BioTools, Inc.

JUPITER, FL, United States

BioTools, Inc.

JUPITER, FL, United States
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Kurouski D.,University at Albany | Lombardi R.A.,Syracuse University | Dukor R.K.,BioTools, Inc. | Lednev I.K.,University at Albany | And 2 more authors.
Chemical Communications | Year: 2010

The controlled reversal of supramolecular helical chirality in protein fibrils is reported for the first time. Normal or reversed insulin fibrils were grown by precise adjustment of pH. AFM images show two polymorphs corresponding to opposite senses of helical twist of the supramolecular structure with the same cross-β-sheet core. © 2010 The Royal Society of Chemistry.


Numajiri Y.,California Institute of Technology | Jimenez-Oses G.,University of California at Los Angeles | Wang B.,BioTools, Inc. | Houk K.N.,University of California at Los Angeles | Stoltz B.M.,California Institute of Technology
Organic Letters | Year: 2015

The enantioselective synthesis of α-disubstituted N-heterocyclic carbonyl compounds has been accomplished using palladium-catalyzed allylic alkylation. These catalytic conditions enable access to various heterocycles, such as morpholinone, thiomorpholinone, oxazolidin-4-one, 1,2-oxazepan-3-one, 1,3-oxazinan-4-one, and structurally related lactams, all bearing fully substituted α-positions. Broad functional group tolerance was explored at the α-position in the morpholinone series. We demonstrate the utility of this method by performing various transformations on our useful products to readily access a number of enantioenriched compounds. © 2015 American Chemical Society.


Kurouski D.,University at Albany | Dukor R.K.,BioTools, Inc. | Lu X.,BioTools, Inc. | Nafie L.A.,BioTools, Inc. | And 2 more authors.
Chemical Communications | Year: 2012

Amyloid fibrils are associated with many neurodegenerative diseases and are considered to be the energetically most favorable form of proteins. Here we report that a small pH change initiates spontaneous transformation of insulin fibrils from one polymorph to another. As a result, fibril supramolecular chirality overturns both accompanying morphological and structural changes. This journal is © The Royal Society of Chemistry 2012.


Li H.,BioTools, Inc. | Nafie L.A.,BioTools, Inc. | Nafie L.A.,Syracuse University
Journal of Raman Spectroscopy | Year: 2012

A new circularly polarized (CP) Raman spectrometer is described that demonstrates simultaneous acquisition of all four forms of circular polarization Raman optical activity (ROA). The instrument is a design extension of a commercially available back scattering circular polarization (SCP) ROA spectrometer. Circular polarization of the incident beam is introduced with a quarter-wave plate, and a half-wave plate alternately positioned in and out of the beam controls the modulation between right circular polarization (RCP) or left circular polarization (LCP) states. Combining this modulation with the simultaneous detection of RCP and LCP scattered Raman radiation allows the measurement of incident circular polarization (ICP), SCP, in-phase dual circular polarization(DCP I) and out-of-phase DCP II-ROA. In addition, three different forms of backscattered Raman spectra, namely unpolarized, highly polarized, and depolarized Raman spectra, as well as a degree of circularity spectrum are obtained. The performance of the new all-CP ROA spectrometer is evaluated with neat α-pinene and aqueous hen lysozyme solution. Copyright © 2011 John Wiley & Sons, Ltd.


Kurouski D.,Albany State University | Dukor R.K.,BioTools, Inc. | Lu X.,BioTools, Inc. | Nafie L.A.,Syracuse University | And 2 more authors.
Biophysical Journal | Year: 2012

Fibrils are β-sheet-rich aggregates that are generally composed of several protofibrils and may adopt variable morphologies, such as twisted ribbons or flat-like sheets. This polymorphism is observed for many different amyloid associated proteins and polypeptides. In a previous study we proposed the existence of another level of amyloid polymorphism, namely, that associated with fibril supramolecular chirality. Two chiral polymorphs of insulin, which can be controllably grown by means of small pH variations, exhibit opposite signs of vibrational circular dichroism (VCD) spectra. Herein, using atomic force microscopy (AFM) and scanning electron microscopy (SEM), we demonstrate that indeed VCD supramolecular chirality is correlated not only by the apparent fibril handedness but also by the sense of supramolecular chirality from a deeper level of chiral organization at the protofilament level of fibril structure. Our microscopic examination indicates that normal VCD fibrils have a left-handed twist, whereas reversed VCD fibrils are flat-like aggregates with no obvious helical twist as imaged by atomic force microscopy or scanning electron microscopy. A scheme is proposed consistent with observed data that features a dynamic equilibrium controlled by pH at the protofilament level between left- and right-twist fibril structures with distinctly different aggregation pathways for left- and right-twisted protofilaments. © 2012 by the Biophysical Society.


He Y.,BioTools, Inc. | Wang B.,BioTools, Inc. | Dukor R.K.,BioTools, Inc. | Nafie L.A.,Syracuse University
Applied Spectroscopy | Year: 2011

Determination of the absolute handedness, known as absolute configuration (AC), of chiral molecules is an important step in any field related to chirality, especially in the pharmaceutical industry. Vibrational optical activity (VOA) has become a powerful tool for the determination of the AC of chiral molecules in the solution state after nearly forty years of evolution. VOA offers a novel alternative, or supplement, to X-ray crystallography, permitting AC determinations on neat liquid, oil, and solution samples without the need to grow single crystals of the pure chiral sample molecules as required for X-ray analysis. By comparing the sign and intensity of the measured VOA spectrum with the corresponding ab initio density functional theory (DFT) calculated VOA spectrum of a chosen configuration, one can unambiguously assign the AC of a chiral molecule. Comparing measured VOA spectra with calculated VOA spectra of all the conformers can also provide solution-state conformational populations. VOA consists of infrared vibrational circular dichroism (VCD) and vibrational Raman optical activity (ROA). Currently, VCD is used routinely by researchers in a variety of backgrounds, including molecular chirality, asymmetric synthesis, chiral catalysis, drug screening, pharmacology, and natural products. Although the application of ROA in AC determination lags behind that of VCD, with the recent implementation of ROA subroutines in commercial quantum chemistry software, ROA will in the future complement VCD for AC determination. In this review, the basic principles of the application of VCD to the determination of absolute configuration in chiral molecules are described. The steps required for VCD spectral measurement and calculation are outlined, followed by brief descriptions of recently published papers reporting the determination of AC in small organic, pharmaceutical, and natural product molecules. © 2011 Society for Applied Spectroscopy.


Fleming A.M.,University of Utah | Orendt A.M.,University of Utah | He Y.,BioTools, Inc. | Zhu J.,University of Utah | And 2 more authors.
Journal of the American Chemical Society | Year: 2013

The diastereomeric spiroiminodihydantoin-2′-deoxyribonucleoside (dSp) lesions resulting from 2′-deoxyguanosine (dG) or 8-oxo-7,8-dihydro- 2′-deoxyguanosine (dOG) oxidation have generated much attention due to their highly mutagenic nature. Their propeller-like shape leads these molecules to display mutational profiles in vivo that are stereochemically dependent. However, there exist conflicting absolute configuration assignments arising from electronic circular dichroism (ECD) and NOESY-NMR experiments; thus, providing definitive assignments of the 3D structure of these molecules is of great interest. In the present body of work, we present data inconsistent with the reported ECD assignments for the dSp diastereomers in the nucleoside context, in which the first eluting isomer from a Hypercarb HPLC column was assigned to be the S configuration, and the second was assigned the R configuration. The following experiments were conducted: (1) determination of the diastereomer ratio of dSp products upon one-electron oxidation of dG in chiral hybrid or propeller G-quadruplexes that expose the re or si face to solvent, respectively; (2) absolute configuration analysis using vibrational circular dichroism (VCD) spectroscopy; (3) reinterpretation of the ECD experimental spectra using time-dependent density functional theory (TDDFT) with the inclusion of 12 explicit H-bonding waters around the Sp free bases; and (4) reevaluation of calculated specific rotations for the Sp enantiomers using the hydration model in the TDDFT calculations. These new insights provide a fresh look at the absolute configuration assignments of the dSp diastereomers in which the first eluting from a Hypercarb-HPLC column is (-)-(R)-dSp and the second is (+)-(S)-dSp. These assignments now provide the basis for understanding the biological significance of the stereochemical dependence of enzymes that process this form of DNA damage. © 2013 American Chemical Society.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 431.69K | Year: 2011

This Small Business Innovation Research (SBIR) Phase II project is focused on the creation of a new revolutionary imaging instrumentation that combines vibrational circular dichroism (VCD) spectroscopy with infrared (IR) spectral microscopy. VCD microscopy represents a new class of spectroscopic imaging diagnostic capable of measuring VCD images with millimeter to sub-millimeter spatial resolution. The recent discovery that long-range structural chirality in protein fibrils is characterized by unusually large and distinctive VCD spectra provides the backdrop for this project. None of the currently available techniques can characterize the fibrillation pathway or the final fibril state with the same ease and detail as VCD. VCD microscopy can be thought of as circular polarization contrast microscopy that is sensitive to long-range chiral order in localized regions of biological samples. The broader impacts of this research are studies of the supramolecular chirality of fibrils. This product is not a small improvement of an existing technology but a distinctly new method of studying long-range biochirality that is more sensitive, provides more detail, and is easy and fast to use. A secondary, higher-impact long-term impact will be clinical research laboratories where this innovation can be used for the detection and characterization of amyloids in vivo, i.e. for tissue biopsies, rapid detection of amyloids and drug screening.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 125.00K | Year: 2010

This Small Business Innovation Research (SBIR) Phase I project is focused on the creation of a new revolutionary imaging instrumentation that combines vibrational circular dichroism (VCD) spectroscopy with infrared (IR) spectral microscopy. VCD microscopy represents a new class of spectroscopic imaging diagnostic capable of measuring VCD images with millimeter to sub-millimeter spatial resolution. The recent discovery that long-range structural chirality in protein fibrils is characterized by unusually large and distinctive VCD spectra provides the backdrop for this project. None of the currently available techniques can characterize the fibrillation pathway or the final fibril state with the same ease and detail as VCD. VCD microscopy can be thought of as circular polarization contrast microscopy that is sensitive to long-range chiral order in localized regions of biological samples. The broader impacts of this research are studies of the supramolecular chirality of fibrils. This product is not a small improvement of an existing technology but a distinctly new method of studying long-range biochirality that is more sensitive, provides more detail, and is easy and fast to use. A secondary, higher-impact long-term impact will be clinical research laboratories where this innovation can be used for the detection and characterization of amyloids in vivo, i.e. for tissue biopsies, rapid detection of amyloids and drug screening.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: SMALL BUSINESS PHASE II | Award Amount: 476.69K | Year: 2011

This Small Business Innovation Research (SBIR) Phase II project is focused on the creation of a new revolutionary imaging instrumentation that combines vibrational circular dichroism (VCD) spectroscopy with infrared (IR) spectral microscopy. VCD microscopy represents a new class of spectroscopic imaging diagnostic capable of measuring VCD images with millimeter to sub-millimeter spatial resolution. The recent discovery that long-range structural chirality in protein fibrils is characterized by unusually large and distinctive VCD spectra provides the backdrop for this project. None of the currently available techniques can characterize the fibrillation pathway or the final fibril state with the same ease and detail as VCD. VCD microscopy can be thought of as circular polarization contrast microscopy that is sensitive to long-range chiral order in localized regions of biological samples.

The broader impacts of this research are studies of the supramolecular chirality of fibrils. This product is not a small improvement of an existing technology but a distinctly new method of studying long-range biochirality that is more sensitive, provides more detail, and is easy and fast to use. A secondary, higher-impact long-term impact will be clinical research laboratories where this innovation can be used for the detection and characterization of amyloids in vivo, i.e. for tissue biopsies, rapid detection of amyloids and drug screening.

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