Chemistry Commons^™

Mmp-13 Selective Α-Sulfone Hydroxamates: A Survey Of P1' Heterocyclic Amide Isosteres, Thomas E. Barta, Daniel P. Becker, Louis J. Bedell, Alan M. Easton

Chemistry: Faculty Publications and Other Works

Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.(1a) Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented.

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

Chemistry: Faculty Publications and Other Works

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.

Electrochemical Studies Of Quinone On Clay-Modified Platinum Electrodes, Thomas Edward Nelson

Theses (2 year embargo)

No abstract provided.

The Unsuspected Pathway Of The Allosteric Transition In Hemoglobin, Stefan Fischer, Kenneth W. Olsen, Kwangho Nam, Martin Karplus

Chemistry: Faculty Publications and Other Works

Large conformational transitions play an essential role in the function of many proteins, but experiments do not provide the atomic details of the path followed in going from one end structure to the other. For the hemoglobin tetramer, the transition path between the unliganded (T) and tetraoxygenated (R) structures is not known, which limits our understanding of the cooperative mechanism in this classic allosteric system, where both tertiary and quaternary changes are involved. The conjugate peak refinement algorithm is used to compute an unbiased minimum energy path at atomic detail between the two end states. Although the results confirm some …

Steps Toward Accurate Large Area Analyzes Of Genesis Solar Wind Samples: Evaluation Of Surface Cleaning Methods Using Total Reflection X-Ray Fluorescence Spectrometry, Martina Schmeling, Donald S. Burnett, Amy Jg Jurewicz, Igor V. Veryovkin

Chemistry: Faculty Publications and Other Works

Total reflection X-ray fluorescence spectrometry (TXRF) was used to analyze residual surface contamination on Genesis solar wind samples and to evaluate different cleaning methods. The Genesis mission collected solar wind during a period of 854 days by embedding the charged particles into collectors made of various ultra clean materials such as silicon, sapphire and silicon-on-sapphire. The sample return capsule unexpectedly crashed on return to Earth fracturing the collectors and exposing them to the desert soil of the landing side. The ubiquitous contaminants are separated from the atoms of solar wind by only 5-15 nm, presenting significant challenges for solar wind …

Synthesis Of An Ortho-Triazacyclophane: N,N',N''-Trimethyltribenzo-1,4,7-Triazacyclononatriene, Andria M. Panagopoulos, Matthias Zeller, Daniel P. Becker

Chemistry: Faculty Publications and Other Works

N,N',N''-Trimethyltribenzo-1,4,7-triazacyclononatriene has been synthesized via sequential palladium-catalyzed Buchwald-Hartwig N-arylation reactions affording the 9-membered triaza o-cyclophane in 35% overall yield. An X-ray crystal structure shows the new cyclophane to have a C(2)-symmetric saddle conformation, as compared to the crown conformation exhibited by the related carbocyclic cyclotriveratrylene (CTV).

Orally Active Mmp-1 Sparing Α-Tetrahydropyranyl And Α-Piperidinyl Sulfone Matrix Metalloproteinase (Mmp) Inhibitors With Efficacy In Cancer, Arthritis, And Cardiovascular Disease, Daniel P. Becker, Thomas E. Barta, Louis J. Bedell, Terri L. Boehm

Chemistry: Faculty Publications and Other Works

α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMP’s-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds.

Palladium(Ii)-Catalyzed Dicarboxymethylation Of Chiral Allylic Alcohols: Chirality Transfer Affording Optically Active Diesters Containing Three Contiguous Chiral Centers, Othman Hamed, Patrick M. Henry, Daniel P. Becker

Chemistry: Faculty Publications and Other Works

This manuscript describes the extension of Stille’s palladium-catalyzed olefin dicarbonylation reaction to chiral allylic alcohols with chirality transfer to afford the corresponding chiral alcohol functionalized with bis-carbomethoxy esters, containing three contiguous chiral centers, in good to excellent diastereoselectivities (78–98%).

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

Chemistry: Faculty Publications and Other Works

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.

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

Chemistry: Faculty Publications and Other Works

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.

Inhibitors Of Bacterial N-Succinyl-L,L-Diaminopimelic Acid Desuccinylase (Dape) And Demonstration Of In Vitro Antimicrobial Activity, Danuta Gillner, Nicola Armoush, Richard C. Holz, Daniel P. Becker

Chemistry: Faculty Publications and Other Works

The dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE) is a critical bacterial enzyme for the construction of the bacterial cell wall. A screen biased toward compounds containing zinc-binding groups (ZBG’s) including thiols, carboxylic acids, boronic acids, phosphonates and hydroxamates has delivered a number of micromolar inhibitors of DapE from Haemophilus influenzae, including the low micromolar inhibitor l-captopril (IC50 = 3.3 μM, Ki = 1.8 μM). In vitro antimicrobial activity was demonstrated for l-captopril against Escherichia coli.

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

Chemistry: Faculty Publications and Other Works

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 …

Universal Scaling Of Nonequilibrium Transport In The Kondo Regime Of Single Molecule Devices, G D. Scott, Z K. Keane, Jacob W. Ciszek, J M. Tour, D Natelson

Chemistry: Faculty Publications and Other Works

Scaling laws and universality are often associated with systems exhibiting emergent phenomena possessing a characteristic energy scale. We report nonequilibrium transport measurements on two different types of single molecule transistor devices in the Kondo regime. The conductance at low bias and temperature adheres to a scaling function characterized by two parameters. This result, analogous to that reported recently in semiconductor dots with Kondo temperatures two orders of magnitude lower, demonstrates the universality of this scaling form. We compare the extracted values of the scaling coefficients to previous experimental and theoretical results.

An Aza-Cyclophane Stacked In Racemic Columnar Assemblies: Whole-Molecule Disorder In A Two-Dimensional Solid Solution, M Zeller

Chemistry: Faculty Publications and Other Works

The oxime derivative of [1.1.1]cyclophane cyclotriveratrylene (CTV) was ring expanded utilizing a Beckmann rearrangement to provide a ten-membered N-acetyl macrocyclic amide that crystallizes as a chloroform monosolvate in columnar assemblies manifesting an unusual disorder within the crystal. Columns made up of this structure consist of infinite columnar assemblies of alternating D and L enantiomers and therefore necessarily are made up of a racemate, yet the chiralities of individual molecules in adjacent columns are independent of one another, leading to the overall formation of a two-dimensional solid solution. The random arrangement of the columns within the structure leads to the …

Beckmann Rearrangement Of Cyclotriveratrylene (Ctv) Oxime: Tandem Beckmann-Electrophilic Aromatic Addition, Marlon R. Lutz Jr., Matthias Zeller, Daniel P. Becker

Chemistry: Faculty Publications and Other Works

The Beckmann rearrangement has been performed on the oxime of cyclotriveratrylene (CTV) with thionyl chloride affording the ring-expanded 10-membered ring amide exclusively in high yield. Modified conditions afford a helical pentacycle derived from an unusual tandem Beckmann rearrangement and electrophilic aromatic addition followed by demethylation and tautomerization.

Synthesis Of Substituted 2-Amino-Cyclobutanones, Nicola Armoush, Preeti Syal, Daniel P. Becker

Chemistry: Faculty Publications and Other Works

A series of weakly nucleophilic nitrogen derivatives including carbamates, amides, sulfonamides, and anilines were reacted with 1,2‐bis(trimethylsilyloxy)cyclobutene under acidic conditions to afford various substituted 2‐aminocyclobutanone derivatives 3a–i in modest to excellent yields.

Simultaneous Measurements Of Electronic Conduction And Raman Response In Molecular Junctions, Daniel R. Ward, Naomi J. Halas, James M. Tour, Jacob W. Ciszek, Yanpeng Wu, Peter Nordlander, Douglas Natelson

Chemistry: Faculty Publications and Other Works

Electronic conduction through single molecules is affected by the molecular electronic structure as well as by other information that is extremely difficult to assess, such as bonding geometry and chemical environment. The lack of an independent diagnostic technique has long hampered single-molecule conductance studies. We report simultaneous measurement of the conductance and the Raman spectra of nanoscale junctions used for single-molecule electronic experiments. Blinking and spectral diffusion in the Raman response of both para-mercaptoaniline and a fluorinated oligophenylyne ethynylene correlate in time with changes in the electronic conductance. Finite difference time domain calculations confirm that these correlations do not result …

Isolation Of The Saddle And Crown Conformers Of Cyclotriveratrylene (Ctv) Oxime, Marlon R. Lutz Jr., David C. French, Peter Rehage, Daniel P. Becker

Chemistry: Faculty Publications and Other Works

The oxime of cyclotriveratrylene (CTV) has been prepared and the individual crown and saddle conformers were isolated and characterized. The equilibrium constant was measured in CDCl3 and in DMSO-d6 and was shown to favor the crown conformer by an order of magnitude in DMSO-d6, relative to an approximately equal mixture at equilibrium in CDCl3. The time course for interconversion of the saddle to the crown was measured by 1H NMR and the t1/2 of the saddle was determined to be 2.45 h in CDCl3 at 25 °C, and 3.71 h in DMSO-d6.

2,3,8,12,13-Penta­Meth­Oxy-5h-Dibenzo­[C,N]Acridin-7(6h)-One Toluene Solvate, Marlon R. Lutz Jr, Matthias Zeller, Daniel P. Becker Ph.D.

Chemistry: Faculty Publications and Other Works

The title compound, C26H25NO6·C7H8, formed by an unexpected tandem reaction of Beckmann rearrangement, electrophilic aromatic addition and subsequent demethyl­ation, was crystallized as its toluene solvate. The crystal under investigation was found to be nonmerohedrally twinned by a rotation around the reciprocal axis [100]; the twin ratio refined to 0.688 (2):0.312 (2). The mol­ecule exhibits an unusual helical arrangement of three six-membered rings that are all connected at one central C atom. The helix effectively performs one full turn around this atom, and the thread pitch, as defined by the distance of the terminal C atoms of the helix, is 4.98 …

Three-Terminal Devices To Examine Single Molecule Conductance Switching, Z K. Keane, Jacob W. Ciszek, J M. Tour, D Natelson

Chemistry: Faculty Publications and Other Works

We report electronic transport measurements of single-molecule transistor devices incorporating bipyridyl-dinitro oligophenylene-ethynylene dithiol (BPDN-DT), a molecule known to exhibit conductance switching in other measurement configurations. We observe hysteretic conductance switching in 8% of devices with measurable currents, and find that dependence of the switching properties on gate voltage is rare when compared to other single-molecule transistor devices. This suggests that polaron formation is unlikely to be responsible for switching in these devices. We discuss this and alternative switching mechanisms.

Single-Molecule Transistors: Electron Transfer In The Solid State, Douglas Natelson, Lam H. Yu, Jacob W. Ciszek, Zachary K. Keane, James M. Tour

Chemistry: Faculty Publications and Other Works

Single-molecule transistors (SMTs) incorporating individual small molecules are unique tools for examining the fundamental physics and chemistry of electronic transport in molecular systems at the single nanometer scale. We describe the fabrication and characterization of such devices, and the synthesis and surface attachment chemistry of novel transition metal complexes that have been incorporated into such SMTs. We present gate-modulated inelastic electron tunneling vibrational spectroscopy of single molecules, strong Kondo physics (T_K ∼ 75 K) as evidence of excellent molecule/electrode electronic coupling, and a demonstration that covalent attachment chemistry can produce SMTs that survive repeated thermal cycling to room …

Pyrrolizidine Esters And Amides As 5-Ht4 Receptor Agonists And Antagonists, Daniel Becker, Daniel L. Flynn, Alan E. Moormann, Roger Nosal

Chemistry: Faculty Publications and Other Works

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 …

Controlling Charge Injection In Organic Field-Effect Transistors Using Self-Assembled Monolayers, B H. Hamadani, D A. Corley, Jacob W. Ciszek, J M. Tour, D Natelson

Chemistry: Faculty Publications and Other Works

We have studied charge injection across the metal/organic semiconductor interface in bottom-contact poly(3-hexylthiophene) (P3HT) field-effect transistors, with Au source and drain electrodes modified by self-assembled monolayers (SAMs) prior to active polymer deposition. By using the SAM to engineer the effective Au work function, we markedly affect the charge injection process. We systematically examine the contact resistivity and intrinsic channel mobility and show that chemically increasing the injecting electrode work function significantly improves hole injection relative to untreated Au electrodes.

Kondo Resonances And Anomalous Gate Dependence In The Electrical Conductivity Of Single-Molecule Transistors, L H. Yu, Z K. Keane, Jacob W. Ciszek, L Cheng, J M. Tour, T Baruah, M R. Pederson, D Natelson

Chemistry: Faculty Publications and Other Works

We report Kondo resonances in the conduction of single-molecule transistors based on transition metal coordination complexes. We find Kondo temperatures in excess of 50 K, comparable to those in purely metallic systems. The observed gate dependence of the Kondo temperature is inconsistent with observations in semiconductor quantum dots and a simple single-dot-level model. We discuss possible explanations of this effect, in light of electronic structure calculations.

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

Chemistry: Faculty Publications and Other Works

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.

Inelastic Electron Tunneling Via Molecular Vibrations In Single-Molecule Transistors, L H. Yu, Z K. Keane, Jacob W. Ciszek, L Cheng, M P. Stewart, J M. Tour, D Natelson

Chemistry: Faculty Publications and Other Works

In single-molecule transistors, we observe inelastic cotunneling features that correspond energetically to vibrational excitations of the molecule, as determined by Raman and infrared spectroscopy. This is a form of inelastic electron tunneling spectroscopy of single molecules, with the transistor geometry allowing in situ tuning of the electronic states via a gate electrode. The vibrational features shift and change shape as the electronic levels are tuned near resonance, indicating significant modification of the vibrational states. When the molecule contains an unpaired electron, we also observe vibrational satellite features around the Kondo resonance.

Azaadamantane Benzamide 5-Ht4 Agonists: Gastrointestinal Prokinetic Sc-54750, Daniel Becker, Daniel L. Flynn, Robert L. Shone, Gary Gullikson

Chemistry: Faculty Publications and Other Works

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.

Bridgehead-Methyl Analog Of Sc-53116 As A 5-Ht4 Agonist, Daniel Becker, Daniel L. Flynn, Clara I. Villamil

Chemistry: Faculty Publications and Other Works

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.

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

Chemistry: Faculty Publications and Other Works

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.

Α-Amino-Β-Sulphone Hydroxamates As Potent Mmp-13 Inhibitors That Spare Mmp-1, Daniel P. Becker Ph.D., Thomas E. Barta, Louis Bedell, Gary Decrescenzo, John Freskos, Daniel P. Getman, Susan L. Hockerman, Madeleine Li, Pramod Mehta, Brent Mischke, Grace E. Munie, Craig Swearingen, Clara I. Villamil

Chemistry: Faculty Publications and Other Works

A series of α-amino-β-sulphone hydroxamates was prepared and evaluated for potency versus MMP-13 and selectivity versus MMP-1. Various substituents were employed on the α-amino group (P1 position), as well as different groups attached to the sulphone group extending into P1′. Low nanomolar potency was obtained for MMP-13 with selectivity versus MMP-1 of >1000× for a number of analogues.

α-Amino-β-sulphone hydroxamates were prepared, which are potent MMP-13 inhibitors with selectivity versus MMP-1 of >1000× for a number of analogues. Selected compounds exhibited oral bioavailability.