Mice, Inbred BALB C , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfoxides/chemical synthesis , Sulfoxides/chemistryABSTRACT
In this work, a series of novel benzyl sulfoxide 2-indolinone derivatives was designed and synthesized as potent anticancer agents. Tyrosine kinase inhibitory activity assay indicated that most of the compounds showed significant activity. The in vitro antiproliferative activity of these compounds was further investigated against five human cancer cell lines (HeLa, HepG2, MCF-7, SCC-15, and A549). Several compounds exhibited evident activities. Among them, (Z)-3-(((4-bromobenzyl)sulfinyl)methylene)indolin-2-one (6j) and (Z)-3-((benzylsulfinyl)methylene)-5-bromoindolin-2-one (6o) were found to be effective tyrosine kinase inhibitors (IC50 = 1.34 and 2.69 µM, respectively) in addition to having noteworthy antitumor potential (the average IC50 value of 6j or 6o was less than 40 µM). This class of novel derivatives has promising potential for further development as anticancer agents.
Subject(s)
Antineoplastic Agents/chemistry , Oxindoles/chemistry , Sulfoxides/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Humans , Oxindoles/chemical synthesis , Oxindoles/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Structure-Activity Relationship , Sulfoxides/chemical synthesis , Sulfoxides/pharmacologyABSTRACT
Modafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered. It was the aim of this study to synthesize and characterize such analogues and, indeed, a series of compounds were showing higher activities on the DAT and a higher selectivity toward DAT versus serotonin and norepinephrine transporters than modafinil. This was achieved by substituting the amide moiety by five- and six-membered aromatic heterocycles. In vitro studies indicated binding to the cocaine pocket on DAT, although molecular dynamics revealed binding different from that of cocaine. Moreover, no release of dopamine was observed, ruling out amphetamine-like effects. The absence of neurotoxicity of a representative analogue may encourage further preclinical studies of the above-mentioned compounds.
Subject(s)
Benzhydryl Compounds/pharmacology , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Uptake Inhibitors/pharmacology , Heterocyclic Compounds/pharmacology , 1-Methyl-4-phenylpyridinium/metabolism , Animals , Benzhydryl Compounds/chemical synthesis , Binding Sites , Dopamine/metabolism , Dopamine Uptake Inhibitors/chemical synthesis , HEK293 Cells , Heterocyclic Compounds/chemical synthesis , Humans , Male , Modafinil , Molecular Docking Simulation , Molecular Dynamics Simulation , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Rats, Sprague-Dawley , Serotonin and Noradrenaline Reuptake Inhibitors/chemical synthesis , Serotonin and Noradrenaline Reuptake Inhibitors/pharmacology , Structure-Activity Relationship , Sulfoxides/chemical synthesis , Sulfoxides/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacologyABSTRACT
A series of compounds have been shown to enhance cognitive function via the dopaminergic system and indeed the search for more active and less toxic compounds is continuing. It was therefore the aim of the study to synthetise and test a novel heterocyclic compound for cognitive enhancement in a paradigm for working memory. Specific and effective dopamine re-uptake inhibition DAT (IC50=4,1±0,8µM) made us test this compound in a radial arm maze (RAM) in the rat. CE-125 (4-((benzhydrylsulfinyl)methyl)-2-cyclopropylthiazole), was tested for dopamine (DAT), serotonin and norepinephrine re-uptake inhibition by a well-established system. The working memory index (WMI) was evaluated in male Sprague Dawley rats that were intraperitoneally injected with CE-125 (1 or 10mg/kg body weight). In order to evaluate basic neurotoxicity, the open field, elevated plus maze, rota rod studies and the forced swim test were carried out. Frontal cortex was taken at the last day of the RAM test and dopamine receptors D1R and D2R, DAT and phosphorylated DAT protein levels were determined. On the 10th day both doses were increasing the WMI as compared to the vehicle-treated group. In both, trained and treated groups, D1R levels were significantly reduced while D2R levels were unchanged. DAT levels were comparable between all groups while phosphorylated DAT levels were increased in the trained group treated with 1mg/kg body weight. CE-125 as a probably non-neurotoxic compound and specific reuptake inhibitor was shown to increase performance (WMI) and modulation of the dopaminergic system is proposed as a possible mechanism of action.
Subject(s)
Dopamine Uptake Inhibitors/pharmacology , Frontal Lobe/drug effects , Memory, Short-Term/drug effects , Nootropic Agents/pharmacology , Receptors, Dopamine D1/metabolism , Sulfoxides/pharmacology , Thiazoles/pharmacology , Animals , Chromatography, High Pressure Liquid , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/chemistry , Frontal Lobe/metabolism , HEK293 Cells , Humans , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Maze Learning/drug effects , Maze Learning/physiology , Memory, Short-Term/physiology , Molecular Structure , Motor Activity/drug effects , Nootropic Agents/chemical synthesis , Nootropic Agents/chemistry , Phosphorylation , Rats, Sprague-Dawley , Receptors, Dopamine D2/metabolism , Sulfoxides/chemical synthesis , Sulfoxides/chemistry , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, roniciclib (pan-CDK inhibitor), BAYâ 1143572 (P-TEFb inhibitor), and AZDâ 6738 (ATR inhibitor), have recently drawn considerable attention. Whilst the interest in this underrepresented functional group in drug discovery is clearly on the rise, there remains an incomplete understanding of the medicinal-chemistry-relevant properties of sulfoximines. Herein we report the synthesis and inâ vitro characterization of a variety of sulfoximine analogues of marketed drugs and advanced clinical candidates to gain a better understanding of this neglected functional group and its potential in drug discovery.
Subject(s)
Drug Design , Protein Kinase Inhibitors/chemistry , Sulfoxides/chemistry , Aminopyridines/chemical synthesis , Aminopyridines/chemistry , Aminopyridines/metabolism , Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Ataxia Telangiectasia Mutated Proteins/metabolism , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclin-Dependent Kinases/metabolism , Estradiol/analogs & derivatives , Estradiol/chemical synthesis , Estradiol/chemistry , Estradiol/metabolism , Fulvestrant , Imatinib Mesylate/chemical synthesis , Imatinib Mesylate/chemistry , Imatinib Mesylate/metabolism , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/metabolism , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Purines/chemical synthesis , Purines/chemistry , Purines/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/metabolism , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/metabolism , Sulfoxides/chemical synthesis , Sulfoxides/metabolism , Vardenafil Dihydrochloride/chemical synthesis , Vardenafil Dihydrochloride/chemistry , Vardenafil Dihydrochloride/metabolismABSTRACT
Aiming at the limited effectiveness of current clinical therapeutic effect of AIDS, novel series of compounds bearing (E)-3,4-dihydroxystyryl sulfone (or sulfoxide) and anilide fragments were designed and synthesized as dual inhibitors of HIV-1 CCR5/IN. The biological results indicated that several target compounds showed inhibitory activity against HIV-1 Bal (R5) infection in TZM-bl cells. Besides targeting the chemokine receptor on the host cell surface, they also displayed binding affinities with HIV-1 integrase using the surface plasmon resonance (SPR) binding assays. Molecular docking studies have inferred the possible binding mode of target compounds against integrase. These data demonstrate that the structure of (E)-3,4-dihydroxystyryl sulfone and sulfoxide derivatives have the potential to derive potent dual inhibitors of HIV-1 Integrase and CCR5.
Subject(s)
Anti-HIV Agents/pharmacology , HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , HIV-1/drug effects , Receptors, CCR5/metabolism , Sulfones/pharmacology , Sulfoxides/pharmacology , Anilides/chemical synthesis , Anilides/chemistry , Anilides/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Design , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/chemistry , HIV-1/enzymology , Humans , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Styrenes/chemical synthesis , Styrenes/chemistry , Styrenes/pharmacology , Sulfones/chemical synthesis , Sulfones/chemistry , Sulfoxides/chemical synthesis , Sulfoxides/chemistry , Virus Replication/drug effectsABSTRACT
Enantiopure ß-hydroxy sulfoxides and catechol sulfoxides were obtained, by chemoenzymatic synthesis, involving dioxygenase-catalysed benzylic hydroxylation or arene cis-dihydroxylation and cis-diol dehydrogenase-catalysed dehydrogenation. Absolute configurations of chiral hydroxy sulfoxides were determined by X-ray crystallography, ECD spectroscopy and stereochemical correlation. The application of a new range of ß-hydroxy sulfoxides as chiral ligands was examined.