Small Molecule Regulation of Self-Association and Catalytic Activity in a Supramolecular Coordination Complex

2014 ◽  
Vol 136 (12) ◽  
pp. 4689-4696 ◽  
Author(s):  
C. Michael McGuirk ◽  
Charlotte L. Stern ◽  
Chad A. Mirkin
Keyword(s):  
Catalytic Activity ◽  
Small Molecule ◽  
Coordination Complex ◽  
Supramolecular Coordination ◽  
Self Association

Selective Formation of a Supramolecular Coordination Complex in the Nanometre Scale with a Ferrocene-based Phospholane Ligand

2021 ◽  
Author(s):  
Reinhard Hoy ◽  
Toni Grell ◽  
Peter Lönnecke ◽  
Evamarie Hey-Hawkins
Keyword(s):  
Coordination Complex ◽  
Supramolecular Coordination ◽  
Selective Formation

A straightforward synthesis of the tetradentate phospholane ligand 1 is reported. The 2:1 [M:L] reaction of 1 with [AuCl(tht)] (tht = tetrahydrothiophen) resulted in a 4:2 [M:L] supramolecular coordination complex...

scholarly journals In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice

2020 ◽  
Vol 73 (1) ◽  
pp. 147-161 ◽  
Author(s):  
Eliot J. Davidowitz ◽  
Pavan K. Krishnamurthy ◽  
Patricia Lopez ◽  
Heidy Jimenez ◽  
Leslie Adrien ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Self Association ◽  
In Vivo Validation

scholarly journals Lewis acid enhancement by hydrogen-bond donors for asymmetric catalysis

Science ◽  
2017 ◽  
Vol 358 (6364) ◽  
pp. 761-764 ◽  
Author(s):  
Steven M. Banik ◽  
Anna Levina ◽  
Alan M. Hyde ◽  
Eric N. Jacobsen
Keyword(s):  
Hydrogen Bond ◽  
Catalytic Activity ◽  
Asymmetric Catalysis ◽  
Small Molecule ◽  
Lewis Acid ◽  
Low Temperatures ◽  
Noncovalent Interactions ◽  
Enantioselective Reactions ◽  
Acidic Complex ◽  
Hydrogen Bond Donors

Small-molecule dual hydrogen-bond (H-bond) donors such as ureas, thioureas, squaramides, and guanidinium ions enjoy widespread use as effective catalysts for promoting a variety of enantioselective reactions. However, these catalysts are only weakly acidic and therefore require highly reactive electrophilic substrates to be effective. We introduce here a mode of catalytic activity with chiral H-bond donors that enables enantioselective reactions of relatively unreactive electrophiles. Squaramides are shown to interact with silyl triflates by binding the triflate counterion to form a stable, yet highly Lewis acidic, complex. The silyl triflate-chiral squaramide combination promotes the generation of oxocarbenium intermediates from acetal substrates at low temperatures. Enantioselectivity in nucleophile additions to the cationic intermediates is then controlled through a network of noncovalent interactions between the squaramide catalyst and the oxocarbenium triflate.

scholarly journals Alanine-Based Chiral Metallogels via Supramolecular Coordination Complex Platforms: Metallogelation Induced Chirality Transfer

2017 ◽  
Vol 140 (9) ◽  
pp. 3257-3263 ◽  
Author(s):  
Yue Sun ◽  
Shuai Li ◽  
Zhixuan Zhou ◽  
Manik Lal Saha ◽  
Sougata Datta ◽  
...  
Keyword(s):  
Coordination Complex ◽  
Chirality Transfer ◽  
Supramolecular Coordination

Identification of disulfide isomerase ERp57 as a target for small molecule cardioprotective agents

RSC Advances ◽  
2015 ◽  
Vol 5 (91) ◽  
pp. 74605-74610 ◽  
Author(s):  
Guozhen Cui ◽  
Luchen Shan ◽  
Ivan Keung Chu ◽  
Guohui Li ◽  
George Pak Heng Leung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Catalytic Activity ◽  
Protective Effect ◽  
Small Molecule ◽  
Inhibitory Effect ◽  
Disulfide Isomerase ◽  
Specific Target ◽  
Proteomic Approach ◽  
Potent Inhibitory Effect

Compound BAA exhibited protective effect against oxidative stress-induced cells injury in H9c2 cardiomyoblast. Chemical proteomic approach identified ERp57 as the specific target for BAA. Furthermore, BAA displayed potent inhibitory effect on the catalytic activity of ERp57.

scholarly journals Small molecule inhibition of Csk alters affinity recognition by T cells

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Boryana N Manz ◽  
Ying Xim Tan ◽  
Adam H Courtney ◽  
Florentine Rutaganira ◽  
Ed Palmer ◽  
...  
Keyword(s):  
T Cells ◽  
Catalytic Activity ◽  
T Cell ◽  
Small Molecule ◽  
Src Family Kinases ◽  
Negative Regulator ◽  
Proliferation Inhibition ◽  
Tcr Signaling ◽  
Cell Responses ◽  
Small Molecule Inhibition

The C-terminal Src kinase (Csk), the primary negative regulator of Src-family kinases (SFK), plays a crucial role in controlling basal and inducible receptor signaling. To investigate how Csk activity regulates T cell antigen receptor (TCR) signaling, we utilized a mouse expressing mutated Csk (CskAS) whose catalytic activity is specifically and rapidly inhibited by a small molecule. Inhibition of CskAS during TCR stimulation led to stronger and more prolonged TCR signaling and to increased proliferation. Inhibition of CskAS enhanced activation by weak but strictly cognate agonists. Titration of Csk inhibition revealed that a very small increase in SFK activity was sufficient to potentiate T cell responses to weak agonists. Csk plays an important role, not only in basal signaling, but also in setting the TCR signaling threshold and affinity recognition.

scholarly journals In vivo validation of therapeutic efficacy of a small molecule lead targeting tau self‐association in JNPL3 mice

2021 ◽  
Vol 17 (S9) ◽  
Author(s):  
James G. Moe ◽  
Patricia Lopez ◽  
Heidy Jimenez ◽  
Leslie Adrien ◽  
John D Eun ◽  
...  
Keyword(s):  
Small Molecule ◽  
Therapeutic Efficacy ◽  
Self Association ◽  
In Vivo Validation

Solvent-Free Assembled Fe-Chitosan Chelates Derived N-Doped Carbon Layer-Encapsulated Fe/Fe3C for ORR and OER

NANO ◽  
2020 ◽  
Vol 15 (06) ◽  
pp. 2050070
Author(s):  
Renxing Huang ◽  
Ying Lei ◽  
Dandan Zhang ◽  
Huaming Xie ◽  
Xingyong Liu ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Transition Metal ◽  
Nitrogen Source ◽  
Small Molecule ◽  
Carbon Layer ◽  
Transition Metal Catalysts ◽  
Solvent Free ◽  
Metal Catalyst ◽  
High Peak Power ◽  
High Catalytic Activity

Carbon encapsulated transition metal catalysts receive extensive attention in electrochemical catalytic oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) due to the unique structure and highly adjustable electronic configuration. Herein, we synthesized 3D porous Active-N-rich graphene-like carbon layer-encapsulated Fe/Fe3C (Fe@NCG) via pyrolysis of a mixture of solvent-free assembled Fe-chitosan chelates and additional small molecule nitrogen source urea, wherein space-confinement effect of chelates suppressed agglomeration of [Formula: see text] ions and small molecule nitrogen source facilitated regulation of N configurations. The optimized catalyst Fe@NCG shows remarkable ORR/OER bifunctional catalytic activity with a half-wave potential of 0.86 V for ORR and a moderate potential difference of 0.85 V in alkaline medium. Comparative studies revealed that Active-N-rich carbon layer and inner well-dispersed Fe/Fe3C nanoparticles and the favorable interface structures between them were responsible for high catalytic activity. Excitingly, the assembled zinc-air battery with Fe@NCG catalysts exhibits a high open-circuit potential (1.45 V), extremely high peak power density (204.50[Formula: see text][Formula: see text] and energy density (814.70[Formula: see text]Wh[Formula: see text][Formula: see text]) as well as robust charge–discharge durability, surpassing those of noble metal catalyst. This proposed simple and universal strategy can also be extended to synthesize carbon encapsulated other transition metal electrocatalysts.

scholarly journals Identification of pharmacodynamics readouts through acute dosing of a small molecule inhibitor of tau self‐association in a tauopathy mouse model

2021 ◽  
Vol 17 (S9) ◽  
Author(s):  
Dhruv R. Patel ◽  
Chaya Sussman ◽  
Mindy Greco ◽  
Edward H. Cheesman ◽  
Patricia Lopez ◽  
...  
Keyword(s):  
Mouse Model ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Self Association

Mechanism of Action of a Small Molecule Inhibitor That Targets Usp9x Deubiquitinase Activity in Multiple Myeloma and Mantle Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1415-1415 ◽  
Author(s):  
Luke F. Peterson ◽  
Hanshi Sun ◽  
Matthew Young ◽  
Hollis D. Showalter ◽  
Andrzej J Jakubowiak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Catalytic Activity ◽  
Board Of Directors ◽  
Small Molecule ◽  
Inhibitory Activity ◽  
Catalytic Domain ◽  
Cell Lymphoma ◽  
Advisory Committees ◽  
High Affinity ◽  
Mantle Cell

Abstract Abstract 1415 A growing number of compounds with proteasome and E3-ligase inhibitory activity have demonstrated clinical activity against multiple myeloma (MM) and mantle cell lymphoma. Some of these compounds are now part of the therapeutic regimen. In addition, there is a growing body of evidence that specific deubiquitinases (DUBs) are overexpressed in hematologic malignancies and may be appropriate myeloma/lymphoma therapeutic targets. However, only a limited number of compounds have been described with cell-permeant and selective activity for DUBs. We previously reported the DUB inhibitory activity of small molecule WP1130. This compound caused rapid inactivation of Usp9x, a DUB reported to be overexpressed in MM and some lymphoma primary specimens. Usp9x associates with the anti-apoptotic protein Mcl-1 and protects it from proteasomal destruction by deubiquitination. We have shown that WP1130 inhibits Usp9x activity (and some additional DUBs) and stimulates proteasomal destruction of Mcl-1. However, the mechanism of Usp9x inhibition by WP1130 has not been described. To investigate this, we synthesized a biotinylated derivative of WP1130 that retains cell-penetrant Usp9x DUB inhibitory activity. Using this as a probe, we demonstrate that WP1130 directly and stably interacts with Usp9x in high salt and ionic detergent, suggesting high affinity complex formation. Proteomic assessment revealed that other previously defined cellular targets of WP1130 (Usp5, Usp14, UCH-L5) also formed high affinity complexes with WP1130-biotin. Additional studies suggested that WP1130-biotin covalently modifies Usp9x through a Michael addition reaction with critical Usp9x cysteine residues that result in the inhibition of DUB activity. To further map the sites of the Usp9x-WP1130 interaction, we produced a recombinant catalytic domain of Usp9x (Usp9xCD) and verified that it retained enzymatic activity that could be inhibited by WP1130, albeit at higher concentrations than that required to inhibit the enzyme in intact cells. Mass spectral analysis of Usp9xCD/WP1130 complexes demonstrated formation of covalent WP1130 adducts with a concentration and time dependent stoichiometry. The catalytic domain was also used to determine the affinity and reversibility of WP1130 binding to Usp9x by solution-phase analysis using Bioforte instrumentation. These studies suggested a slow but high-affinity (<1 μM), irreversible binding of WP1130 to the catalytic domain in addition to a second, low-affinity, reversible binding mode. Molecular simulation was used to identify accessible and energetically favorable Cys residues that could represent the location(s) of high-affinity WP1130 binding. These sites are being confirmed by proteomic assessment of WP1130-biotin-retaining peptides derived from trypsinization of Usp9x/WP1130 adducts. Further structural simulation of Usp9x using homology modeling suggested that the catalytic domain of Usp9x contains a unique lobe (aa1576–1642), which lies close to recently described sites of mTOR phosphorylation. Our initial studies suggest that inhibition of mTOR (with Torin-2) in MM cells results in activation of Usp9x activity. The role of phosphorylation in the regulation of Usp9x activity and stability is currently being investigated but our initial observations suggest that Usp9x plays an important regulatory role in the mTOR/5'-AMP kinase cascade. Collectively, our studies suggest that WP1130 inhibits Usp9x activity through covalent modification of critical Cys residues important for Usp9x catalytic activity. Identification of these sites and how phosphorylation influences Usp9x catalytic activity are critical for developing more potent and selective Usp9x inhibitors. Since Usp9x expression has been associated with short survival and poor prognosis in MM patients, potent and selective Usp9x inhibitors could show therapeutic promise for MM patients and other cancers with up-regulated Usp9x activity. Disclosures: Jakubowiak: Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria. Talpaz:ARIAD: Research Funding.

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