7 results on '"Natale NR"'
Search Results
2. 10-N-heterocylic aryl-isoxazole-amides (AIMs) have robust anti-tumor activity against breast and brain cancer cell lines and useful fluorescence properties.
- Author
-
Weaver MJ, Stump S, Campbell MJ, Backos DS, Li C, Reigan P, Adams E, Beall HD, and Natale NR
- Subjects
- Amides chemical synthesis, Amides chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Brain Neoplasms metabolism, Brain Neoplasms pathology, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Heterocyclic Compounds chemical synthesis, Heterocyclic Compounds chemistry, Humans, Isoxazoles chemical synthesis, Isoxazoles chemistry, Molecular Docking Simulation, Molecular Structure, Structure-Activity Relationship, Amides pharmacology, Antineoplastic Agents pharmacology, Brain Neoplasms drug therapy, Breast Neoplasms drug therapy, Fluorescence, Heterocyclic Compounds pharmacology, Isoxazoles pharmacology
- Abstract
A novel series of anthracenyl-isoxazole amide (AIM) antitumor agents containing N-heterocycles in the 10 position (N-het) were synthesized using palladium cross-coupling. The unique steric environment of the N-het-AIMs required individual optimization in each case. Lanthanide mediated double activation was used to couple the dimethylamino pyrrole moiety, required for antitumor action. Robust antitumor activity was observed against breast and brain cancer cell lines. The compounds were docked with the c-myc oncogene promoter sequence, which adopts a G4 quadruplex DNA conformation, and represents the working hypothesis for biological action. The N-het-AIMs have useful fluorescence properties, allowing for observation of their distribution within tumor cells., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
3. Isoxazolo[3,4-d]pyridazinones positively modulate the metabotropic glutamate subtypes 2 and 4.
- Author
-
Gates C, Backos DS, Reigan P, Kang HJ, Koerner C, Mirzaei J, and Natale NR
- Subjects
- Allosteric Regulation, Animals, Receptors, Metabotropic Glutamate chemistry, Structure-Activity Relationship, Isoxazoles chemistry, Pyridazines chemistry, Pyridazines pharmacology, Receptors, Metabotropic Glutamate drug effects
- Abstract
Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) are selective positive modulators of the metabotropic glutamate receptors (mGluRs) subtypes 2 and 4, with no functional cross reactivity at mGluR
1a , mGLuR5 or mGluR8 . Modest binding for two of the [3,4-d]s is observed at the allosteric fenobam mGluR5 site, but not sufficient to translate into a functional effect. The structure activity relationship (SAR) for mGluR2 and mGluR4 are distinct: the compounds which select for mGluR2 all contain fluorine on the N-6 aryl group. Furthermore, the [3,4-d]s in this study showed no significant binding at inhibitory GABAA, nor excitatory NMDA receptors, and previously we had disclosed that they lack significant activity at the System Xc-Antiporter. A homology model based on Conn's mGluR1 crystal structure was examined, and suggested explanations for a preference for allosteric over orthosteric binding, subtype selectivity, and suggested avenues for optimization of efficacy as a reasonable working hypothesis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
4. Dimeric isoxazolyl-1,4-dihydropyridines have enhanced binding at the multi-drug resistance transporter.
- Author
-
Steiger SA, Li C, Backos DS, Reigan P, and Natale NR
- Subjects
- Animals, Crystallography, X-Ray, Dimerization, Drug Resistance, Multiple drug effects, Humans, Isoxazoles chemistry, Isoxazoles pharmacology, Mice, Molecular Docking Simulation, Protein Binding, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Dihydropyridines chemistry, Dihydropyridines pharmacology
- Abstract
A series of dimeric isoxazolyl-1,4-dihydropyridines (IDHPs) were prepared by click chemistry and examined for their ability to bind the multi-drug resistance transporter (MDR-1), a member of the ATP-binding cassette superfamily (ABC). Eight compounds in the present study exhibited single digit micromolar binding to this efflux transporter. One monomeric IDHP m-Br-1c, possessed submicromolar binding of 510nM at MDR-1. Three of the dimeric IDHPs possessed <1.5µM activity, and 4b and 4c were observed to have superior binding selectivity compared to their corresponding monomers verses the voltage gated calcium channel (VGCC). The dimer with the best combination of activity and selectivity for MDR-1 was analog 4c containing an m-Br phenyl moiety in the 3-position of the isoxazole, and a tether with five ethyleneoxy units, referred to herein as Isoxaquidar. Two important controls, mono-triazole 5 and pyridine 6, also were examined, indicating that the triazole - incorporated as part of the click assembly as a spacer - contributes to MDR-1 binding. Compounds were also assayed at the allosteric site of the mGluR5 receptor, as a GPCR 7TM control, indicating that the p-Br IDHPs 4d, 4e and 4f with tethers of from n=2 to 5 ethylenedioxy units, had sub-micromolar affinities with 4d being the most efficacious at 193nM at mGluR5. The results are interpreted using a docking study using a human ABC as our current working hypothesis, and suggest that the distinct SARs emerging for these three divergent classes of biomolecular targets may be tunable, and amenable to the development of further selectivity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
5. 4-Isoxazolyl-1,4-dihydropyridines exhibit binding at the multidrug-resistance transporter.
- Author
-
Hulubei V, Meikrantz SB, Quincy DA, Houle T, McKenna JI, Rogers ME, Steiger S, and Natale NR
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, Caco-2 Cells, Calcium Channels chemistry, Calcium Channels metabolism, Dicarbethoxydihydrocollidine chemical synthesis, Dicarbethoxydihydrocollidine chemistry, Dicarbethoxydihydrocollidine metabolism, Dihydropyridines chemistry, Humans, Isoxazoles chemical synthesis, Isoxazoles chemistry, Magnetic Resonance Spectroscopy, Models, Chemical, Protein Binding, Structure-Activity Relationship, Thermodynamics, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Dicarbethoxydihydrocollidine analogs & derivatives, Dihydropyridines metabolism, Isoxazoles metabolism
- Abstract
The 4-isoxazolyl-dihydropyridines (IDHPs) exhibit inhibition of the multidrug-resistance transporter (MDR-1), and exhibit an SAR distinct from their activity at voltage gated calcium channels (VGCC). Among the four most active IDHPs, three were branched at C-5 of the isoxazole, including the most active analog, 1k., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
6. Isoxazole analogues bind the system xc- transporter: structure-activity relationship and pharmacophore model.
- Author
-
Patel SA, Rajale T, O'Brien E, Burkhart DJ, Nelson JK, Twamley B, Blumenfeld A, Szabon-Watola MI, Gerdes JM, Bridges RJ, and Natale NR
- Subjects
- Amino Acid Transport System y+ antagonists & inhibitors, Amino Acid Transport System y+ chemistry, Amino Acids chemistry, Amino Acids pharmacology, Binding Sites, Cell Line, Tumor, Crystallography, X-Ray, Glutamic Acid metabolism, Humans, Hydrazones chemistry, Hydrazones pharmacology, Models, Molecular, Molecular Structure, Protein Binding, Structure-Activity Relationship, Amino Acid Transport System y+ metabolism, Cell Membrane Permeability drug effects, Isoxazoles chemistry, Isoxazoles pharmacology
- Abstract
Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc-. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc-, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y=Y'=3,5-(CF(3))(2), which both inhibited glutamate uptake by the System xc- transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
7. Design, synthesis and biological evaluation of a novel class of anticancer agents: anthracenylisoxazole lexitropsin conjugates.
- Author
-
Han X, Li C, Mosher MD, Rider KC, Zhou P, Crawford RL, Fusco W, Paszczynski A, and Natale NR
- Subjects
- Anthracenes chemistry, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Azoles chemistry, Cell Line, Tumor, Drug Design, Drug Screening Assays, Antitumor, Humans, Magnetic Resonance Spectroscopy, Netropsin chemical synthesis, Netropsin chemistry, Netropsin pharmacology, Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship, Anthracenes chemical synthesis, Anthracenes pharmacology, Antineoplastic Agents chemical synthesis, Azoles chemical synthesis, Azoles pharmacology, Netropsin analogs & derivatives
- Abstract
The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs) (While not a strict acronym, the designation AIM is in honor of the memory of Professor Albert I. Meyers.) (22-33) are described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinreb's amide formation technique, using SmCl(3) as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institute's (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented.
- Published
- 2009
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.