scholarly journals Developments in Carbohydrate-Based Metzincin Inhibitors

2020 ◽  
Vol 13 (11) ◽  
pp. 376
Author(s):  
Doretta Cuffaro ◽  
Elisa Nuti ◽  
Felicia D’Andrea ◽  
Armando Rossello
Keyword(s):  
Matrix Metalloproteinases ◽  
Small Molecules ◽  
Water Solubility ◽  
Clinical Development ◽  
Sugar Moiety ◽  
Novel Approach ◽  
Poor Water Solubility ◽  
A Disintegrin And Metalloproteinase ◽  
Target Enzyme

Matrix metalloproteinases (MMPs) and A disintegrin and Metalloproteinase (ADAMs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. Upregulation of metzincin activity is a major feature in many serious pathologies such as cancer, inflammations, and infections. In the last decades, many classes of small molecules have been developed directed to inhibit these enzymes. The principal shortcomings that have hindered clinical development of metzincin inhibitors are low selectivity for the target enzyme, poor water solubility, and long-term toxicity. Over the last 15 years, a novel approach to improve solubility and bioavailability of metzincin inhibitors has been the synthesis of carbohydrate-based compounds. This strategy consists of linking a hydrophilic sugar moiety to an aromatic lipophilic scaffold. This review aims to describe the development of sugar-based and azasugar-based derivatives as metzincin inhibitors and their activity in several pathological models.

A Fused Thiophene-S,S-Dioxide-Based Super-Photostable Fluorescent Marker for Lipid Droplets

2020 ◽  
Author(s):  
Masayasu Taki ◽  
Keiji Kajiwara ◽  
Eriko Yamaguchi ◽  
Yoshikatsu Sato ◽  
Shigehiro Yamaguchi
Keyword(s):  
Small Molecules ◽  
Lipid Droplets ◽  
Trajectory Analysis ◽  
Super Resolution ◽  
Fluorescent Marker ◽  
Selective Staining ◽  
Fluorescent Markers ◽  
Biological Studies ◽  
Particle Level

Lipid droplets (LDs) are essential organelle in most eukaryotes, and tracking intracellular LDs dynamics using synthetic small molecules is crucial for biological studies. However, only a limited number of fluorescent markers that satisfy all requirements, such as the selective staining of LDs, high photostability, and sufficient biocompatibility, have been developed. Herein, we report a series of donor-p-acceptor dyes based on the thiophene-containing fused polycyclic scaffold [1]benzothieno[3,2-<i>b</i>][1]benzothiophene (BTBT), in which either or both thiophene rings are oxidized into thiophene-<i>S</i>,<i>S</i>-dioxide to form an electron-accepting building block. Among these dyes, LAQ1 satisfied all the aforementioned requirements, and allowed us capturing ultra-small LDs on the endoplasmic reticulum (ER) membrane by stimulation emission depletion (STED) microscopy with a super-resolution below the diffraction limit of light. Moreover, the extremely high photostability of LAQ1 enabled recording the lipolysis of LDs and the concomitant lipogenesis as well as long-term trajectory analysis of micro LDs at the single particle level in living cells.

Investigating the influence of aromatic moieties on the formulation of hydrophobic natural products and drugs in poly(2-oxazoline) based amphiphiles

2018 ◽  
Author(s):  
Robert Luxenhofer ◽  
Michael M Lübtow ◽  
Lukas Hahn ◽  
Thomas Lorson ◽  
Rainer Schobert
Keyword(s):  
Natural Products ◽  
Small Molecules ◽  
Water Solubility ◽  
Drug Loading ◽  
High Drug ◽  
Long Term Stability ◽  
Aromatic Content ◽  
Important Interaction ◽  
Amorphous Structures ◽  
High Drug Loading

Many natural compounds with interesting biomedical properties share one physicochemical property, namely a low water solubility. Polymer micelles are, among others, a popular means to solubilize hydrophobic compounds. The specific molecular interactions between the polymers and the hydrophobic drugs are diverse and recently it has been discussed that macromolecular engineering can be used to optimize drug loaded micelles. Specifically, π-π stacking between small molecules and polymers has been discussed as an important interaction that can be employed to increase drug loading and formulation stability. Here, we test this hypothesis using four different polymer amphiphiles with varying aromatic content and various natural products that also contain different relative amounts of aromatic moieties. While in the case of paclitaxel, having the lowest relative content of aromatic moieties, the drug loading decreases with increasing relative aromatic amount in the polymer, the drug loading of curcumin, having a much higher relative aromatic content, is increased. Interestingly, the loading using schizandrin A, a dibenzo[a,c]cyclooctadiene lignan with intermediate relative aromatic content is not influenced significantly by the aromatic content of the polymers employed. The very high drug loading, long term stability, the ability to form stable highly loaded binary coformulations in different drug combinations, small sized formulations and amorphous structures in all cases, corroborate earlier reports that poly(2-oxazoline) based micelles exhibit an extraordinarily high drug loading and are promising candidates for further biomedical applications. The presented results underline that the interaction between the polymers and the incorporated small molecules are complex and must be investigated in every specific case.<br>

NMR Studies of the Inclusion Complexes Between Ezetimibe and Cyclodextrins

2018 ◽  
Vol 69 (7) ◽  
pp. 1838-1841
Author(s):  
Hajnal Kelemen ◽  
Angella Csillag ◽  
Bela Noszal ◽  
Gabor Orgovan
Keyword(s):  
Inclusion Complex ◽  
Inclusion Complexes ◽  
Water Solubility ◽  
Solution Nmr ◽  
Spectroscopic Techniques ◽  
Nmr Studies ◽  
The Poor ◽  
Poor Water Solubility

Ezetimibe, the antihyperlipidemic drug of poor bioavailability was complexed with native and derivatized cyclodextrins.The complexes were characterized in terms stability, stoichiometry and structure using various 1D and 2D solution NMR spectroscopic techniques. The complexes were found to be of moderate stability (logK[3). The least stable inclusion complex is formed with b-cyclodextrin, while the ezetimibe-methylated-b--cyclodextrin has a 7-fold higher stability. The results can be useful to improve the poor water-solubility and the concomitant bioavailability of ezetimibe.

Targeting Micrornas With Small Molecules: A Novel Approach to Treating Breast Cancer

2010 ◽  
Author(s):  
George A. Calin ◽  
Shuxing Zhang ◽  
Waldemar Priebe
Keyword(s):  
Breast Cancer ◽  
Small Molecules ◽  
Novel Approach

Development of a Performance-Related Framework for Asphalt Mixture Design for the Illinois Tollway

2021 ◽  
pp. 036119812110148
Author(s):  
Behnam Jahangiri ◽  
Punyaslok Rath ◽  
Hamed Majidifard ◽  
William G. Buttlar
Keyword(s):  
Asphalt Mixture ◽  
Field Performance ◽  
Compact Tension ◽  
T Test ◽  
Novel Approach ◽  
Final Adjustment ◽  
Development And Validation ◽  
High Degree ◽  
Selection Of

Various agencies have begun to research and introduce performance-related specifications (PRS) for the design of modern asphalt paving mixtures. The focus of most recent studies has been directed toward simplified cracking test development and evaluation. In some cases, development and validation of PRS has been performed, building on these new tests, often by comparison of test values to accelerated pavement test studies and/or to limited field data. This study describes the findings of a comprehensive research project conducted at Illinois Tollway, leading to a PRS for the design of mainline and shoulder asphalt mixtures. A novel approach was developed, involving the systematic establishment of specification requirements based on: 1) selection of baseline values based on minimally acceptable field performance thresholds; 2) elevation of thresholds to account for differences between short-term lab aging and expected long-term field aging; 3) further elevation of thresholds to account for variability in lab testing, plus variability in the testing of field cores; and 4) final adjustment and rounding of thresholds based on a consensus process. After a thorough evaluation of different candidate cracking tests in the course of the project, the Disk-shaped Compact Tension—DC(T)—test was chosen to be retained in the Illinois Tollway PRS and to be presented in this study for the design of crack-resistant mixtures. The DC(T) test was selected because of its high degree of correlation with field results and its excellent repeatability. Tailored Hamburg rut depth and stripping inflection point thresholds were also established for mainline and shoulder mixes.

A Novel Approach Towards Cementing Design Achieved Significant Improvement in Long Term Zonal Isolation

2019 ◽  
Author(s):  
Ala Suleiman ◽  
Bashar Hilal ◽  
Phalgun Paila ◽  
Sahir Abdelhadi ◽  
Khalid Alwahedi ◽  
...  
Keyword(s):  
Novel Approach ◽  
Zonal Isolation

Stabilisation of Hg1-xCdxTe:Hg1-yCdyTex ≠ y) Heterointerfaces and Applications in Infra Red Devices

1990 ◽  
Vol 216 ◽  
Author(s):  
Paul A. Clifton ◽  
Paul D. Brown
Keyword(s):  
Barrier Layer ◽  
Epitaxial Layers ◽  
Long Wavelength ◽  
Long Term Stability ◽  
Novel Approach ◽  
Infra Red ◽  
Passivation Layers ◽  
Cdte Buffer ◽  
Initial Results

ABSTRACTThe interface between Hg1-xCdxTe(0 ≦ x ≦ 1) and Hg1-yCdyTe(0 ≦ y ≦ 1) epitaxial layers of different composition (x ≠ y) is unstable with regard to the intermixing of the Hg and Cd cations within the Group II sublattice. This phenomenon may give rise to long-term stability problems in HgTe-(Hg,Cd)Te superlattices and composition grading between (Hg,Cd)Te absorber layers and CdTe buffer or passivation layers in epitaxial infra red detectors. In this paper, a novel approach to the inhibition of interdiffusion in these systems is discussed. This involves the growth of an intervening ZnTe barrier layer at the heterointerface between two (Hg,Cd)Te layers. Initial results are presented which indicate the effectiveness of this technique in reducing interdiffusion in an experimental heterostructure grown by MOVPE. Some possible applications in a variety of HgTe-based long wavelength devices are discussed.

scholarly journals Acute graft-versus-host disease: a bench-to-bedside update

Blood ◽  
2014 ◽  
Vol 124 (3) ◽  
pp. 363-373 ◽  
Author(s):  
Shernan G. Holtan ◽  
Marcelo Pasquini ◽  
Daniel J. Weisdorf
Keyword(s):  
Small Molecules ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Multiple Modalities ◽  
Graft Versus Host ◽  
The Past ◽  
Prevention And Treatment ◽  
Near Future ◽  
Acute Graft

Abstract Over the past 5 years, many novel approaches to early diagnosis, prevention, and treatment of acute graft-versus-host disease (aGVHD) have been translated from the bench to the bedside. In this review, we highlight recent discoveries in the context of current aGVHD care. The most significant innovations that have already reached the clinic are prophylaxis strategies based upon a refinement of our understanding of key sensors, effectors, suppressors of the immune alloreactive response, and the resultant tissue damage from the aGVHD inflammatory cascade. In the near future, aGVHD prevention and treatment will likely involve multiple modalities, including small molecules regulating immunologic checkpoints, enhancement of suppressor cytokines and cellular subsets, modulation of the microbiota, graft manipulation, and other donor-based prophylaxis strategies. Despite long-term efforts, major challenges in treatment of established aGVHD still remain. Resolution of inflammation and facilitation of rapid immune reconstitution in those with only a limited response to corticosteroids is a research arena that remains rife with opportunity and urgent clinical need.

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