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1.
Bioorg Med Chem ; 24(3): 435-43, 2016 Feb 01.
Article in English | MEDLINE | ID: mdl-26386818

ABSTRACT

A novel class of synthetic tubulin polymerization disruptors, based on a substituted pyrazin-2-one core, has been discovered. These molecules have proven to be potent broad spectrum fungicides, with activity on agriculturally important ascomycete and basidiomycete pathogens. They have also been found to be particularly potent against human rhabdomyosarcoma cells. Using an efficient synthetic route, the agricultural and medicinal activity was explored.


Subject(s)
Antineoplastic Agents/pharmacology , Fungicides, Industrial/pharmacology , Pyrazines/pharmacology , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Tubulin/metabolism , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Fungicides, Industrial/chemistry , Humans , Microbial Sensitivity Tests , Molecular Structure , Pyrazines/chemistry , Structure-Activity Relationship
2.
Biosens Bioelectron ; 35(1): 284-290, 2012 May 15.
Article in English | MEDLINE | ID: mdl-22456097

ABSTRACT

It is well recognized that label-free biosensors are the only class of sensors that can rapidly detect antigens in real-time and provide remote environmental monitoring and point-of-care diagnosis that is low-cost, specific, and sensitive. Electrical impedance spectroscopy (EIS) based label-free biosensors have been used to detect a wide variety of antigens including bacteria, viruses, DNA, and proteins due to the simplicity of their detection technique. However, their commercial development has been hindered due to difficulty in interpreting the change in impedance upon antigen binding and poor signal reproducibility as a result of surface fouling and non-specific binding. In this study, we develop a circuit model to adequately describe the physical changes at bio functionalized surface and provide an understanding of the detection mechanism based on electron exchange between electrolyte and surface through pores surrounding antibody-antigen. The model was successfully applied to extract quantitative information about the bio surface at different stages of surface functionalization. Further, we demonstrate boron-doped ultrananocrystalline diamond (UNCD) microelectrode array (3 × 3 format, 200 µm diameter) improves signal reproducibility significantly and increases sensitivity by four orders of magnitude. This study marks the first demonstration of UNCD array based biosensor that can reliably detect a model Escherichia coli K12 bacterium using EIS, positioning this technology for rapid adoption in point-of-use applications.


Subject(s)
Antigens/analysis , Biosensing Techniques/methods , Nanoparticles , Antibodies, Bacterial , Antibodies, Immobilized , Antigens, Bacterial/analysis , Biosensing Techniques/statistics & numerical data , Diamond , Dielectric Spectroscopy , Electrochemical Techniques , Escherichia coli K12/immunology , Escherichia coli K12/isolation & purification , Microelectrodes , Nanoparticles/ultrastructure , Reproducibility of Results , Surface Properties
3.
Adv Funct Mater ; 21(6): 1040-1050, 2011 Mar 21.
Article in English | MEDLINE | ID: mdl-21949497

ABSTRACT

Immunoassays for detection of bacterial pathogens rely on the selectivity and stability of bio-recognition elements such as antibodies tethered to sensor surfaces. The search for novel surfaces that improve the stability of biomolecules and assay performance has been pursued for a long time. However, the anticipated improvements in stability have not been realized in practice under physiological conditions because the surface functionalization layers on commonly used substrates, silica and gold, are themselves unstable on time scales of days. In this paper, we show that covalent linking of antibodies to diamond surfaces leads to substantial improvements in biological activity of proteins as measured by the ability to selectively capture cells of the pathogenic bacterium Escherichia coli O157:H7 even after exposure to buffer solutions at 37 °C for extended periods of time, approaching 2 weeks. Our results from ELISA, XPS, fluorescence microscopy, and MD simulations suggest that by using highly stable surface chemistry and controlling the nanoscale organization of the antibodies on the surface, it is possible to achieve significant improvements in biological activity and stability. Our findings can be easily extended to functionalization of micro and nanodimensional sensors and structures of biomedical diagnostic and therapeutic interest.

4.
Proc Natl Acad Sci U S A ; 108(3): 983-8, 2011 Jan 18.
Article in English | MEDLINE | ID: mdl-20884854

ABSTRACT

Carbon is an extremely versatile family of materials with a wide range of mechanical, optical, and mechanical properties, but many similarities in surface chemistry. As one of the most chemically stable materials known, carbon provides an outstanding platform for the development of highly tunable molecular and biomolecular interfaces. Photochemical grafting of alkenes has emerged as an attractive method for functionalizing surfaces of diamond, but many aspects of the surface chemistry and impact on biological recognition processes remain unexplored. Here we report investigations of the interaction of functionalized diamond surfaces with proteins and biological cells using X-ray photoelectron spectroscopy (XPS), atomic force microscopy, and fluorescence methods. XPS data show that functionalization of diamond with short ethylene glycol oligomers reduces the nonspecific binding of fibrinogen below the detection limit of XPS, estimated as > 97% reduction over H-terminated diamond. Measurements of different forms of diamond with different roughness are used to explore the influence of roughness on nonspecific binding onto H-terminated and ethylene glycol (EG)-terminated surfaces. Finally, we use XPS to characterize the chemical stability of Escherichia coli K12 antibodies on the surfaces of diamond and amine-functionalized glass. Our results show that antibody-modified diamond surfaces exhibit increased stability in XPS and that this is accompanied by retention of biological activity in cell-capture measurements. Our results demonstrate that surface chemistry on diamond and other carbon-based materials provides an excellent platform for biomolecular interfaces with high stability and high selectivity.


Subject(s)
Antibodies, Bacterial/chemistry , Chemistry, Physical/methods , Diamond/chemistry , Fibrinogen/chemistry , Microscopy, Atomic Force/methods , Photoelectron Spectroscopy/methods , Avidin/chemistry , Escherichia coli K12/immunology , Ethylene Glycol , Fluorescence , Protein Binding , Surface Properties
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