Resume

• 2009

  Ph.D.

  Organic Chemistry

  The Lindsley Lab

  Chemical Biology Association of Students Executive Board

  Chemical Biology Certificate Program

  Vanderbilt Institute for Chemical Biology Symposium Planning Committee

  American Chemical Society

  Vanderbilt University

• 2005

  B.S.

  Biology

  Phi Beta Kappa Honor Society

  Mortar Board Honor Society

  Alpha Epsilon Delta Honor Society

  Manresa Orientation Team (Freshman Orientation)

  Teacher's Assistant-Chemistry 105

  Learning Assistance Center Supplemental Instructor and Tutor

  Intramural (floor hockey

  softball

  volleyball)

  Community Action Day Site Leader

  South Asian Society Dance Team

  Alternative Breaks-Service Trips to Baltimore and Tucson

  Speaker at the First Year Student Retreat

  Certificate in College Teaching

  Vanderbilt University

  Certificate in Chemical Biology

  Vanderbilt University

• 3

  Keri A. Tallman

  Michelle D. Armstrong

  David S. Myers

  Hyekyung P. Cho

  Thomas P. Mathews

  Yun Xiang

  Sarah A. Scott

  Journal of Biological Chemistry

  Phosphatidic acid (PA) is a lipid second messenger located at the intersection of several lipid metabolism and cell signaling events including membrane trafficking

  survival

  and proliferation. Generation of signaling PA has long been primarily attributed to the activation of phospholipase D (PLD). PLD catalyzes the hydrolysis of phosphatidylcholine into PA. A variety of both receptor-tyrosine kinase and G-protein-coupled receptor stimulations have been shown to lead to PLD activation and PA generation. This study focuses on profiling the PA pool upon P2Y6 receptor signaling manipulation to determine the major PA producing enzymes. Here we show that PLD

  although highly active

  is not responsible for the majority of stable PA being produced upon UDP stimulation of the P2Y6 receptor and that PA levels are tightly regulated. By following PA flux in the cell we show that PLD is involved in an initial increase in PA upon receptor stimulation; however

  when PLD is blocked

  the cell compensates by increasing PA production from other sources. We further delineate the P2Y6 signaling pathway showing that phospholipase Cβ3 (PLCβ3)

  PLCδ1

  DGKζ and PLD are all downstream of receptor activation. We also show that DGKζ is a novel negative regulator of PLD activity in this system that occurs through an inhibitory mechanism with PKCα. These results further define the downstream events resulting in PA production in the P2Y6 receptor signaling pathway.

  Regulation of Phospholipase D activity and phosphatidic acid production downstream of the Purinergic (P2Y6) receptor

  Development of dual PLD1/2 and PLD2 selective inhibitors from a common 1

  8-triazaspiro[4.5]decane core: discovery of ML298 and ML299 that decrease invasive migration in U87-MG glioblastoma cells

  H. Alex Brown

  Ryan Morrison

  J Scott Daniels

  Paul G Thomas

  Thomas H Oguin III

  Kyle A Brown

  Sarah A Scott

  An iterative parallel synthesis effort identified a PLD2 selective inhibitor

  ML298 (PLD1 IC50 > 20 000 nM

  PLD2 IC50 = 355 nM) and a dual PLD1/2 inhibitor

  ML299 (PLD1 IC50 = 6 nM

  PLD2 IC50 = 20 nM). SAR studies revealAn iterative parallel synthesis effort identified a PLD2 selective inhibitor

  ML298 (PLD1 IC50 > 20 000 nM

  PLD2 IC50 = 355 nM) and a dual PLD1/2 inhibitor

  ML299 (PLD1 IC50 = 6 nM

  PLD2 IC50 = 20 nM). SAR studies revealed that a small structural change (incorporation of a methyl group) increased PLD1 activity within this classically PLD2-preferring core and that the effect was enantiospecific. Both probes decreased invasive migration in U87-MG glioblastoma cells.ed that a small structural change (incorporation of a methyl group) increased PLD1 activity within this classically PLD2-preferring core and that the effect was enantiospecific. Both probes decreased invasive migration in U87-MG glioblastoma cells.

  Development of dual PLD1/2 and PLD2 selective inhibitors from a common 1

  8-triazaspiro[4.5]decane core: discovery of ML298 and ML299 that decrease invasive migration in U87-MG glioblastoma cells

  In this Letter

  we describe a novel three-step

  one-pot procedure for the enantioselective synthesis of N-benzyl protected morpholines and orthogonally N

  N′-protected piperazines with chiral alkyl groups installed at the C2 position of each heterocyclic core via organocatalysis. This methodology allows for the rapid preparation of functionalized morpholines and piperazines that are not readily accessible through any other chemistry in good to excellent % ee (55–98% ee).

  Enantioselective synthesis of C2-functionalized

  N-protected morpholines and orthogonally N

  N’-protected piperazines via organocatalysis

  A short

  high yielding protocol has been developed for the enantioselective and general synthesis of C2-functionalized

  benzyl protected morpholines and orthogonally N

  N′-protected piperazines from a common intermediate.

  A General

  Enantioselective Synthesis of Protected Morpholines and Piperazines

  Gary A. Sulikowski

  A short

  high-yielding protocol involving the enantioselective α-chlorination of aldehydes has been developed for the enantioselective synthesis of C2-functionalized aziridines and N-alkyl terminal azetidines from a common intermediate. This methodology allows for the rapid preparation of functionalized aziridines in 50–73% overall yields and 88–94% ee

  and azetidines in 22–32% overall yields and 84–92% ee. Moreover

  we developed a scalable and cost-effective route to the key organocatalyst (54% overall yield

  >95% dr).

  A General

  Enantioselective Synthesis of N-Alkyl Terminal Aziridines and C2-Functionalized Azetidines via Organocatalysis

  O'Reilly

  Nashville State Community College

  University of Wisconsin-Madison

  Vanderbilt University

  University of Wisconsin-River Falls

  Xavier University

  - taught 3 study groups/week\n- study groups in general chemistry during my first year and organic chemistry in my second year

  Xavier University

  University of Wisconsin-Madison

  Madison

  Wisconsin

  See Arnold O. Beckman Postdoctoral Fellow description above.

  Postdoctoral Research Associate

  - taught 2 semesters of general chemistry lecture and laboratory\n- class sizes were around 30 students\n- designed the syllabus

  grading scales

  tests

  and homework assignments

  Adjunct Professor

  Greater Nashville Area

  TN

  Nashville State Community College

  River Falls

  WI

  Teach chemistry in the classroom and research in the laboratory.

  Assistant Professor

  University of Wisconsin-River Falls

  Madison

  Wisconsin

  I am one of two people in charge of a seminar series\n- organize monthly speakers that either present on current research or career development skills\n- the seminars are sponsored by Sigma-Aldrich

  which provides lunch to those who attend

  Co-Director

  Postdoctoral Seminar Series

  University of Wisconsin-Madison

  Madison

  Wisconsin

  I perform chemical biology research in the Blackwell Laboratory at the University of Wisconsin-Madison. \n\n- I synthesize small molecules to explore their activity as quorum sensing inhibitors\n- I perform assays to evaluate the activity of various compounds at LuxR-type receptors in Gram-negative bacteria\n- I use site directed mutagenesis involving PCR

  cloning

  and transformations to evaluate how structural components of LuxR-type receptors relate to their ligand binding properties

  Arnold O. Beckman Postdoctoral Fellow

  University of Wisconsin-Madison

  Department of Chemistry\nLaboratory of Craig W. Lindsley\nDissertation Title: Application of Organocatalysis to the Synthesis of Chiral Morpholines

  Piperazines

  Aziridines

  Azetidines

  B-Fluoroamines

  and y-fluoroamines; Discovery of Selective Phospholipase D Inhibitors with Optimized in vivo Properties\n\n- applied enamine organocatalysis to develop general methods of synthesizing chiral pharmaceutically relevant heterocycles\n- effectively implemented modern medicinal chemistry methods while developing selective inhibitors of phospholipase D\n- collaborated with the laboratories of H. Alex Brown and Paul G. Thomas\n- utilized microwave assisted synthesis protocols

  automated flash column chromatography

  HPLC

  LC-MS

  and NMR techniques for compound synthesis

  purification

  and characterization\n- taught undergraduate level recitation for sections of 20-30 students\n- substituted taught for Prof. Michelle Sulikowski during her summer organic courses with class sizes of greater than 60 students\n- mentored various undergraduate students

  and taught synthetic techniques to junior graduate students

  Graduate Research Assistant

  Greater Nashville Area

  TN

  Vanderbilt University

  - involved in training and payroll for supplemental instructors

  Student Leader

  Supplemental Instruction

  Cincinnati

  Ohio Area

  Xavier University

  - planned and coordinated career development

  social events

  and seminars for graduate students and postdocs\n- engaged with over 80 research groups that are part of the Vanderbilt Institute of Chemical Biology\n- organized two annual Vanderbilt Institute of Chemical Biology Symposia that featured oral and poster presentations from over 70 graduate students and postdocs and an oral presentation from a non-Vanderbilt keynote speaker

  Secretary and Executive Board Member

  Chemical Biology Association of Students

  Greater Nashville Area

  TN

  Vanderbilt University

• Microsoft Office

  Chemistry

  Word

  Biochemistry

  Microsoft Word

  Life Sciences

  HPLC

  Research

  Organic Chemistry

  PCR

  Spectroscopy

  Data Analysis

  PowerPoint

  Molecular Biology

  Lunch

  Science

  UV/Vis

  Mass Spectrometry

  NMR

  Cell Culture

  Name Reactions for Carbocyclic Ring Formations

  Richard J. Mullins

  John Wiley and Sons

  Inc.

  We wrote a chapter in this book about the 'Houben-Hoesch Reaction.'

  Name Reactions for Carbocyclic Ring Formations

  H. Alex Brown

  Sarah A. Scott

  This Letter describes the on-going SAR efforts based on two scaffolds

  a PLD1-biased piperidinyl benzimidazolone and a PLD2-biased piperidinyl triazaspirone

  with the goal of enhancing PLD inhibitory potency and isoform selectivity. Here

  we found that addition of an α-methyl moiety within the PLD2-biased piperidinyl triazaspirone scaffold abolished PLD2 preference

  while the incorporation of substituents onto the piperidine moiety of the PLD1-biased piperidinyl benzimidazolone

  or replacement with a bioisosteric [3.3.0] core

  generally retained PLD1 preference

  but at diminished significance. The SAR uncovered within these two allosteric PLD inhibitor series further highlights the inherent challenges of developing isoform selective PLD inhibitors.

  Further evaluation of novel structural modifications to scaffolds that engender PLD isoform selective inhibition.

  In this Letter

  we describe a short

  high yielding protocol for the enantioselective (87–96% ee) and general synthesis of β-fluoroamines and previously difficult to access γ-fluoroamines from commercial aldehydes via organocatalysis.

  A general

  enantioselective synthesis of β and γ-fluoroamines

  Helen E. Blackwell

  Many common bacterial pathogens utilize quorum sensing to coordinate group behaviors and initiate virulence at high cell densities. The use of small molecules to block quorum sensing provides a means of abrogating pathogenic phenotypes

  but many known quorum sensing modulators have limitations

  including hydrolytic instability and displaying non-monotonic dose curves (indicative of additional targets and/or modes of action). To address these issues

  we undertook a structure-based scaffold-hopping approach to develop new chemical modulators of the LasR quorum sensing receptor in Pseudomonas aeruginosa. We combined components from a triphenyl derivative known to strongly agonize LasR with chemical moieties known for LasR antagonism and generated potent LasR antagonists that are hydrolytically stable across a range of pH values. Additionally

  many of these antagonists do not exhibit non-monotonic dose effects

  delivering probes that inhibit LasR across a wider range of assay conditions relative to known lactone-based ligands.

  Structure-Based Design and Biological Evaluation of Triphenyl Scaffold-Based Hybrid Compounds as Hydrolytically Stable Modulators of a LuxR-Type Quorum Sensing Receptor

  H. Alex Brown

  Richard C. Larock

  Dai-II Jung

  Chul-Hee Cho

  Kyle A Brown

  Cierra T. Spencer

  Sarah A. Scott

  ACS Chemical Biology

  Phospholipase D (PLD) hydrolyses cellular lipids to produce the important lipid second messenger phosphatidic acid. A PLD enzyme expressed by Pseudomonas aeruginosa (PldA) has been shown to be important in bacterial infection

  and NAPE-PLD has emerged as being key in the synthesis of endocannabinoids. In order to better understand the biology and therapeutic potential of these less explored PLD enzymes

  small molecule tools are required. Selective estrogen receptor modulators (SERMs) have been previously shown to inhibit mammalian PLD (PLD1 and PLD2). By targeted screening of a library of SERM analogues

  additional parallel synthesis

  and evaluation in multiple PLD assays

  we discovered a novel desketoraloxifene-based scaffold that inhibited not only the two mammalian PLDs but also structurally divergent PldA and NAPE-PLD. This finding represents an important first step toward the development of small molecules possessing universal inhibition of divergent PLD enzymes to advance the field.

  Discovery of desketoraloxifene analogues as inhibitors of mammalian

  Pseudomonas aeruginosa

  and NAPE phospholipase D enzymes.

  Chemical strategies to block quorum sensing (QS) could provide a route to attenuate virulence in bacterial pathogens. Considerable research has focused on this approach in Pseudomonas aeruginosa

  which uses the LuxR-type receptor LasR to regulate much of its QS network. Non-native ligands that antagonize LasR have been developed

  yet we have little understanding of the mode by which these compounds interact with LasR and alter its function

  as the receptor is unstable in their presence. Herein

  we report an approach to circumvent this challenge through the study of a series of synthetic LasR agonists with varying levels of potency. Structural investigations of these ligands with the LasR ligand-binding domain reveal that certain agonists can enforce a conformation that deviates from that observed for other

  often more potent agonists. These results

  when combined with cell-based and biophysical analyses

  suggest a functional model for LasR that could guide future ligand design.

  Structural and Biochemical Studies of Non-native Agonists of the LasR Quorum-Sensing Receptor Reveal an L3 Loop “Out” Conformation for LasR

  H. Alex Brown

  J. Scott Daniels

  Ryan D. Morrison

  Paul G. Thomas

  Sarah A. Scott

  Thomas H. Oguin III

  Further chemical optimization of the halopemide-derived family of dual phospholipase D1/2 (PLD1/2) inhibitors afforded ML395 (VU0468809)

  a potent

  >80-fold PLD2 selective allosteric inhibitor (cellular PLD1

  IC50>30 000 nm; cellular PLD2

  IC50=360 nm). Moreover

  ML395 possesses an attractive in vitro DMPK profile

  improved physiochemical properties

  ancillary pharmacology (Eurofins Panel) cleaner than any other reported PLD inhibitor

  and has been found to possess interesting activity as an antiviral agent in cellular assays against a range of influenza strains (H1

  H3

  H5 and H7).

  Discovery of a highly selective PLD2 inhibitor (ML395): a new probe with improved physiochemical properties and broad-spectrum antiviral activity against influenza strains

  H. Alex Brown