POSTER SESSION

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Taming Shapeshifting Anions: Total Synthesis of Ocellatusone C, by Andre Sanchez

Taming Shapeshifting Anions: Total Synthesis of Ocellatusone C, by Andre Sanchez

Bridged bicyclo[3.3.1] and [3.2.2]nonane carbon frameworks are privileged structural motifs found in over 1000 natural products– many with therapeutic relevance to human disease. Empowered by a synthetic design rooted in late-stage diversification, we present the discovery, study, and facile synthesis of unusual shapeshifting anions and their subsequent application to the total synthesis of the polyketide natural product, ocellatusone C. Site-selective core functionalization of a readily...

Progress Towards the Asymmetric Synthesis of Alopecurone C featuring C-H Insert... by Yuanshin Shiue

Progress Towards the Asymmetric Synthesis of Alopecurone C featuring C-H Insert... by Yuanshin Shiue

The alopecurone family, isolated from Sophora alopecuroides, shows promise as a potential lead compound for drug discovery due to its promising biological properties. For instance, alopecurone C has reported antibiotic activity against greater than 20 strains of methicillin-resistant Staphylococcus aureus (MRSA). Herein, we report two divergent synthetic routes to alopecurone C, F, and L and derivatives. The first-generation route utilizes a highly enantioselective C–H insertion reaction...

Copper-Catalyzed Benzylic C–H Cross Couplings Enabled by Redox Buffering, by Si-Jie Chen

Copper-Catalyzed Benzylic C–H Cross Couplings Enabled by Redox Buffering, by Si-Jie Chen

The prevalent use of C(sp2)-hybridized reagents in traditional cross-coupling reactions has resulted in largely "flat" compounds and contributed to a growing demand of three-dimensionality in compound libraries. C(sp3)–H bonds adjacent to aromatic rings are ubiquitous moieties in medicinally relevant building blocks. These benzylic C(sp3)–H bonds are intrinsically reactive and represent a wealth of opportunities for C–H functionalization and synthesis of three-dimensional (3D) structures...

Biomimetic Total Synthesis and Investigation of the Non‑Enzymatic Chemistry of... by Rahul D. Shinga

Biomimetic Total Synthesis and Investigation of the Non‑Enzymatic Chemistry of... by Rahul D. Shinga

The first total synthesis of an antimycobacterial natural product oxazinin A that takes advantage of a multi-component cascade reaction of anthranilic acid and a precursor polyketide containing an aldehyde. The route utilized for the synthesis of the pseudodimeric oxazinin A validates a previously proposed biosynthetic mechanism, invoking a non-enzymatic pathway to the complex molecule. Further investigation of the non-enzymatic formation of oxazinin A using 1H-15N HMBC NMR spectroscopy allowed

Diastereoselective Addition of Prochiral Nucleophilic Alkenes to α-Chiral... by David A. Gutierrez

Diastereoselective Addition of Prochiral Nucleophilic Alkenes to α-Chiral... by David A. Gutierrez

The Lewis-acid-promoted addition of prochiral E- and Z-allyl nucleophiles to chiral α-alkoxy N-tosyl imines is described. Alkene geometry is selectively transferred to the newly formed carbon–carbon bond, resulting in stereochemical control of C1, C2, and C3 of the resulting 2-alkoxy-3-N-tosyl-4-alkyl-5-hexene products. A computational analysis to elucidate the high selectivity is also presented. This methodology was employed in the synthesis of two naturally occurring isomers of clausenamide

Impact of host flexibility on selectivity in the enantioselective supramolecular-host... by Judy Pan

Impact of host flexibility on selectivity in the enantioselective supramolecular-host... by Judy Pan

A highly enantioselective aza-Darzens reaction (up to 99% ee) catalyzed by an enantiopure supramolecular host has been discovered. To understand the role of host structure on reaction outcome, nine new gallium(III)-based enantiopure supramolecular assemblies were prepared via substitution of the external chiral amide. Despite the distal nature of the substitution in these catalysts, changes in enantioselectivity (61% ee to 90% ee) in the aziridine product were observed...

Progress Toward the Diversification of 2-Pyrones, by Kristen Gardner

Progress Toward the Diversification of 2-Pyrones, by Kristen Gardner

The versatility of 2-pyrones as starting materials for ring-forming processes en route to bioactive compounds such as pharmaceuticals has been explored for almost a century. Direct pericyclic annulations of 2-pyrones, such as [4+2]-cycloadditions and 4π electrocyclizations, have proven to be effective tactics for accessing synthetically versatile bicycles that have been applied, for example, in natural product total synthesis. Alternatively, novel annulation...

Synthesis and Development of Chiral Amide Silanol-Containing Ligands for Asymm... by Yun-Pu Chang

Synthesis and Development of Chiral Amide Silanol-Containing Ligands for Asymm... by Yun-Pu Chang

Silanol compounds contain a unique Si‚àíOH bond with opportunities to design new ligands for asymmetric catalysis. Although simple alkyl silanols have been previously utilized as ancillary ligands for metal-catalyzed transformations, their application has been relatively underexplored in enantioselective catalysis due to challenges in synthesis and limited investigations of functionalized silanol-containing ligands. Using silanol-containing ligands for asymmetric catalysis offers advantages...

Photo-Brook Rearrangement of Acylsilanes as a Strategy for Photoaffinity Probe Design by Annika Page

Photo-Brook Rearrangement of Acylsilanes as a Strategy for Photoaffinity Probe Design by Annika Page

Photoaffinity labeling (PAL) is a powerful tool for the identification of non-covalent small molecule-protein interactions that are critical to drug discovery and medicinal chemistry, but this approach is limited to only a small subset of robust photocrosslinkers. The identification of new photoreactive motifs capable of covalent target capture is therefore highly desirable. We report the design, synthesis, and evaluation of a new class of PAL warheads based on the UV-triggered 1,2-photo...

Total Synthesis of Resiniferatoxin, by Vasil H. Vasilev

Total Synthesis of Resiniferatoxin, by Vasil H. Vasilev

A 15-step Total Synthesis of Resiniferatoxin: The total synthesis of the structurally complex and highly biologically active daphnane diterpenoid resiniferatoxin was achieved via a stereoselective and convergent synthetic route in 15 steps (longest linear sequence). Key carbon-carbon bond forming reactions to construct the daphnane diterpene core of this natural product include an allylation/Heck cyclization cascade as well as a sequence of highly diastereoselective aldol reaction and SmI2...

Progress towards the Asymmetric Synthesis of Cycloartobiloxanthanone and... by Cheng-En Hsieh

Progress towards the Asymmetric Synthesis of Cycloartobiloxanthanone and... by Cheng-En Hsieh

Herein, we report the progress towards the total syntheses of cycloartobiloxanthanone and phayomphenol A1. Two natural products possess promising bioactivities that could have great potential as lead compounds for drug discovery. Cycloartobiloxanthanone could be synthesized by the fusion of a benzodihydrofuran fragment and a chromene fragment. The chromene core has been prepared in 40% yield (gram scale) in only 6 steps. Three different synthetic routes to the key benzodihydrofuran interm...

Total synthesis of baphicacanthcusine A enabled by sequential ring contractions, by Paul Sinclair

Total synthesis of baphicacanthcusine A enabled by sequential ring contractions, by Paul Sinclair

Recent phytochemical investigations of the flowering plant B. cusia have yielded numerous bioactive natural products containing multiple pseudoindoxyl heterocycles affixed to a central five-membered ring. The bis-pseudoindoxyl alkaloid baphicacanthcusine A is exemplary of this class of natural products and is a challenging synthetic target due to its dense functionalization and three contiguous stereocenters. Herein we report the first total synthesis of baphicacanthcusine A from the known...

Catalytic Enantioselective Synthesis of Siloxanols from Prochiral Silanediols, by Jacob Dalton

Catalytic Enantioselective Synthesis of Siloxanols from Prochiral Silanediols, by Jacob Dalton

Enantioenriched chiral-at-silicon compounds have been studied as chiral auxiliaries, resolving agents, and as drug candidates. Chiral silicon compounds offer unique reactivities and physical properties that are not available for carbon chemistry and are thus of great interest. There are currently limited methods for the synthesis of enantioenriched silicon centers. In this work, we report the enantioselective synthesis of bifunctional stereogenic-at-silicon compounds via silylation of a...

Organic Synthesis

Fragment-Based Drug Discovery of 14-3-3/Client Stabilizers, by Dyana Kenanova

Fragment-Based Drug Discovery of 14-3-3/Client Stabilizers, by Dyana Kenanova

Protein-protein interactions (PPIs) are pivotal to biological processes and their dysregulation is closely associated with the development of disease. The Arkin lab and our colleagues have developed a systematic strategy for targeting PPIs via a small molecule disulfide tethering screen. Although this strategy is well validated for discovering PPI inhibitors, it is far less explored in discovering PPI stabilizers. Methods to modulate specific edges in a PPI network via selective stabilization...

Synthesis and Properties of Stable Metal Halide Molecular Clusters in Solid State, by Heng Zhang

Synthesis and Properties of Stable Metal Halide Molecular Clusters in Solid State, by Heng Zhang

Molecular clusters (MCs) function as building block for bulk crystals, for which the properties can be tuned by controlling the size, composition, and intra-cluster interactions of clusters. By understanding the growth process and structure of MCs, it benefits with the understanding and tuning of large-size nanocrystals or bulk crystals. Here, we synthesized and characterized small sized and stable MCs composed of PbBr2 and butylamine (BTYA), which show identical optical properties from solution

Intercept and redirect: The role of vanadium dependent haloperoxidases on... by Jackson Baumgartner

Intercept and redirect: The role of vanadium dependent haloperoxidases on... by Jackson Baumgartner

Vanadium-dependent haloperoxidases (VHPOs) are a unique family of enzymes that utilize a histidine-bound vanadate cofactor and hydrogen peroxide to oxidize a halide to hypohalous acid. Previously, Streptomycete homologs were discovered to be involved in the site-selective and substrate-specific halogenation of meroterpenoid natural products. Since then, site-selective VHPOs have remained under-explored despite the broad species distribution, high biocatalytic potential, and environmental...

Conditional Uncaging based on Bioorthogonal Chemistry, by Márton Bojtár

Conditional Uncaging based on Bioorthogonal Chemistry, by Márton Bojtár

In this work the the proof of concept study of a bioorthogonal click reaction activatable photocage system is demonstrated. In additional to the fluorescence, the bioorthogonal tetrazine motif efficiently quenches the excited state of a coumarin derivative necessary for photolysis resulting in disabled photoresponsivity. Transformation of the tetrazine moiety in a bioorthogonal click-reaction fully restores its sensitivity for light. Since bioorthogonal reactions enable highly specific...

11B NMR as a Small Molecule Discovery Tool, by Riley M. Blue

11B NMR as a Small Molecule Discovery Tool, by Riley M. Blue

Boron is an essential element found in plants and animals; however its essential role in mammalian life is still poorly understood. Currently in the field, the boron containing compounds isolated so far have displayed interesting biological and biomedical signatures when incorporated into metabolites. The boron-containing compounds that have been discovered display the broad fields they can be applied to that expand beyond drugs and into the understanding of how biological systems function...

Optical Determination of Absolute Membrane Potential Throughout the Cell... by Susanna Yaeger-Weiss

Optical Determination of Absolute Membrane Potential Throughout the Cell... by Susanna Yaeger-Weiss

All cells maintain a membrane potential (Vm) that is critical for cell function and plays a role in a variety of cellular processes. Cell cycle regulation has been extensively studied due to its fundamental role in biology. Although preliminary evidence suggests that changes in membrane potential occur during the cell cycle, the possible role of Vm in cell cycle regulation is still unknown due to limitations in voltage imaging. The Miller lab has developed a series of VoltageFluors (VFs)...

Development and RNA SELEX of Passively Cell-Permeable Cyclic Peptides, by Kevin Yang

Development and RNA SELEX of Passively Cell-Permeable Cyclic Peptides, by Kevin Yang

RNA, as a cellular information carrier and gene regulator, has been implicated in many human diseases. The therapeutic potential of targeting RNA with drug-like small molecules is being increasingly recognized and explored, but the Ro5 drug space is becoming less able to address low complexity, difficult to drug macromolecule surfaces. Additionally, the physicochemical properties required to selectively target RNA from a membrane-permeable, therapeutically relevant paradigm remain unprobed...

Characterization of Cellular Prion Protein Modified with a Membrane Anchor in a... by Amy Freiberg

Characterization of Cellular Prion Protein Modified with a Membrane Anchor in a... by Amy Freiberg

Fatal neurodegenerative diseases are endemic to the aged population, with common symptoms including loss of memory and movement. The pathology of all neurodegenerative diseases is characterized by protein dysregulation in the brain. The cellular prion protein (PrPC), discovered by Nobel Laureate Dr. Stanley Prusiner, represents the causative agent of a class of transmissible neurodegenerative diseases known as prion diseases. Despite knowledge that PrPC initiates early events of toxicity at...

Turn-on Voltage-Sensitive Indicators for Hyperpolarized Membranes, by Jack McCann

Turn-on Voltage-Sensitive Indicators for Hyperpolarized Membranes, by Jack McCann

Fluorescent reporters provide a powerful way to interrogate biochemistry and biophysics in a non-invasive and high-throughput manner. Our group has been developing voltage-sensitive fluorophores (VF dyes) that respond to changes in biological membrane potential (Vm). This is done by utilizing photoinduced electron transfer (PeT) to modulate fluorescence in response to changes in the biological environment. PeT-based indicators rely on PeT either into the excited state (acceptor PeT) or out...

Fitness landscape-guided engineering of locally supercharged virus-like particle... by Paige Pistono

Fitness landscape-guided engineering of locally supercharged virus-like particle... by Paige Pistono

Protein-based nanoparticles are attractive models for studying self assembly and relatively underexplored as drug delivery vehicles. Virus-like particles (VLPs) are particularly of interest, as they can deliver many copies of a drug molecule per particle delivery event and bestow protective elements, such as shielding charged molecules from unfavorable electrostatic interactions or preventing nucleic acid degradation. In this work, we use the fitness landscape of the bacteriophage MS2 VLP...

Photoactivatable Nitrone Reagents for Methionine Bioconjugation, by Kacper Skakuj

Photoactivatable Nitrone Reagents for Methionine Bioconjugation, by Kacper Skakuj

While our understanding of the biological roles played by methionine residues continues to grow, the number of methods for selective covalent modification of these residues remains low. To address this discrepancy, we expand the oxaziridine-based redox activated chemical tagging (ReACT) methodology by developing nitrones as a photoactivatable bioconjugation reagents. We find that α,N-diaryl nitrones can efficiently photoisomerize to oxaziridines and the resulting α,N-diaryl oxaziridines...

Enhanced Cellular Delivery of Nucleotide-based STING Agonists using an Engineered... Paul Huang

Enhanced Cellular Delivery of Nucleotide-based STING Agonists using an Engineered... Paul Huang

Nucleotides are powerful therapeutic tools with a diverse array of disease applications. One class of these are cyclic dinucleotides (CDNs). These small-molecule messengers are agonists in the cGAS-STING pathway, which senses cytosolic DNA from pathogens or the host cell nucleus and triggers downstream global immune responses. Activation of cGAS-STING in cancer tissue has been shown to direct tumor clearance by immune cells, and STING agonists such as CDNs are a promising area of research...

Chemical Biology & Bioinorganic

Deciphering the Pharmacophore of Structurally Restrained DMT Analogs, by Andy Basargin

Deciphering the Pharmacophore of Structurally Restrained DMT Analogs, by Andy Basargin

Depressive disorders ranging from mild to severe are among the leading causes of disability in America. Since the emergence of the Covid pandemic, the percentage of Americans affected by depressive disorders has tripled. Current available anti-depressants are slow-acting and lack broad efficacy. Recent studies by Johns Hopkins Medicine researchers showed that the serotonergic hallucinogen psilocybin, an analog of N,N-Dimethylamine (DMT), provided fast-acting relief to major depressive...

Discovery and Preclinical Pharmacology of INE963, a Potent and Fast-Acting... by Anne–Catherine Mata

Discovery and Preclinical Pharmacology of INE963, a Potent and Fast-Acting... by Anne–Catherine Mata

A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage Plasmodium falciparum (Pf) growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, and toxicity properties and extended pharmacological profiles culminated in the identification of INE963 (1), which demonstrates potent...

Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule... by Andrew Ecker

Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule... by Andrew Ecker

KRAS mutations are one of the most common oncogenic drivers in human cancer. While small molecule inhibitors for the G12C mutant have been successfully developed, allele-specific inhibition for other KRAS hotspot mutants remains challenging. Here we report the discovery of covalent chemical ligands for the common oncogenic mutant K-Ras(G12R). These ligands bind in the Switch II pocket and irreversibly react with the mutant arginine residue. An X-ray crystal structure reveals an imidazolium...

A Non-hallucinogenic Analog of LSD with Potential for Treating Neuropsychiatric... by Jeremy R. Tuck

A Non-hallucinogenic Analog of LSD with Potential for Treating Neuropsychiatric... by Jeremy R. Tuck

A new class of therapeutics, known as psychoplastogens, which can rapidly elicit changes to structural and functional neural plasticity, has shown exceptional promise towards the treatment of neuropsychiatric diseases. One such psychoplastogen is lysergic acid diethylamide (LSD), a semi-synthetic ergoline alkaloid derived from lysergic acid and potent serotonin (5-HT) receptor agonist. However, LSD also produces intense, long-lasting hallucinations, and accordingly is incompatible with...

Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African... by Maxime Dauphinais

Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African... by Maxime Dauphinais

Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the Trypanosoma genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome...

The Computational Investigation of the Role of Sulfur Noncovalent Interactions... by Volga Kojasoy

The Computational Investigation of the Role of Sulfur Noncovalent Interactions... by Volga Kojasoy

Noncovalent interactions involving sulfur atoms significantly contribute to the protein and peptide structure, stability, and bioactivity. The uniquely folded structure of a protein is generated by the cooperation of many individual noncovalent interactions. Although only one of these interactions may contribute only a few kcals energetically to protein stability, a balance between various noncovalent interactions participates in building the overall protein framework. The impact of sulfur...

Synthesis and Evaluation of Silyl Amphiphilic Lactones for Control of Bacterial... by Linnea Dolph

Synthesis and Evaluation of Silyl Amphiphilic Lactones for Control of Bacterial... by Linnea Dolph

Non-polar alkyl and lipid groups are being recognized for having comparable importance in protein-ligand complex formation as their polar counterparts. This importance can be demonstrated by both the numerous lipid-containing natural products family as well as the addition of non-polar groups to existing drug targets that can increase both potency and efficacy. The development of silyl-containing lipophilic pharmacophores is proposed as a novel way to expand the existing hydrophobic chemical...

Turning cold tumors hot: discovery of novel TLR7 agonists as systemic agent... by Yam Poudel

Turning cold tumors hot: discovery of novel TLR7 agonists as systemic agent... by Yam Poudel

Potent TLR7 agonist can turn cold tumors hot in combination with immune check-point blockade agents such as Opdivo. We have designed and developed novel and TLR7 agonists that exhibited potent in vitro and in vivo activity.

Structure-based optimization of covalent, small molecule stabilizers of... by Markella Konstantinido

Structure-based optimization of covalent, small molecule stabilizers of... by Markella Konstantinido

The stabilization of protein - protein interactions (PPIs) has emerged as a promising strategy in chemical biology and drug discovery. Of particular interest within the PPIs are the “hub” proteins. The extensive interactome of “hub” proteins provides tremendous potential for drug discovery, but at the same time raises the question of selective targeting. Here, we are focusing on the hub protein 14-3-3, a scaffolding, highly abundant adaptor protein and aim to show that despite the...

Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs… by Julia Schaletzky

Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs… by Julia Schaletzky

SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with over 500 million confirmed cases and 6 million deaths. At this time, the only FDA-approved therapeutic for COVID-19 is remdesivir, a broad-spectrum antiviral nucleoside analog. Efficacy is only moderate, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted...

Turning the Other Cheek: Influence of the cis-Tetrafluorocyclohexyl Motif on... by Yong Wang

Turning the Other Cheek: Influence of the cis-Tetrafluorocyclohexyl Motif on... by Yong Wang

The targeted introduction of substituents in order to tailor a molecule’s pharmacologic, physicochemical, and metabolic properties has long been of interest to medicinal chemists. The all-cis tetrafluorocyclohexyl motif─dubbed Janus face, due to its electrostatically polarized cyclohexyl ring─represents one such example where chemists might incorporate a metabolically stable, polar, lipocompatible motif. To better understand its potential utility, we have synthesized three series...

GS-4224: A potent, oral small molecule PD-L1 inhibitor, by Michael Graupe

GS-4224: A potent, oral small molecule PD-L1 inhibitor, by Michael Graupe

Therapeutic antibodies that block the PD-1/PD-L1 interaction have rapidly become a key backbone of cancer therapy. A small molecule targeting the same interaction could have several advantages over an antibody, such as oral administration, higher penetration into the tumor, lack of systemic immunogenicity, and ease of manufacture. Here we present our PD-L1 inhibitor GS-4224 which is currently undergoing clinical trials. Utilizing protein X-ray crystallography, we discovered a lead series...

Core Exploration in the Discovery of Lenacapavir - a First-in-class Long-Acting HIV... by Kevin Chou

Core Exploration in the Discovery of Lenacapavir - a First-in-class Long-Acting HIV... by Kevin Chou

Daily oral antiretroviral therapies (ART) provide many life-saving treatment options for millions of people with HIV (PWH) and have shown to be effective in preventing new infections. Nonetheless, new classes of antiretroviral agents are continually needed to treat people with multidrug resistant HIV-1 and long-acting agents can help people with suboptimal adherence to daily oral regimens. The HIV-1 capsid protein is a novel and attractive target for therapeutic intervention due to its...

Predicting binding affinities of nucleic acid ligands with free energy perturbation, by Schrödinger

Predicting binding affinities of nucleic acid ligands with free energy perturbation, by Schrödinger

The accurate prediction of ligand binding affinities can play a major role in driving drug discovery programs. Among various methods for calculating binding affinities, free energy perturbation (FEP) calculations have been established as one of the most reliable and rigorous approaches. However, the application of this method has overwhelmingly been focused on small molecules binding to proteins. Yet with their important roles in essential cellular processes, such as cellular reproduction...

Medicinal & Computational Chemistry