ABSTRACT
The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) exhibits remarkable anticancer efficacy; however, its therapeutic potential is hindered by its toxicity to gastrointestinal (GI) tissues. We recently reported the discovery of DRP-104, a tumor-targeted DON prodrug with excellent efficacy and tolerability, which is currently in clinical trials. However, DRP-104 exhibits limited aqueous solubility, and the instability of its isopropyl ester promoiety leads to the formation of an inactive M1-metabolite, reducing overall systemic prodrug exposure. Herein, we aimed to synthesize DON prodrugs with various ester and amide promoieties with improved solubility, GI stability, and DON tumor delivery. Twenty-one prodrugs were synthesized and characterized in stability and pharmacokinetics studies. Of these, P11, tert-butyl-(S)-6-diazo-2-((S)-2-(2-(dimethylamino)acetamido)-3-phenylpropanamido)-5-oxo-hexanoate, showed excellent metabolic stability in plasma and intestinal homogenate, high aqueous solubility, and high tumor DON exposures and preserved the ideal tumor-targeting profile of DRP-104. In conclusion, we report a new generation of glutamine antagonist prodrugs with improved physicochemical and pharmacokinetic attributes.
Subject(s)
Neoplasms , Prodrugs , Humans , Prodrugs/chemistry , Diazooxonorleucine/pharmacokinetics , Glutamine , Esters/therapeutic use , Neoplasms/drug therapyABSTRACT
Two distinct diazo precursors, imidazotetrazine and nitrous amide, were explored as promoieties in designing prodrugs of 6-diazo-5-oxo-l-norleucine (DON), a glutamine antagonist. As a model for an imidazotetrazine-based prodrug, we synthesized (S)-2-acetamido-6-(8-carbamoyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)-5-oxohexanoic acid (4) containing the entire scaffold of temozolomide, a precursor of the DNA-methylating agent clinically approved for the treatment of glioblastoma multiforme. For a nitrous amide-based prodrug, we synthesized 2-acetamido-6-(((benzyloxy)carbonyl)(nitroso)amino)-5-oxohexanoic acid (5) containing a N-nitrosocarbamate group, which can be converted to a diazo moiety via a mechanism similar to that of streptozotocin, a clinically approved diazomethane-releasing drug containing an N-nitrosourea group. Preliminary characterization confirmed formation of N-acetyl DON (6), also known as duazomycin A, from compound 4 in a pH-dependent manner while compound 5 did not exhibit sufficient stability to allow further characterization. Taken together, our model studies suggest that further improvements are needed to translate this prodrug approach into glutamine antagonist-based therapy.
Subject(s)
Diazooxonorleucine/analogs & derivatives , Diazooxonorleucine/pharmacology , Glutamine/antagonists & inhibitors , Prodrugs/chemistry , Prodrugs/pharmacology , Diazooxonorleucine/chemistry , Drug Design , Drug Stability , Molecular StructureABSTRACT
BACKGROUND: Given the emergent aging population, the identification of effective treatments for Alzheimer's disease (AD) is critical. OBJECTIVE: We investigated the therapeutic efficacy of JHU-083, a brain-penetrable glutamine antagonist, in treating AD using the humanized APOE4 knock-in mouse model. METHODS: Cell culture studies were performed using BV2 cells and primary microglia isolated from hippocampi of adult APOE4 knock-in mice to evaluate the effect of JHU-083 treatment on LPS-induced glutaminase (GLS) activity and inflammatory markers. Six-month-old APOE4 knock-in mice were administered JHU-083 or vehicle via oral gavage 3x/week for 4-5 months and cognitive performance was assessed using the Barnes maze. Target engagement in the brain was confirmed using a radiolabeled GLS enzymatic activity assay, and electrophysiology, gastrointestinal histology, blood chemistry, and CBC analyses were conducted to evaluate the tolerability of JHU-083. RESULTS: JHU-083 inhibited the LPS-mediated increases in GLS activity, nitic oxide release, and pro-inflammatory cytokine production in cultured BV2 cells and primary microglia isolated from APOE4 knock-in AD mice. Chronic treatment with JHU-083 in APOE4 mice improved hippocampal-dependent Barnes maze performance. Consistent with the cell culture findings,postmortem analyses of APOE4 mice showed increased GLS activity in hippocampal CD11b+ enriched cells versus age-matched controls, which was completely normalized by JHU-083 treatment. JHU-083 was well-tolerated, showing no weight loss effect or overt behavioral changes. Peripheral nerve function, gastrointestinal histopathology, and CBC/clinical chemistry parameters were all unaffected by chronic JHU-083 treatment. CONCLUSION: These results suggest that the attenuation of upregulated hippocampal glutaminase by JHU-083 represents a new therapeutic strategy for AD.
Subject(s)
Apolipoprotein E4 , Azo Compounds/pharmacology , Caproates/pharmacology , Cognition/drug effects , Glutaminase/antagonists & inhibitors , Glutamine/antagonists & inhibitors , Hippocampus/drug effects , Alzheimer Disease/drug therapy , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Animals , Apolipoprotein E4/genetics , Azo Compounds/therapeutic use , Caproates/therapeutic use , Cell Line , Cells, Cultured , Cognition/physiology , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Female , Glutaminase/metabolism , Glutamine/metabolism , Hippocampus/metabolism , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microglia/drug effects , Microglia/metabolism , Microglia/pathologyABSTRACT
The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. By contrast, effector T cells responded to glutamine antagonism by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent antitumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a "metabolic checkpoint" for tumor immunotherapy.
Subject(s)
Azo Compounds/pharmacology , Caproates/pharmacology , Glutamine/metabolism , Immunotherapy, Adoptive , Neoplasms, Experimental/immunology , Neoplasms, Experimental/therapy , Tumor Escape , Animals , CD8-Positive T-Lymphocytes/immunology , Citric Acid Cycle/drug effects , Energy Metabolism , Female , Glucose/metabolism , Glutamine/antagonists & inhibitors , Immunologic Memory , Lymphocyte Activation , Lymphocytes, Tumor-Infiltrating/immunology , Male , Mice, Inbred BALB C , Mice, Inbred C57BL , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Tumor MicroenvironmentABSTRACT
Mas-related G-protein-coupled receptor X1 (MRGPRX1) is a human sensory neuron-specific receptor and has been actively investigated as a therapeutic target for the treatment of pain. By use of two HTS screening hit compounds, 4-(4-(benzyloxy)-3-methoxybenzylamino)benzimidamide (5a) and 4-(2-(butylsulfonamido)-4-methylphenoxy)benzimidamide (11a), as molecular templates, a series of human MRGPRX1 agonists were synthesized and evaluated for their agonist activity using HEK293 cells stably transfected with human MrgprX1. Conversion of the benzamidine moiety into a 1-aminoisoquinoline moiety carried out in the later stage of structural optimization led to the discovery of a highly potent MRGPRX1 agonist, N-(2-(1-aminoisoquinolin-6-yloxy)-4-methylphenyl)-2-methoxybenzenesulfonamide (16), not only devoid of positively charged amidinium group but also with superior selectivity over opioid receptors. In mice, compound 16 displayed favorable distribution to the spinal cord, the presumed site of action for the MRGPRX1-mediated analgesic effects.
Subject(s)
Benzamidines/pharmacology , Isoquinolines/pharmacology , Receptors, G-Protein-Coupled/agonists , Analgesics/chemistry , Analgesics/pharmacology , Animals , Benzamidines/chemistry , Chronic Pain/drug therapy , Drug Design , HEK293 Cells , Humans , Isoquinolines/chemistry , Magnetic Resonance Spectroscopy , Male , Mice , Neurons/metabolismABSTRACT
OBJECTIVE: To measure the impact of JHU-083, a novel prodrug of the glutamine antagonist 6-diazo-5-oxo-l-norleucine, on immune cell proliferation and activation, along with physical and cognitive impairments associated with the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. METHODS: Splenic-derived T cells and bone marrow-derived dendritic cells (DCs) were cultured, activated, and treated daily with vehicle or JHU-083. Proliferation and activation were measured via flow cytometry and IncuCyte live cell analysis. C57BL/6 mice were immunized for EAE. Vehicle or JHU-083 was administered orally every other day either from the time of immunization in the prevention paradigm or from the time of disease onset in the treatment paradigm. Disease scores and body weight were monitored. In the treatment paradigm, cognition was evaluated using the Barnes maze test. RESULTS: JHU-083 selectively inhibits T-cell proliferation and decreases T-cell activation, with no effect on DCs. In vivo, orally administered JHU-083 significantly decreases EAE severity in both prevention and treatment paradigms and reverses EAE-induced cognitive impairment. CONCLUSIONS: JHU-083, a well-tolerated, brain penetrable glutamine antagonist, is a promising novel treatment for both the physical and cognitive deficits of MS.
Subject(s)
Azo Compounds/pharmacology , Caproates/pharmacology , Cognitive Dysfunction/drug therapy , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Multiple Sclerosis/drug therapy , Animals , Behavior, Animal/drug effects , Cells, Cultured , Cognitive Dysfunction/etiology , Encephalomyelitis, Autoimmune, Experimental/complications , Female , Glutamine , Male , Mice , Mice, Inbred C57BL , Multiple Sclerosis/complicationsABSTRACT
HIV-associated neurocognitive disorders (HAND) have been linked to dysregulation of glutamate metabolism in the central nervous system (CNS) culminating in elevated extracellular glutamate and disrupted glutamatergic neurotransmission. Increased glutamate synthesis via upregulation of glutaminase (GLS) activity in brain immune cells has been identified as one potential source of excess glutamate in HAND. However, direct evidence for this hypothesis in an animal model is lacking, and the viability of GLS as a drug target has not been explored. In this brief report, we demonstrate that GLS inhibition with the glutamine analogue 6-diazo-5-oxo-L-norleucine (DON) can reverse cognitive impairment in the EcoHIV-infected mouse model of HAND. However, due to peripheral toxicity DON is not amenable to clinical use in a chronic disease such as HAND. We thus tested JHU083, a novel, brain penetrant DON prodrug predicted to exhibit improved tolerability. Systemic administration of JHU083 reversed cognitive impairment in EcoHIV-infected mice similarly to DON, and simultaneously normalized EcoHIV-induced increases in cerebrospinal fluid (CSF) glutamate and GLS activity in microglia-enriched brain CD11b + cells without observed toxicity. These studies support the mechanistic involvement of elevated microglial GLS activity in HAND pathogenesis, and identify JHU083 as a potential treatment option. Graphical Abstract Please provide Graphical Abstract caption.Glutamine Antagonist JHU083 Normalizes Aberrant Glutamate Production and Cognitive Deficits in the EcoHIV Murine Model of HIV-Associated Neurocognitive Disorders .
Subject(s)
AIDS Dementia Complex , Azo Compounds/therapeutic use , Caproates/therapeutic use , Cognition Disorders/drug therapy , Glutamates/biosynthesis , Glutamine/antagonists & inhibitors , Prodrugs/therapeutic use , Animals , Azo Compounds/pharmacokinetics , CD11b Antigen/analysis , Caproates/pharmacokinetics , Cognition Disorders/cerebrospinal fluid , Cognition Disorders/etiology , Cognition Disorders/virology , Conditioning, Classical/drug effects , Fear , Glutamates/cerebrospinal fluid , HIV-1/genetics , HIV-1/pathogenicity , Leukemia Virus, Murine/genetics , Leukemia Virus, Murine/pathogenicity , Male , Maze Learning/drug effects , Memory, Short-Term/drug effects , Mice , Mice, Inbred C57BL , Microglia/drug effects , Microglia/metabolism , Norleucine/analogs & derivatives , Norleucine/therapeutic use , Prodrugs/pharmacokinetics , Reassortant Viruses/genetics , Reassortant Viruses/pathogenicity , Spatial Learning/drug effectsABSTRACT
During this process, we found that we need add the following sentence in the manuscript within the Acknowledgement section.
ABSTRACT
There are a number of clinically effective treatments for stress-associated psychiatric diseases, including major depressive disorder (MDD). Nonetheless, many patients exhibit resistance to first-line interventions calling for novel interventions based on pathological mechanisms. Accumulating evidence implicates altered glutamate signaling in MDD pathophysiology, suggesting that modulation of glutamate signaling cascades may offer novel therapeutic potential. Here we report that JHU-083, our recently developed prodrug of the glutaminase inhibitor 6-diazo-5-oxo-L-norleucine (DON) ameliorates social avoidance and anhedonia-like behaviors in mice subjected to chronic social defeat stress (CSDS). JHU-083 normalized CSDS-induced increases in glutaminase activity specifically in microglia-enriched CD11b+ cells isolated from the prefrontal cortex and hippocampus. JHU-083 treatment also reverses the CSDS-induced inflammatory activation of CD11b+ cells. These results support the importance of altered glutamate signaling in the behavioral abnormalities observed in the CSDS model, and identify glutaminase in microglia-enriched CD11b+ cells as a pharmacotherapeutic target implicated in the pathophysiology of stress-associated psychiatric conditions such as MDD.
Subject(s)
CD11b Antigen , Depression/prevention & control , Diazooxonorleucine , Glutaminase/drug effects , Hippocampus/drug effects , Inflammation/drug therapy , Prefrontal Cortex/drug effects , Prodrugs , Animals , Behavior, Animal/drug effects , Depression/etiology , Diazooxonorleucine/pharmacology , Disease Models, Animal , Hippocampus/immunology , Hippocampus/metabolism , Inflammation/immunology , Inflammation/metabolism , Male , Mice , Mice, Inbred C57BL , Prefrontal Cortex/immunology , Prefrontal Cortex/metabolism , Prodrugs/pharmacology , Signal Transduction , Stress, Psychological/complicationsABSTRACT
The deadliest complication of Plasmodium falciparum infection is cerebral malaria (CM), with a case fatality rate of 15 to 25% in African children despite effective antimalarial chemotherapy. No adjunctive treatments are yet available for this devastating disease. We previously reported that the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) rescued mice from experimental CM (ECM) when administered late in the infection, a time by which mice had already suffered blood-brain barrier (BBB) dysfunction, brain swelling, and hemorrhaging. Herein, we used longitudinal MR imaging to visualize brain pathology in ECM and the impact of a new DON prodrug, JHU-083, on disease progression in mice. We demonstrate in vivo the reversal of disease markers in symptomatic, infected mice following treatment, including the resolution of edema and BBB disruption, findings usually associated with a fatal outcome in children and adults with CM. Our results support the premise that JHU-083 is a potential adjunctive treatment that could rescue children and adults from fatal CM.
Subject(s)
Diazooxonorleucine/antagonists & inhibitors , Diazooxonorleucine/therapeutic use , Glutamine/antagonists & inhibitors , Magnetic Resonance Imaging/methods , Malaria, Cerebral/drug therapy , Malaria, Cerebral/pathology , Malaria, Falciparum/drug therapy , Malaria, Falciparum/pathology , Adult , Animals , Antimalarials/therapeutic use , Biomarkers , Blood-Brain Barrier/pathology , Brain/parasitology , Brain/pathology , Brain Edema/diagnostic imaging , Brain Edema/pathology , Child , Diazooxonorleucine/administration & dosage , Disease Models, Animal , Disease Progression , Female , Humans , Malaria, Cerebral/diagnostic imaging , Malaria, Cerebral/parasitology , Malaria, Falciparum/diagnostic imaging , Mice , Mice, Inbred C57BL , Plasmodium falciparum/pathogenicityABSTRACT
Mebendazole (MBZ) was developed as a broad-spectrum anthelmintic but has recently shown efficacy as an anticancer agent. The use of MBZ for cancer, however, is challenging due to its poor solubility leading to poor bioavailability. Herein, we developed a prodrug approach with various N-linked promoieties including acyloxymethyl, aminoacyloxymethyl, and substituted phosphonooxymethyl in attempt to improve these characteristics. Compound 12, containing an (((((isopropoxycarbonyl)oxy)methoxy)phosphoryl)oxy)methyl promoiety, showed a >10â¯000-fold improvement in aqueous solubility. When evaluated in mice, 12 displayed a 2.2-fold higher plasma AUC0- t and a 1.7-fold improvement in brain AUC0- t with a calculated oral bioavailability of 52%, as compared to 24% for MBZ-polymorph C (MBZ-C), the most bioavailable polymorph. In dogs, 12 showed a 3.8-fold higher plasma AUC0- t with oral bioavailability of 41% compared to 11% for MBZ-C. In summary, we have identified a prodrug of MBZ with better physicochemical properties and enhanced bioavailability in both mice and dog.
Subject(s)
Anthelmintics/metabolism , Mebendazole/metabolism , Nitrogen/chemistry , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Water/chemistry , Administration, Oral , Animals , Biological Availability , Dogs , Drug Stability , Male , Mice , Prodrugs/administration & dosage , Prodrugs/metabolism , Solubility , Structure-Activity Relationship , Tissue DistributionABSTRACT
Aberrant excitatory neurotransmission associated with overproduction of glutamate has been implicated in the development of HIV-associated neurocognitive disorders (HAND). The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 14) attenuates glutamate synthesis in HIV-infected microglia/macrophages, offering therapeutic potential for HAND. We show that 14 prevents manifestation of spatial memory deficits in chimeric EcoHIV-infected mice, a model of HAND. 14 is not clinically available, however, because its development was hampered by peripheral toxicities. We describe the synthesis of several substituted N-(pivaloyloxy)alkoxy-carbonyl prodrugs of 14 designed to circulate inert in plasma and be taken up and biotransformed to 14 in the brain. The lead prodrug, isopropyl 6-diazo-5-oxo-2-(((phenyl(pivaloyloxy)methoxy)carbonyl)amino)hexanoate (13d), was stable in swine and human plasma but liberated 14 in swine brain homogenate. When dosed systemically in swine, 13d provided a 15-fold enhanced CSF-to-plasma ratio and a 9-fold enhanced brain-to-plasma ratio relative to 14, opening a possible clinical path for the treatment of HAND.
Subject(s)
Aminocaproates/pharmacology , Azo Compounds/pharmacology , Diazooxonorleucine/pharmacology , Neurocognitive Disorders/drug therapy , Nootropic Agents/pharmacology , Prodrugs/pharmacology , Aminocaproates/administration & dosage , Aminocaproates/chemical synthesis , Animals , Azo Compounds/administration & dosage , Azo Compounds/chemical synthesis , Blood/metabolism , Brain/metabolism , Diazooxonorleucine/administration & dosage , Drug Stability , Female , Glutamic Acid/metabolism , Glutaminase/antagonists & inhibitors , HIV Infections/complications , Humans , Male , Mice, Inbred C57BL , Neurocognitive Disorders/etiology , Nootropic Agents/administration & dosage , Nootropic Agents/chemical synthesis , Prodrugs/administration & dosage , Prodrugs/chemical synthesis , Swine , Viral Load/drug effectsABSTRACT
PURPOSE: To study new skin penetration/permeation enhancers based on amphiphilic galactose derivatives. METHODS: Two series of alkyl and alkenyl galactosides were synthesized and evaluated for their enhancing effect on transdermal/topical delivery of theophylline (TH), hydrocortisone (HC) and cidofovir (CDV), reversibility of their effects on transepidermal water loss (TEWL) and skin impedance, interaction with the stratum corneum using infrared spectroscopy, and cytotoxicity on keratinocytes and fibroblasts. RESULTS: Initial evaluation identified 1-(α-D-galactopyranosyl)-(2E)-pentadec-2-ene A15 as a highly potent enhancer - it increased TH and HC flux through human skin 8.5 and 5 times, respectively. Compound A15 increased the epidermal concentration of a potent antiviral CDV 7 times over that reached by control and Span 20 (an established sugar-based enhancer). Infrared spectroscopy of human stratum corneum indicated interaction of A15 with skin barrier lipids but not proteins. These effects of A15 on the skin barrier were reversible (both TEWL and skin impedance returned to baseline values within 24 h after A15 had been removed from skin). In vitro toxicity of A15 on HaCaT keratinocytes and 3T3 fibroblasts was acceptable, with IC50 values over 60 µM. CONCLUSIONS: Galactosyl pentadecene A15 is a potent enhancer with low toxicity and reversible action.
Subject(s)
Alkenes/chemistry , Galactose/analogs & derivatives , Galactose/chemistry , Galactosides/chemistry , Skin Absorption/drug effects , Administration, Cutaneous , Alkenes/administration & dosage , Cidofovir , Cytosine/administration & dosage , Cytosine/analogs & derivatives , Cytosine/chemistry , Drug Liberation , Epidermis/metabolism , Fibroblasts/drug effects , Fibroblasts/metabolism , Galactosides/administration & dosage , Humans , Hydrocortisone/administration & dosage , Hydrocortisone/chemistry , Keratinocytes/drug effects , Keratinocytes/metabolism , Lipids/chemistry , Organophosphonates/administration & dosage , Organophosphonates/chemistry , Permeability , Skin/metabolism , Structure-Activity Relationship , Theophylline/administration & dosage , Theophylline/chemistry , WaterABSTRACT
PURPOSE: Skin permeation/penetration enhancers are substances that enable drug delivery through or into the skin. METHODS: To search for new enhancers with high but reversible activity and acceptable toxicity, we synthesized a series of D-glucose derivatives, both hydrophilic and amphiphilic. RESULTS: Initial evaluation of the ability of these sugar derivatives to increase permeation and penetration of theophylline through/into human skin compared with a control (no enhancer) or sorbitan monolaurate (Span 20; positive control) revealed dodecyl 6-amino-6-deoxy-α-D-glucopyranoside 5 as a promising enhancer. Furthermore, this amino sugar 5 increased epidermal concentration of a highly hydrophilic antiviral cidofovir by a factor of 7. The effect of compound 5 on skin electrical impedance suggested its direct interaction with the skin barrier. Infrared spectroscopy of isolated stratum corneum revealed no effect of enhancer 5 on the stratum corneum proteins but an overall decrease in the lipid chain order. The enhancer showed acceptable toxicity on HaCaT keratinocyte and 3T3 fibroblast cell lines. Finally, transepidermal water loss returned to baseline values after enhancer 5 had been removed from the skin. CONCLUSIONS: Compound 5, a dodecyl amino glucoside, is a promising enhancer that acts through a reversible interaction with the stratum corneum lipids.
Subject(s)
Glucosides/pharmacology , Lipids/physiology , Skin/drug effects , Administration, Cutaneous , Administration, Topical , Antiviral Agents/administration & dosage , Antiviral Agents/metabolism , Cell Line , Cell Survival , Chemistry, Pharmaceutical , Cidofovir , Cytosine/administration & dosage , Cytosine/analogs & derivatives , Cytosine/metabolism , Drug Delivery Systems , Epidermis/drug effects , Epidermis/metabolism , Glucosides/chemical synthesis , Hexoses/pharmacology , Humans , Hydrophobic and Hydrophilic Interactions , Keratinocytes/drug effects , Keratinocytes/metabolism , Organophosphonates/administration & dosage , Organophosphonates/metabolism , Permeability , Skin/metabolism , Skin Absorption , Structure-Activity Relationship , Theophylline/administration & dosage , Theophylline/metabolismABSTRACT
Compounds with polyfluorinated molecular fragments possess unique properties associated with the presence of a large number of fluorine atoms that affect lipophilicity and conformational rigidity of the parent molecule along with other effects. The aim of this review is to provide an overview of synthesized compounds possessing perfluoroalkylated or polyfluorinated chains that have been tested for bioactivity or as potential drug candidates for the treatment of various diseases. As far as the length of the perfluoroalkylated chain is concerned the focus is centered on the compound bearing perfluoroethyl or tetrafluoroethyl as well as longer chains. The perfluoroalkylated compounds discussed are classified according to their biological activity.
Subject(s)
Drug Discovery , Fluorocarbons/chemistry , Fluorocarbons/pharmacology , Alkylation , Animals , Drug Discovery/methods , HumansABSTRACT
An approach to stereoselective synthesis of alpha- or beta-3-C-glycosylated L- or D-1,2-glucals starting from the corresponding alpha- or beta-glycopyranosylethanals is described. The key step of the approach is the stereoselective cycloaddition of chiral vinyl ethers derived from both enantiomers of mandelic acid. The preparation of 1,5-anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-C-[(2,3,4,6-tetra-O-benzyl-beta-D-glucopyranosyl)methyl]-L-arabino-hex-1-enitol, 1,5-anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-C-[(2,3,4,6-tetra-O-benzyl-beta-D-glucopyranosyl)methyl]-D-arabino-hex-1-enitol, and 1,5-anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-C-[(2,3,4-tri-O-benzyl-alpha-L-fucopyranosyl)methyl]-D-arabino-hex-1-enitol serves as an example of this approach.