About

Michael Hilinski is an Associate Professor of Chemistry at the University of Virginia. He earned his B.S. from Tufts University in 2000 and his Ph.D. from Stanford University in 2007. Following his doctoral studies, he was a DOD postdoctoral fellow at the University of Virginia from 2009 to 2013. His research focuses on the science of organic synthesis, which is central to the discovery and manufacturing of pharmaceuticals and fine chemicals. His work aims to advance the field of synthesis to enable the production of any molecule in a manner that minimizes cost, time, manpower, and environmental impact, thereby removing synthetic barriers to the discovery of new therapeutics.

Research topics

• Chemistry
• Organic chemistry
• Combinatorial chemistry
• Photochemistry
• Inorganic chemistry
• Physical chemistry

Selected publications

• A first-in-class small-molecule inhibitor targeting AVIL exhibits safety and antitumor efficacy in preclinical models of glioblastoma

  Science Translational Medicine · 2026-01-28 · 4 citations

  article

  Glioblastoma (GBM) is the most common and deadliest malignancy of the brain. Despite decades of intense research, there has been little change to the overall survival of patients with GBM. Our laboratory recently identified the actin-binding protein advillin (AVIL) as being overexpressed, oncogenic, and necessary for tumorigenesis in GBM. Here, we further examined AVIL expression in GBMs and found that it was enriched across molecular subtypes and states, including GBM stem cells and temozolomide-resistant samples. In contrast, we found that AVIL was scarcely expressed in normal human brain tissue. In addition, Avil knockout in mice had no adverse effects, suggesting that there may be a wide therapeutic window for therapies targeting AVIL. Using high-throughput small-molecule screening, we identified a direct inhibitor of AVIL that bound to the protein and also blocked AVIL binding to its substrate, actin. It induced a transcriptome profile similar to that of AVIL silencing by siRNA and caused down-regulation of FOXM1 and LIN28B, two known downstream targets of AVIL. Moreover, it exhibited selectivity toward tumor cells, sparing astrocytes and neural stem cells in vitro. In vivo, we found that the compound readily crosses the blood-brain barrier and could be delivered orally. We then demonstrated efficacy in five GBM mouse models without evidence of side effects. In summary, we have identified an efficacious first-in-class compound targeting an oncogene in GBM. Further optimization of the molecule may offer an effective therapeutic intervention for GBM.

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• Metal-Free Homogeneous O₂ Reduction by an Iminium-Based Electrocatalyst

  Journal of the American Chemical Society · 2024 · 8 citations

  • Chemistry
  • Inorganic chemistry
  • Photochemistry

  O is produced. This difference in selectivity is attributed to the interception of the free superoxide intermediate under electrochemical conditions by the reduced catalyst, accessing an alternate inner-sphere pathway.

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• Correction to “Metal-Free Homogeneous O₂ Reduction by an Iminium-Based Electrocatalyst”

  Journal of the American Chemical Society · 2024-04-15

  erratumOpen access

  ADVERTISEMENT RETURN TO ARTICLES ASAPPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to "Metal-Free Homogeneous O2 Reduction by an Iminium-Based Electrocatalyst"Emma N. CookEmma N. CookMore by Emma N. Cookhttps://orcid.org/0000-0002-0568-3600, Anna E. DavisAnna E. DavisMore by Anna E. Davis, Michael K. Hilinski*Michael K. HilinskiMore by Michael K. Hilinskihttps://orcid.org/0000-0003-2861-7099, and Charles W. Machan*Charles W. MachanMore by Charles W. Machanhttps://orcid.org/0000-0002-5182-1138Cite this: J. Am. Chem. Soc. 2024, XXXX, XXX, XXX-XXXPublication Date (Web):April 15, 2024Publication History Received20 March 2024Published online15 April 2024https://doi.org/10.1021/jacs.4c03956© 2024 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0. License Summary*You are free to share (copy and redistribute) this article in any medium or format and to adapt (remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:Creative Commons (CC): This is a Creative Commons license.Attribution (BY): Credit must be given to the creator.View full license*DisclaimerThis summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials. This publication is Open Access under the license indicated. Learn MoreArticle Views-Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (619 KB) Get e-Alertsclose Get e-Alerts

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• Amine Organocatalysis of Remote, Chemoselective C(sp³)–H Hydroxylation

  ACS Catalysis · 2022 · 23 citations

  Senior authorCorresponding
  • Chemistry
  • Combinatorial chemistry
  • Organic chemistry

  We introduce an organocatalytic approach for oxaziridinium-mediated C-H hydroxylation that employs secondary amines as catalysts. We also demonstrate the advantages of this operationally simple catalytic strategy for achieving high yielding and highly selective remote hydroxylation of compounds bearing oxidation-sensitive functional groups such as alcohols, ethers, carbamates, and amides. By employing hexafluoroisopropanol as the solvent in the absence of water, a proposed hydrogen bonding effect leads to, among other advantages, as high as ≥99:1 chemoselectivity for remote aliphatic hydroxylation of 2° alcohols, an otherwise unsolved synthetic challenge normally complicated by substantial amounts of alcohol oxidation. Initial studies of the reaction mechanism indicate the formation of an oxaziridinium salt as the active oxidant, and a C-H oxidation step that proceeds in a stereospecific manner via concerted insertion or hydrogen atom transfer/radical rebound. Furthermore, preliminary results indicate that site selectivity can be affected by amine catalyst structure. In the long term, we anticipate that this will enable new strategies for catalyst control of selectivity based on the abundance of catalytic scaffolds that have proliferated over the last twenty years as a result of Nobel Prize-winning discoveries.

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• Vinylazaarenes as dienophiles in Lewis acid-promoted Diels–Alder reactions

  Chemical Science · 2021 · 12 citations

  Senior authorCorresponding
  • Chemistry
  • Combinatorial chemistry
  • Organic chemistry

  Described are the first examples of Lewis acid-promoted Diels-Alder reactions of vinylpyridines and other vinylazaarenes with unactivated dienes. Cyclohexyl-appended azaarenes constitute a class of substructures of rising prominence in drug discovery. Despite this, thermal variants of the vinylazaarene Diels-Alder reaction are rare and have not been adopted for synthesis, and Lewis acid-promoted variants are virtually unexplored. The presented work addresses this gap and in the process furnishes increased scope, dramatically higher yields, improved regioselectivity, and high levels of diastereoselectivity compared to prior thermal examples. These reactions provide scalable access to druglike scaffolds not readily available through other methods. More broadly, these studies establish a useful new class of dienophiles that, based on preliminary mechanistic studies, should be amenable to conventional strategies for enantioselective catalysis.

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• 1,1,1‐Trifluoro‐2‐Hexanone

  2020-01-23

  articleSenior author
  PublisherDOI

• Rh(II)-Catalyzed Nitrene-Transfer [5 + 1] Cycloadditions of Aryl-Substituted Vinylcyclopropanes

  Organic Letters · 2019-03-25 · 36 citations

  articleOpen accessSenior authorCorresponding

  Formal [5 + 1] cycloadditions between aryl-substituted vinylcyclopropanes and nitrenoid precursors are reported. The method, which employs Rh2(esp)2 as a catalyst, leads to the highly regioselective formation of substituted tetrahydropyridines. Preliminary mechanistic studies support a stepwise, polar mechanism enabled by the previously observed Lewis acidity of Rh-nitrenoids. Overall, this work expands the application of nitrene-transfer cycloaddition, a relatively underexplored approach to heterocycle synthesis, to the formation of six-membered rings.

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• Intermolecular scandium triflate-promoted nitrene-transfer [5 + 1] cycloadditions of vinylcyclopropanes

  Organic & Biomolecular Chemistry · 2019-01-01 · 6 citations

  articleSenior authorCorresponding

  Sc(OTf)3-promoted [5 + 1] cycloaddition of vinylcyclopropanes with PhINTs is reported, enabling the regioselective preparation of a range of 1,2,3,6-tetrahydropyridine scaffolds under mild conditions. This represents the second example of a [5 + 1] nitrene-transfer cycloaddition and exhibits complementary substrate scope to the antecedent work, expanding the range of N-heterocycles accessible via this strategy.

  PublisherDOI

• Organocatalytic Olefin Aziridination via Iminium-Catalyzed Nitrene Transfer: Scope, Limitations, and Mechanistic Insight

  The Journal of Organic Chemistry · 2019-06-07 · 24 citations

  articleOpen accessSenior authorCorresponding

  Olefin aziridination via organocatalytic nitrene transfer offers potential complementarity to metal-catalyzed methods; however there is a lack of reports of such reactions in the literature. Herein is reported a method that employs an iminium salt to catalyze the aziridination of styrenes by [ N-( p-toluenesulfonyl)imino]phenyliodinane (PhINTs). These reactions are hypothesized to proceed via a diaziridinium salt as the active oxidant. In addition to outlining the scope and limitations of the method, evidence for a polar, stepwise mechanism is presented, which provides new insight into the nature of iminium catalysis of nitrene transfer.

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• Mechanism of Iminium Salt-Catalyzed C(sp³)–H Amination: Factors Controlling Hydride Transfer versus H-Atom Abstraction

  ACS Catalysis · 2019-12-09 · 7 citations

  articleOpen accessCorresponding

  Carbon–nitrogen bonds are extremely prevalent in pharmaceuticals, natural products, and other biologically relevant molecules such as nucleic acids and proteins. Intermolecular amination of C(sp3)–H bonds by catalytic nitrene transfer is a promising method for forging C–N bonds. An organocatalytic approach to nitrene transfer by way of an iminium salt offers a site-selective method for C(sp3)–H amination. Understanding of this amination mechanism including the nature of the relevant intermediates and the factors controlling the mechanism of the N–H bond formation step would aid in the design of catalysts and C(sp3)–H amination methods. In this work, the mechanism of the iminium salt-catalyzed C(sp3)–H amination via nitrene transfer was elucidated computationally using quantum mechanical methods and molecular dynamics simulations. Dispersion-corrected density functional theory calculations provide support for an open singlet biradical species in equilibrium with the lower energy triplet species. Calculations further reveal that, while the singlet biradical species undergoes N–H bond formation by a hydride transfer process, the triplet species forms the N–H bond by H-atom abstraction. Molecular dynamics simulations rule out the possibility of a fast rebound of the carbon substrate following N–H bond formation. A predictive model for mode of activation and site selectivity that is consistent with experimental observations is presented.

  PublisherOA PDFDOI

Recent grants

• Organocatalytic Site-Selective C-H Bond Functionalization

  NIH · $1.5M · 2017–2022

• CAREER: New Methods for the Synthesis of Nitrogen-Containing Heterocycles

  NSF · $675k · 2019–2024

Frequent coauthors

• Logan A. Combee

  University of Michigan–Ann Arbor

  16 shared

• Paul A. Wender

  Stanford University

  13 shared

• Susan L. Mooberry

  The University of Texas Health Science Center at San Antonio

  12 shared

• Nicolas Soldermann

  Novartis (Switzerland)

  8 shared

• William G. Shuler

  7 shared

• Julie E. Laudenschlager

  6 shared

• Shea L. Johnson

  Cerevel Therapeutics (United States)

  6 shared

• Isaac D. Falk

  Gilead Sciences (United States)

  5 shared