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Articles 1 - 20 of 20
Full-Text Articles in Physical Sciences and Mathematics
Alpha-Alkyl-Alpha-Amino-Beta-Sulphone Hydroxamates As Potent Mmp Inhibitors That Spare Mmp-1, Daniel Becker, Gary A. Decrescenzo, John Freskos, Daniel P. Getman
Alpha-Alkyl-Alpha-Amino-Beta-Sulphone Hydroxamates As Potent Mmp Inhibitors That Spare Mmp-1, Daniel Becker, Gary A. Decrescenzo, John Freskos, Daniel P. Getman
Daniel P. Becker
A series of α-alkyl-α-amino-β-sulphone hydroxamates was prepared and evaluated for potency versus MMP-2 and MMP-13, and for selectivity versus MMP-1. Low nanomolar potency was obtained with selectivity versus MMP-1 ranging from >10 to >1000. Selected compounds were orally bioavailable.
Rearrangement Of Cyclotriveratrylene (Ctv) Diketone: 9,10-Diarylanthracenes With Oled Applications, Samuel R. Sarsah, Marlon R. Lutz Jr., Matthias Zeller, David S. Crumrine, Daniel Becker
Rearrangement Of Cyclotriveratrylene (Ctv) Diketone: 9,10-Diarylanthracenes With Oled Applications, Samuel R. Sarsah, Marlon R. Lutz Jr., Matthias Zeller, David S. Crumrine, Daniel Becker
Daniel P. Becker
Electroluminescent 9,10-diaryl anthracenes have been shown to be promising host and hole-transporting materials in organic electroluminescence due to their high thermal stability, electrochemical reversibility, and wide band gap useful for organic light-emitting diodes (OLEDs), especially blue OLEDs. Oxidation of cyclotriveratrylene (CTV) to the corresponding diketone and subsequent bromination resulted in an unexpected rearrangement to a highly functionalized 9-aryl-10-bromoanthracene derivative, which was employed in Suzuki couplings to synthesize a series of 9,10-diaryl compounds that are structural analogues of anthracene derivatives used in the preparation of OLEDs but are more highly functionalized, including electron-donating methoxy groups in addition to substitution by a …
Synthetic Strategies For The Construction Of Enantiomeric Azanoradamantanes, Daniel Becker, Roger Nosal, Daniel L. Zabrowski, Daniel Flynn
Synthetic Strategies For The Construction Of Enantiomeric Azanoradamantanes, Daniel Becker, Roger Nosal, Daniel L. Zabrowski, Daniel Flynn
Daniel P. Becker
The amino azanoradamantane hexahydro-2,5b-methano-IH-3aS,3aa,6aa-cyclopenta-[clpyrrole-4a-amine 1and the corresponding enantiomer ent-1 have been prepared along with benzamide derivatives SC-52491and SC-52490, respectively, which are of pharmaceutical interest. The key meso-azabicyclo[3.3.0] intermediate 3 was prepared via three separate routes: a [3+2] cycloaddition route, a radical cyclization/ionic cyclization route, and a reductive Pauson-Khand route.
Synthesis, Crystal Structure, And Rearrangements Of Ortho-Cyclophane Cyclotetraveratrylene (Cttv) Tetraketone, Marlon R. Lutz Jr., Matthias Zeller, Samuel R.S. Sarsah, Artur Filipowicz, Hailey Wouters, Daniel Becker
Synthesis, Crystal Structure, And Rearrangements Of Ortho-Cyclophane Cyclotetraveratrylene (Cttv) Tetraketone, Marlon R. Lutz Jr., Matthias Zeller, Samuel R.S. Sarsah, Artur Filipowicz, Hailey Wouters, Daniel Becker
Daniel P. Becker
Oxidation of cyclotetraveratrylene (CTTV) with potassium permanganate in pyridine under reflux gave tetraketone (the [14]ketonand) 3 which exists as a previously unobserved barrel conformation with S4symmetry in the crystal structure, although the more familiar ‘boat’ conformer was shown by semi-empirical AM1 calculations to be 3.03 kcal/mol lower in energy. In addition to CTTV tetraketone 3, an isomeric bis-spirolactone 4 was isolated from the basic oxidation conditions, analogous to the product of trans-annular attack and rearrangement observed with oxidation of cyclotriveratrylene, whereas in acid at elevated temperatures, tetraketone 3 underwent a very efficient rearrangement and decarboxylation to afford the highly symmetric …
Orally Bioavailable Dual Mmp-1/Mmp-14 Sparing, Mmp-13 Selective Alpha-Sulfone Hydroxamates, Daniel Becker, Stephen A. Kolodziej, Susan L. Hockerman, Terri L. Boehm, Jeffery N. Carroll
Orally Bioavailable Dual Mmp-1/Mmp-14 Sparing, Mmp-13 Selective Alpha-Sulfone Hydroxamates, Daniel Becker, Stephen A. Kolodziej, Susan L. Hockerman, Terri L. Boehm, Jeffery N. Carroll
Daniel P. Becker
A series of phenyl piperidine α-sulfone hydroxamate derivatives has been prepared utilizing a combination of solution-phase and resin-bound library technologies to afford compounds that are potent and highly selective for MMP-13, are dual-sparing of MMP-1 and MMP-14 (MT1-MMP) and exhibit oral bioavailability in rats.
Enantioselective Synthesis Of Dual Serotonergic Azanoradamantane Sc-52491, Daniel Becker, Robert K. Husa, Alan E. Moormann, Clara I. Villamil
Enantioselective Synthesis Of Dual Serotonergic Azanoradamantane Sc-52491, Daniel Becker, Robert K. Husa, Alan E. Moormann, Clara I. Villamil
Daniel P. Becker
A racemic synthesis of azanoradamantane (±)-3 was accomplished via Yamamoto's MAD-catalyzed Diels-Alder protocol. Subsequently, a scalable asymmetric synthesis of azanoradamantane benzamide SC-52491 was carried out employing Helmchen's asymmetric Diels-Alder methodology to construct all four contiguous asymmetric centers with the correct relative stereochemistry and in 99.3% e.e.
Large-Scale Structural Rearrangement Of A Serine Hydrolase From Francisella Tularensis Facilitates Catalysis, Ekaterina V. Filippova, Leigh A. Watson, Misty L. Kuhn, Brett Geissler, Daniel Becker
Large-Scale Structural Rearrangement Of A Serine Hydrolase From Francisella Tularensis Facilitates Catalysis, Ekaterina V. Filippova, Leigh A. Watson, Misty L. Kuhn, Brett Geissler, Daniel Becker
Daniel P. Becker
Tularemia is a deadly, febrile disease caused by infection by the gram-negative bacterium, Francisella tularensis. Members of the ubiquitous serine hydrolase protein family are among current targets to treat diverse bacterial infections. Herein we present a structural and functional study of a novel bacterial carboxylesterase (FTT258) from F. tularensis, a homologue of human acyl protein thioesterase (hAPT1). The structure of FTT258 has been determined in multiple forms, and unexpectedly large conformational changes of a peripheral flexible loop occur in the presence of a mechanistic cyclobutanone ligand. The concomitant changes in this hydrophobic loop and the newly exposed hydrophobic substrate binding …
Mmp-13 Selective Isonipecotamide Alpha-Sulfone Hydroxamates, Stephen A. Kolodziej, Susan L. Hockerman, Gary A. Decrescenzo, Joseph J. Mcdonald, Grace E. Munie, Theresa R. Fletcher, Nathan Stehle, Craig Swearingen, Daniel Becker
Mmp-13 Selective Isonipecotamide Alpha-Sulfone Hydroxamates, Stephen A. Kolodziej, Susan L. Hockerman, Gary A. Decrescenzo, Joseph J. Mcdonald, Grace E. Munie, Theresa R. Fletcher, Nathan Stehle, Craig Swearingen, Daniel Becker
Daniel P. Becker
A series of N-aryl isonipecotamide α-sulfone hydroxamate derivatives has been prepared utilizing a combination of solution-phase and resin-bound library technologies to afford compounds that are potent and highly selective for MMP-13.
Asymmetric Α-Hydroxy Ketone Synthesis By Direct Ketone Oxidation Using A Bimetallic Palladium(Ii) Complex, Othman A. Hamed, Arab El-Qisairi, Hanan Qaseer, Emad M. Hamed, Patrick M. Henry, Daniel Becker
Asymmetric Α-Hydroxy Ketone Synthesis By Direct Ketone Oxidation Using A Bimetallic Palladium(Ii) Complex, Othman A. Hamed, Arab El-Qisairi, Hanan Qaseer, Emad M. Hamed, Patrick M. Henry, Daniel Becker
Daniel P. Becker
No abstract provided.
Mmp-13 Selective Alpha-Sulfone Hydroxamates: Identification Of Selective P1' Amides, Yvette M. Fobian, John N. Freskos, Thomas E. Barta, Louis J. Bedell, Daniel Becker
Mmp-13 Selective Alpha-Sulfone Hydroxamates: Identification Of Selective P1' Amides, Yvette M. Fobian, John N. Freskos, Thomas E. Barta, Louis J. Bedell, Daniel Becker
Daniel P. Becker
Continuing our interest in designing compounds preferentially potent and selective for MMP-13, we report on a series of hydroxamic acids with a flexible amide P1' substituents. We identify an amide which spares both MMP-1 and -14, and shows >500 fold selectivity for MMP-13 versus MMP-2 and -8.
Apparent Alkyl Transfer And Phenazine Formation Via An Aryne Intermediate, Daniel Becker, Andria M. Panagopoulos, Doug Steinman, Alexandra Goncharenko, Kyle Geary, Carlene Schleisman, Elizabeth Spaargaren, Matthias Zeller
Apparent Alkyl Transfer And Phenazine Formation Via An Aryne Intermediate, Daniel Becker, Andria M. Panagopoulos, Doug Steinman, Alexandra Goncharenko, Kyle Geary, Carlene Schleisman, Elizabeth Spaargaren, Matthias Zeller
Daniel P. Becker
Treatment of chlorotriaryl derivatives 3a and 3d or fluorotriaryl derivatives 3b and 3e with potassium diisopropylamide afforded alkyl-shifted phenazine derivatives 5a/5b, rather than the expected 9-membered triazaorthocyclophane 2a. The phenazine derivatives were isolated in 78–98% yield depending on the halogen and alkyl group present. In the absence of the halogen (chloro or fluoro), the apparent alkyl shift proceeds more slowly and cannot proceed via the intermediacy of the aryne intermediate. Mechanistic possibilities include intramolecular nucleophilic attack on an aryne intermediate leading to a zwitterionic intermediate and alkyl transfer via a 5-endo-tet process, or via a Smiles rearrangement.
Bridgehead-Methyl Analog Of Sc-53116 As A 5-Ht4 Agonist, Daniel Becker, Daniel L. Flynn, Clara I. Villamil
Bridgehead-Methyl Analog Of Sc-53116 As A 5-Ht4 Agonist, Daniel Becker, Daniel L. Flynn, Clara I. Villamil
Daniel P. Becker
Pyrrolizidine benzamide (±)-2, the bridgehead-methyl analog of SC-53116, was prepared and evaluated for 5-HT4 agonism activity in the rat tunica muscularis (TMM) mucosae assay. Compound (±)-2 has an EC50 of 449 nM in the TMM assay, as compared to 23 nM for SC-53116, and 66 nM for the racemate of SC-53116.
Synthesis And Structure-Activity Relationships Of Ss- And A-Piperidine Sulphone Hydroxamic Acid Matrix Metalloproteinase Inhibitors With Oral Antitumor Efficacy, Daniel Becker, Clara I. Villamil, Thomas E. Barta, Louis J. Bedell
Synthesis And Structure-Activity Relationships Of Ss- And A-Piperidine Sulphone Hydroxamic Acid Matrix Metalloproteinase Inhibitors With Oral Antitumor Efficacy, Daniel Becker, Clara I. Villamil, Thomas E. Barta, Louis J. Bedell
Daniel P. Becker
α-Piperidine-β-sulfone hydroxamate derivatives were explored that are potent for matrix metalloproteinases (MMP)-2, -9, and -13 and are sparing of MMP-1. The investigation of the β-sulfones subsequently led to the discovery of hitherto unknown α-sulfone hydroxamates that are superior to the corresponding β-sulfones in potency for target MMPs, selectivity vs MMP-1, and exposure when dosed orally. α-Piperidine-α-sulfone hydroxamate 35f (SC-276) was advanced through antitumor and antiangiogenesis assays and was selected for development. Compound 35f demonstrates excellent antitumor activity vs MX-1 breast tumor in mice when dosed orally as monotherapy or in combination with paclitaxel.
A Thermodynamic And Kinetic Characterization Of The Solvent Dependence Of The Saddle-Crown Equilibrium Of Cyclotriveratrylene (Ctv) Oxime, David C. French, Marlon R. Lutz Jr., Chichi Lu, Matthias Zeller, Daniel Becker
A Thermodynamic And Kinetic Characterization Of The Solvent Dependence Of The Saddle-Crown Equilibrium Of Cyclotriveratrylene (Ctv) Oxime, David C. French, Marlon R. Lutz Jr., Chichi Lu, Matthias Zeller, Daniel Becker
Daniel P. Becker
The equilibration of the saddle conformer of cyclotriveratrylene (CTV) oxime to the corresponding crown conformer was followed by (1)H NMR in five separate solvents, and kinetic and thermodynamic parameters were determined from the NMR data. The oxime saddle conformers of 3 are favored in CDCl(3) (K(eq) = [saddle]/[crown] = 1.4), whereas the CTV oxime crown conformer 3a is favored in three more polar solvents studied (DMSO-d(6), acetonitrile-d(3), acetone-d(6)). Surprisingly, the CTV oxime crown conformer is also slightly favored in the nonpolar solvent 1,4-dioxane-d(8). These behaviors are discussed in terms of hydrogen bonding, entropy, and possible host-guest considerations. An X-ray crystal …
Isolation Of A Highly Functionalized Troeger’S Base Derivative Via A Novel Reaction, Daniel Becker, Patricia M. Finnegan, Paul W. Collins
Isolation Of A Highly Functionalized Troeger’S Base Derivative Via A Novel Reaction, Daniel Becker, Patricia M. Finnegan, Paul W. Collins
Daniel P. Becker
Heating a solution of methyl 5-chloro-4-[(ethoxyoxoacetyl) amino]-2-methoxybenz-oate, 3 in DMSO gave rise to the formation of the highly substitute
Serotonin 5-Ht4 Agonist Activity Of A Series Of Meso-Azanoradamantane Benzamides, Daniel Becker, Roger Nosal, Clara I. Villamil, Gary Gullikson
Serotonin 5-Ht4 Agonist Activity Of A Series Of Meso-Azanoradamantane Benzamides, Daniel Becker, Roger Nosal, Clara I. Villamil, Gary Gullikson
Daniel P. Becker
A series of meso-amino(methyl)azanoradamantane benzamides has been prepared and evaluated for 5-HT4agonism activity in the rat tunica muscularis mucosae (TMM) assay. Compound 8i is the most potent 5-HT4agonist in the series, with an EC50 of 217 nM.
Preparation Of Trifluoromethyl Lactol Derivatives Via Base Initiated Cyclobutanol Ring Opening To A Laterally Lithiated Trifluoromethyl Ketone, Daniel Becker, Daniel L. Flynn
Preparation Of Trifluoromethyl Lactol Derivatives Via Base Initiated Cyclobutanol Ring Opening To A Laterally Lithiated Trifluoromethyl Ketone, Daniel Becker, Daniel L. Flynn
Daniel P. Becker
Benzocyclobutenone derivatives 4 are converted to the corresponding trifluoromethylcyclobutanols 5 by treatment with trifluoromethyltrimethylsilane in the presence of tetra-n-butylammonium fluoride. These trifluoromethylcyclobutanol derivatives are then treated with LiTMP in the presence of aromatic aldehydes to afford trifluoromethyllactols 6 via a laterally-lithiated trifluoromethylketone intermediate.
Azaadamantane Benzamide 5-Ht4 Agonists: Gastrointestinal Prokinetic Sc-54750, Daniel Becker, Daniel L. Flynn, Robert L. Shone, Gary Gullikson
Azaadamantane Benzamide 5-Ht4 Agonists: Gastrointestinal Prokinetic Sc-54750, Daniel Becker, Daniel L. Flynn, Robert L. Shone, Gary Gullikson
Daniel P. Becker
Azaadamantanone 1 was converted to a series of aminoazaadamantane benzamides 9a–d, which were profiled for serotonin receptor activity. Aminomethylazaadamantane SC-54750 is a potent 5-HT4 agonist and 5-HT3 antagonist with in vivo efficacy in gastroparesis models and also inhibits cisplatin-induced emesis.
One-Pot Preparation Of 1,3-Dihydro-1- (Trifluoromethyl)Isobenzofuran-1-Ol Derivatives From 1,2-Dibromobenzene, Daniel Becker, Hui Li, Daniel L. Flynn
One-Pot Preparation Of 1,3-Dihydro-1- (Trifluoromethyl)Isobenzofuran-1-Ol Derivatives From 1,2-Dibromobenzene, Daniel Becker, Hui Li, Daniel L. Flynn
Daniel P. Becker
A one-pot method for the preparation of 1,3-dihydro-1-(trifluoromethyl)isobenzofuran-1-ol derivatives 5from 1,2-dibromobenzene is described
Pyrrolizidine Esters And Amides As 5-Ht4 Receptor Agonists And Antagonists, Daniel Becker, Daniel L. Flynn, Alan E. Moormann, Roger Nosal
Pyrrolizidine Esters And Amides As 5-Ht4 Receptor Agonists And Antagonists, Daniel Becker, Daniel L. Flynn, Alan E. Moormann, Roger Nosal
Daniel P. Becker
A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay. Several pyrrolizidine derivatives were identified with high affinity for the 5-HT(4) receptor, including benzamide 12a (SC-53116), a potent and selective 5-HT(4) partial agonist that exhibits efficacy in promoting antral contractions and activity in promoting gastric emptying in canine models. Also discovered were 5-HT(4) receptor antagonists, including imidazopyridine amide 12h (SC-53606), which is a potent and selective 5-HT(4) receptor antagonist with …