scholarly journals Mechanically Triggered Carbon Monoxide Release with Turn-On Aggregation-Induced Emission

2021 ◽  
Author(s):  
Yunyan Sun ◽  
William Neary ◽  
Zach Burke ◽  
Hai Qian ◽  
Lingyang Zhu ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Small Molecules ◽  
Mechanical Stress ◽  
Small Molecule ◽  
Mechanochemical Reaction ◽  
Aggregation Induced Emission ◽  
Molecular Weights ◽  
Future Design ◽  
Turn On ◽  
Dynamic Therapy

Polymers that release functional small molecules under mechanical stress potentially serve as next-generation materials for catalysis, sensing, and mechanochemical dynamic therapy. To further expand the function of mechanoresponsive materials, the discovery of chemistries capable of small molecule release are highly desirable. In this report, we detail a non-scissile bifunctional mechanophore (i.e., dual mechano-activated properties) based on a unique mechanochemical reaction involving norborn-2-en-7-one (NEO). One property is the release of carbon monoxide (CO) upon pulsed solution ultrasonication. A release efficiency of 58% is observed at high molecular weights (Mn = 158.8 kDa), equating to ~154 molecules of CO re-leased per chain. The second property is the bright cyan emission from the macromolecular product in its aggregated state, resulting in a turn-on fluorescence readout coincident with CO release. This report not only demonstrates a unique strategy for the release of small molecule in a non-scissile way, but also guides future design of force-responsive aggregation-induced emission (AIE) luminogens.

scholarly journals STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii200-ii200
Author(s):  
Stephen Skirboll ◽  
Natasha Lucki ◽  
Genaro Villa ◽  
Naja Vergani ◽  
Michael Bollong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Small Molecules ◽  
Small Molecule ◽  
Large Scale ◽  
Critical Role ◽  
Tumor Formation ◽  
Cell Type ◽  
Caspase 1 ◽  
Activation Assay

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner. METHODS A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation. RESULTS We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation. CONCLUSIONS Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.

Preparation of a porous polymer monolithic column with an ionic liquid as a porogen and its applications for the separation of small molecules in high performance liquid chromatography

2015 ◽  
Vol 7 (18) ◽  
pp. 7879-7888 ◽  
Author(s):  
Jiafei Wang ◽  
Xiaoya Jiang ◽  
Hang Zhang ◽  
Sha Liu ◽  
Ligai Bai ◽  
...  
Keyword(s):  
Ionic Liquid ◽  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
Small Molecules ◽  
Small Molecule ◽  
High Performance ◽  
Monolithic Column ◽  
Porous Polymer ◽  
Column Efficiency ◽  
Polymer Monolithic Column

A monolith based on an ionic liquid as a porogen was prepared to enhance the column efficiency of small molecule separation in HPLC.

A “turn-on” small molecule fluorescent sensor for the determination of Al3+ ion in real samples: theoretical calculations, and photophysical and electrochemical properties

2021 ◽  
Vol 45 (39) ◽  
pp. 18400-18411
Author(s):  
Süreyya Oğuz Tümay ◽  
Ahmet Şenocak ◽  
Arif Mermer
Keyword(s):  
Small Molecule ◽  
Fluorescent Sensor ◽  
Theoretical Calculations ◽  
Sample Analysis ◽  
Fluorescence Sensing ◽  
Paper Test ◽  
Real Samples ◽  
Real Sample Analysis ◽  
Turn On

The fluorescence sensing properties of a naphthalene-based acetohydrazide (3) were investigated. A highly selective “turn-on” response was obtained towards Al3+ ions, and this was used for real sample analysis and development of paper test strips.

scholarly journals A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

2016 ◽  
Vol 12 ◽  
pp. 125-138 ◽  
Author(s):  
Steven C Zimmerman
Keyword(s):  
Small Molecules ◽  
Supramolecular Chemistry ◽  
Myotonic Dystrophy ◽  
Small Molecule ◽  
Early Life ◽  
Rational Design ◽  
Early Experience ◽  
Therapeutic Agents ◽  
Early Career ◽  
Molecular Tweezers

This review summarizes part of the author’s research in the area of supramolecular chemistry, beginning with his early life influences and early career efforts in molecular recognition, especially molecular tweezers. Although designed to complex DNA, these hosts proved more applicable to the field of host–guest chemistry. This early experience and interest in intercalation ultimately led to the current efforts to develop small molecule therapeutic agents for myotonic dystrophy using a rational design approach that heavily relies on principles of supramolecular chemistry. How this work was influenced by that of others in the field and the evolution of each area of research is highlighted with selected examples.

scholarly journals Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)

2020 ◽  
Author(s):  
Chao Wang ◽  
Juan Diez ◽  
Hajeung Park ◽  
Christoph Becker-Pauly ◽  
Gregg B. Fields ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Small Molecule ◽  
Hydroxamic Acid ◽  
Therapeutic Potential ◽  
Preceding Paper ◽  
Close Relative ◽  
Specific Inhibition ◽  
Selective Inhibitors

Meprin α is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin α, or its close relative meprin β, over numerous other metzincins which, if inhibited, would elicit unwanted effects. We recently identified possible molecular starting points for meprin α-specific inhibition through an HTS effort (see part I, preceding paper). In part II we report the optimization of a potent and selective hydroxamic acid meprin α inhibitor probe which may help define the therapeutic potential for small molecule meprin α inhibition and spur further drug discovery efforts in the area of zinc metalloproteinase inhibition.

scholarly journals A Simple Displacement Aptamer Assay on Resistive Pulse Sensor for Small Molecule Detection

2020 ◽  
Author(s):  
Rhushabh Maugi ◽  
bernadette gamble ◽  
david bunka ◽  
Mark Platt
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Label Free ◽  
Resistive Pulse ◽  
Pulse Sensor ◽  
Label Free Detection ◽  
Ssdna Aptamer ◽  
Aptamer Assay ◽  
Small Molecule Detection ◽  
Surface Changes

A universal aptamer-based sensing strategy is proposed using DNA modified nanocarriers and Resistive Pulse Sensing for the rapid and label free detection of small molecules. The surface of a magnetic nanocarrier was first modified with a ssDNA aka linker which is designed to be partially complimentary in sequence to a ssDNA aptamer. The aptamer and linker form a stable dsDNA complex on the nanocarriers surface. Upon the addition of the target molecule, a conformational change takes place where the aptamer preferentially binds to the target over the linker; causing the aptamer to be released into solution. The RPS measures the change in velocity of the nanocarrier as its surface changes from dsDNA to ssDNA, and its velocity is used as a proxy for the concentration of the target. We illustrate the versatility of the assay by demonstrating the detection of the antibiotic Moxifloxacin, and chemotherapeutics Imatinib and Irinotecan.

scholarly journals Discovery and mechanism of action of small molecule inhibitors of ceramidases

2021 ◽  
Author(s):  
Sebastien Granier ◽  
Robert D Healey ◽  
Essa Saied ◽  
Xiaojing Cong ◽  
Gergely Karsai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Small Molecules ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Integral Membrane Proteins ◽  
Sphingolipid Metabolism ◽  
New Paradigm ◽  
Biophysical Characterization ◽  
Sphingosine 1 Phosphate

Sphingolipid metabolism is tightly controlled by enzymes to regulate essential processes such as energy utilisation and cell proliferation. The central metabolite is ceramide, a pro-apoptotic lipid catabolized by ceramidase enzymes to ultimately produce pro-proliferative sphingosine-1-phosphate. Human ceramidases can be soluble proteins (acid and neutral ceramidase) or integral membrane proteins (alkaline ceramidases). Increasing ceramide levels to increase apoptosis has shown efficacy as a cancer treatment using small molecules inhibiting a soluble ceramidase. Due to the transmembrane nature of alkaline ceramidases, no specific small molecule inhibitors have been reported. Here, we report novel fluorescent substrates (FRETceramides) of ceramidases that can be used to monitor enzyme activity in real-time. We use FRETceramides to discover the first drug-like inhibitors of alkaline ceramidase 3 (ACER3) which are active in cell-based assays. Biophysical characterization of enzyme:inhibitor interactions reveal a new paradigm for inhibition of lipid metabolising enzymes with non-lipidic small molecules.

scholarly journals A New Big-Data Paradigm for Target Identification and Drug Discovery

2017 ◽  
Author(s):  
Neel S. Madhukar ◽  
Prashant K. Khade ◽  
Linda Huang ◽  
Kaitlyn Gayvert ◽  
Giuseppe Galletti ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Clinical Application ◽  
Small Molecule ◽  
Target Identification ◽  
Clinical Development ◽  
Data Types ◽  
Public Data ◽  
Drug Target Identification ◽  
Approved Drugs

AbstractDrug target identification is one of the most important aspects of pre-clinical development yet it is also among the most complex, labor-intensive, and costly. This represents a major issue, as lack of proper target identification can be detrimental in determining the clinical application of a bioactive small molecule. To improve target identification, we developed BANDIT, a novel paradigm that integrates multiple data types within a Bayesian machine-learning framework to predict the targets and mechanisms for small molecules with unprecedented accuracy and versatility. Using only public data BANDIT achieved an accuracy of approximately 90% over 2000 different small molecules – substantially better than any other published target identification platform. We applied BANDIT to a library of small molecules with no known targets and generated ∼4,000 novel molecule-target predictions. From this set we identified and experimentally validated a set of novel microtubule inhibitors, including three with activity on cancer cells resistant to clinically used anti-microtubule therapies. We next applied BANDIT to ONC201 – an active anti- cancer small molecule in clinical development – whose target has remained elusive since its discovery in 2009. BANDIT identified dopamine receptor 2 as the unexpected target of ONC201, a prediction that we experimentally validated. Not only does this open the door for clinical trials focused on target-based selection of patient populations, but it also represents a novel way to target GPCRs in cancer. Additionally, BANDIT identified previously undocumented connections between approved drugs with disparate indications, shedding light onto previously unexplained clinical observations and suggesting new uses of marketed drugs. Overall, BANDIT represents an efficient and highly accurate platform that can be used as a resource to accelerate drug discovery and direct the clinical application of small molecule therapeutics with improved precision.

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