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Small Molecule Antagonists of Cell-Surface Heparan Sulfate and Heparin–Protein Interactions
Electronic Supplementary Material (ESI) for Chemical Science. This journal is © The Royal Society of Chemistry 2015 Small Molecule Antagonists of Cell-Surface Heparan Sulfate and Heparin–Protein Interactions Ryan J. Weiss,a Philip L.S.M. Gordts,b Dzung Le,c,d Ding Xu,e Jeffrey D. Esko,b,d and Yitzhak Tor*a,d aDepartment of Chemistry and Biochemistry, bDepartment of Cellular and Molecular Medicine, cDepartment of Medicine, dGlycobiology Research and Training Center, University of California, San Diego, 9500 Gilman Dr., La Jolla, California 92093, United States. eDepartment of Oral Biology, University at Buffalo, 12 Capen Hall, Buffalo, New York 14260. Table of Contents S.1 – Synthesis and characterization of surfen analogs ............................................. 2 S.2 – Synthesis and characterization of building blocks .........................................11 S.3 – General procedure for precipitation of HCl salts ...........................................11 S.4 – X-ray crystal structures ...................................................................................14 S.5 – FGF2 binding inhibition curves ......................................................................21 S.6 – sRAGE Binding Inhibition Data .....................................................................22 S.7 – Biotinylation of FGF2 .....................................................................................22 S.8 – Biotinylation of sRAGE .................................................................................23 S.9 – Example of -
Small Molecule Antagonists of Cell-Surface Heparan Sulfate and Heparin–Protein Interactions† Cite This: Chem
Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue Small molecule antagonists of cell-surface heparan sulfate and heparin–protein interactions† Cite this: Chem. Sci.,2015,6, 5984 Ryan J. Weiss,a Philip L. S. M. Gordts,b Dzung Le,cd Ding Xu,e Jeffrey D. Eskobd and Yitzhak Tor*ad Surfen, bis-2-methyl-4-amino-quinolyl-6-carbamide, was previously reported as a small molecule antagonist of heparan sulfate (HS), a key cell-surface glycosaminoglycan found on all mammalian cells. To generate structure–activity relationships, a series of rationally designed surfen analogs was synthesized, where its dimeric structure, exocyclic amines, and urea linker region were modified to probe the role of each moiety in recognizing HS. An in vitro assay monitoring inhibition of fibroblast growth factor 2 binding to wild-type CHO cells was utilized to quantify interactions with cell surface HS. The dimeric molecular structure of surfen and its aminoquinoline ring systems was essential for its interaction with HS, and certain dimeric analogs displayed higher inhibitory potency than surfen and were also shown to block downstream FGF signaling in mouse embryonic fibroblast cells. These Creative Commons Attribution-NonCommercial 3.0 Unported Licence. molecules were also able to antagonize other HS–protein interactions including the binding of soluble Received 4th April 2015 RAGE to HS. Importantly, selected molecules were shown to neutralize heparin and other heparinoids, Accepted 21st July 2015 including the synthetic pentasaccharide fondaparinux, in a factor Xa chromogenic assay and in vivo in DOI: 10.1039/c5sc01208b mice. These results suggest that small molecule antagonists of heparan sulfate and heparin can be of www.rsc.org/chemicalscience therapeutic potential for the treatment of disorders involving glycosaminoglycan–protein interactions. -
(12) Patent Application Publication (10) Pub. No.: US 2004/0132766A1 Griesgraber (43) Pub
US 2004O132766A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0132766A1 Griesgraber (43) Pub. Date: Jul. 8, 2004 (54) 1H-MIDAZO DIMERS Publication Classification (76) Inventor: George W. Griesgraber, Eagan, MN (US) (51) Int. Cl." .................... A61K 31/4745; CO7D 471/02 Correspondence Address: (52) U.S. Cl. ............................................ 514/303; 546/118 3M INNOVATIVE PROPERTIES COMPANY PO BOX 33427 ST. PAUL, MN 55133-3427 (US) (57) ABSTRACT (21) Appl. No.: 10/670,957 (22)22) FileFilled: Sep.ep. ZS,25, 2003 1H-imidazo dimer compounds are useful as immune Related U.S. Application Data response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines (60) Provisional application No. 60/413,848, filed on Sep. and are useful in the treatment of a variety of conditions 26, 2002. including viral diseases and neoplastic diseases. US 2004/O132766 A1 Jul. 8, 2004 1H-MIDAZO DIMERS ing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or CROSS REFERENCE TO RELATED other mechanisms. APPLICATION 0001. This application claims priority to U.S. Provisional SUMMARY OF THE INVENTION Application No. 60/413,848, filed Sep. 26, 2002. 0007. It has now been found that certain 1H-imidazo dimer compounds induce cytokine biosynthesis. In one FIELD OF THE INVENTION aspect, the present invention provides 1H-imidazo dimer 0002 The present invention relates to 1H-imidazo dimers compounds of the Formula (I): and to pharmaceutical compositions containing Such dimerS. In addition this invention relates to the use of these dimers as immunomodulators, for inducing cytokine biosynthesis in (I) animals, and in the treatment of diseases, including viral and NH2 NH2 neoplastic diseases. -
Biodegradable Poly(Ester Amide)S – a Remarkable Opportunity for the Biomedical Area: Review on the Synthesis, Characterization and Applications
CORE Metadata, citation and similar papers at core.ac.uk Provided by Estudo Geral Accepted Manuscript Title: Biodegradable poly(ester amide)s – a remarkable opportunity for the biomedical area: review on the synthesis, characterization and applications Author: Ana C. Fonseca Maria H. Gil Pedro N. Simoes˜ PII: S0079-6700(13)00145-7 DOI: http://dx.doi.org/doi:10.1016/j.progpolymsci.2013.11.007 Reference: JPPS 852 To appear in: Progress in Polymer Science Received date: 13-6-2013 Revised date: 20-11-2013 Accepted date: 26-11-2013 Please cite this article as: Fonseca AC, Gil MH, Simo˜ es PN, Biodegradable poly(ester amide)s ndash a remarkable opportunity for the biomedical area: review on the synthesis, characterization and applications, Progress in Polymer Science (2013), http://dx.doi.org/10.1016/j.progpolymsci.2013.11.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Biodegradable poly(ester amide)s – a remarkable opportunity for the biomedical area: review on the synthesis, characterization and applications Ana C. Fonseca, Maria H. Gil, Pedro N. Simões Department of Chemical Engineering, University of Coimbra, Rua Sílvio Lima-Pólo II, 3030-790 Coimbra, Portugal Corresponding author: Tel. -
Small Molecule Antagonists of Cell-Surface Heparan Sulfate and Heparin–Protein Interactions† Cite This: Chem
Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue Small molecule antagonists of cell-surface heparan sulfate and heparin–protein interactions† Cite this: Chem. Sci.,2015,6, 5984 Ryan J. Weiss,a Philip L. S. M. Gordts,b Dzung Le,cd Ding Xu,e Jeffrey D. Eskobd and Yitzhak Tor*ad Surfen, bis-2-methyl-4-amino-quinolyl-6-carbamide, was previously reported as a small molecule antagonist of heparan sulfate (HS), a key cell-surface glycosaminoglycan found on all mammalian cells. To generate structure–activity relationships, a series of rationally designed surfen analogs was synthesized, where its dimeric structure, exocyclic amines, and urea linker region were modified to probe the role of each moiety in recognizing HS. An in vitro assay monitoring inhibition of fibroblast growth factor 2 binding to wild-type CHO cells was utilized to quantify interactions with cell surface HS. The dimeric molecular structure of surfen and its aminoquinoline ring systems was essential for its interaction with HS, and certain dimeric analogs displayed higher inhibitory potency than surfen and were also shown to block downstream FGF signaling in mouse embryonic fibroblast cells. These Creative Commons Attribution-NonCommercial 3.0 Unported Licence. molecules were also able to antagonize other HS–protein interactions including the binding of soluble Received 4th April 2015 RAGE to HS. Importantly, selected molecules were shown to neutralize heparin and other heparinoids, Accepted 21st July 2015 including the synthetic pentasaccharide fondaparinux, in a factor Xa chromogenic assay and in vivo in DOI: 10.1039/c5sc01208b mice. These results suggest that small molecule antagonists of heparan sulfate and heparin can be of www.rsc.org/chemicalscience therapeutic potential for the treatment of disorders involving glycosaminoglycan–protein interactions. -
Engineering Chitosan Using Α, Ω-Dicarboxylic Acids—An
Journal of Biomaterials and Nanobiotechnology, 2013, 4, 151-164 151 http://dx.doi.org/10.4236/jbnb.2013.42021 Published Online April 2013 (http://www.scirp.org/journal/jbnb) Engineering Chitosan Using α, -Dicarboxylic Acids—An Approach to Improve the Mechanical Strength and Thermal Stability G. Sailakshmi1, Tapas Mitra1, Suvro Chatterjee2, A. Gnanamani1* 1Microbiology Division, CSIR-Central Leather Research Institute, Chennai, India; 2AU-KBC Research Centre, MIT, Anna Univer- sity, Chennai, India. Email: *[email protected] Received January 19th, 2013; revised March 5th, 2013; accepted April 7th, 2013 Copyright © 2013 G. Sailakshmi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ABSTRACT The current scenario in tissue engineering research demands materials of requisite properties, viz., high porosity, me- chanical stability, thermal stability, biocompatibility and biodegradability for clinical applications. However, bringing these properties in single biomaterial is a challenging task, which needs intensive research on suitable cross-linking agents. In the present study, 3D scaffold was prepared with above said properties using chitosan and oxalic (O), malonic (M), succinic (S), glutaric (G), adipic (A), pimelic (P), suberic (SU), azelaic (AZ) and sebacic (SE) acid (OMS- GAP-SAS) individually as a non covalent cross-linkers as well as the solvent for chitosan. Assessment on degree of cross-linking, mechanical strength, FT-IR analysis, morphological observation, thermal stability, binding interactions (molecular docking), in vitro biocompatibility and its efficacy as a wound dressing material were performed. Results revealed the degree of cross-linking for OMSGAP-SAS engineered chitosan were in the range between ≈55% - 65% and the biomaterial demonstrated thermal stability more than 300˚C and also exhibited ≥3 - 4 fold increase in mechani- cal strength compared to chitosan alone.