A5078826524- Chemical synthesis and alkaloids
- Alkaloids: synthesis and pharmacology
- Ubiquitin and proteasome pathways
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Cancer-related gene regulation
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- Advanced Synthetic Organic Chemistry
- Cancer-related Molecular Pathways
- Glioma Diagnosis and Treatment
- Cancer, Hypoxia, and Metabolism
- Psychedelics and Drug Studies
- Crystallography and molecular interactions
- Phosphorus compounds and reactions
- Chemical Synthesis and Reactions
- Cholinesterase and Neurodegenerative Diseases
- Cancer Treatment and Pharmacology
- Chemical Synthesis and Analysis
- Lung Cancer Treatments and Mutations
- Chemistry and Chemical Engineering
- HIV/AIDS drug development and treatment
- Catalytic C–H Functionalization Methods
- Chromatography in Natural Products
- Microtubule and mitosis dynamics
Ontario Institute for Cancer Research
2016-2024
McMaster University
2013-2023
University of North Carolina at Chapel Hill
2020
Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present collection chemical probes and associated reagents data to elucidate the function human murine PMTs in cellular studies. Our provides inhibitors antagonists that together modulate most key methylation marks on histones H3 H4, providing an important resource for modulating epigenomes. We describe comprehensive comparative characterization probe respect their...
WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement MLL1 gene associated with onset and progression acute myeloid lymphoblastic leukemias, targeting WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding small molecule ligands to WDR5 can modulate its MLL1, suppressing methyltransferase activity. Initial structure–activity relationship...
Increased activity of the lysine methyltransferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present first antagonists that block protein–protein interaction between N-terminal PWWP domain H3K36me2. Using virtual screening experimental validation, identified small-molecule antagonist 3f, which binds NSD2-PWWP1 a Kd 3.4 μM abrogates histone...
Abstract A total synthesis of the anticancer natural product (+)‐ trans ‐dihydrolycoricidine is reported from α‐azidoacetone and cinnamaldehyde precursors. Key elements include an asymmetric organocatalytic sequence proceeding by a regiospecific secondary‐amine‐catalyzed syn Michael addition followed intramolecular aldol reaction. The results in formation advanced intermediate, containing three stereogenic centers, one step which was converted into title compound eight steps.
Protein arginine methyltransferase 6 (PRMT6) catalyzes monomethylation and asymmetric dimethylation of residues in various proteins, plays important roles biological processes, is associated with multiple cancers. To date, a highly selective PRMT6 inhibitor has not been reported. Here we report the discovery characterization first-in-class, allosteric PRMT6, (R)-2 (SGC6870). potent (IC50 = 77 ± nM) outstanding selectivity for over broad panel other methyltransferases nonepigenetic targets....
The Amaryllidaceae alkaloid trans-dihydrolycoricidine 7 and three analogues 8–10 were produced via asymmetric chemical synthesis. Alkaloid proved superior to acyclovir, the current standard for herpes simplex virus, type 1 (HSV-1) infection. Compound potently inhibited lytic HSV-1 infection, significantly reduced reactivation, more varicella zoster virus (VZV) A configurationally defined (3R)-secondary alcohol at C3 crucial efficacious inhibition of
Synthesis of a new pinacolacetal-phosphonium salt and its reaction with aldehydes to give homologated acetals two-carbon unsaturated is presented. The chemistry takes place in water under mild conditions the sequence can be performed one-flask operation.
Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape this disease has led to identification serine/threonine kinase ALK2 as a potential target therapeutic intervention. In work, we adopted open science approach develop series potent type I inhibitors are orally bio-available and brain-penetrant. Initial efforts resulted in discovery M4K2009, analogue previously reported inhibitor LDN-214117....
The total synthesis of four novel mono-methoxy and hydroxyl substituted ring-A dihydronarciclasine derivatives enabled identification the 7-hydroxyl derivative as a potent selective antiviral agent targeting SARSCoV-2 HSV-1. concentration this small molecule that inhibited HSV-1 infection by 50% (IC50), determined using induced pluripotent stem cells (iPCS)-derived brain organ organoids generated from two iPCS lines, was estimated to be 0.504 µM 0.209 µM. No significant reduction in organoid...
AbstractThe development of semi-stabilized, stabilized, and functionalized ylides derived from short-chain trialkylphosphines in the Wittig-type olefination reactions toward synthesis alkenes, including stilbenes, styrenes, 1,3-dienes, as well reagents for homologation reactions, are described. The methods allow easy access to alkenes with high (E)-stereoselectivity good yield. These conducted weak bases aqueous media, which allows separation water-soluble phosphine oxides. a mild...
Abstract An asymmetric total synthesis of the natural product (+)‐trans‐dihydronarciclasine has been achieved from α‐azidoacetone and cinnamaldehyde precursors via a stepwise [3+3]‐organocatalytic cascade. The anti‐Zika virus activity this compound is also reported for first time.
USP5 is a deubiquitinase that has been implicated in range of diseases, including cancer, but no USP5-targeting chemical probe reported to date. Here, we present the progression series occupies C-terminal ubiquitin-binding site poorly characterized zinc-finger ubiquitin binding domain (ZnF-UBD) and competitively inhibits catalytic activity enzyme. Exploration structure–activity relationship, complemented with crystallographic characterization ZnF-UBD bound multiple ligands, led...
Despite decades of research on new diffuse intrinsic pontine glioma (DIPG) treatments, little or no progress has been made improving patient outcomes. In this work, we explored novel scaffold modifications
Abstract Acyclovir (ACV) is an effective antiviral agent for treating lytic Herpes Simplex virus, type 1 (HSV-1) infections, and it has dramatically reduced the mortality rate of herpes simplex encephalitis. However, HSV-1 resistance to ACV its derivatives being increasingly documented, particularly among immunocompromised individuals. The burgeoning drug compels search a new generation more efficacious anti-herpetic drugs. We have previously shown that trans-dihydrolycoricidine (R430),...
Abstract A total synthesis of the anticancer natural product (+)‐ trans ‐dihydrolycoricidine is reported from α‐azidoacetone and cinnamaldehyde precursors. Key elements include an asymmetric organocatalytic sequence proceeding by a regiospecific secondary‐amine‐catalyzed syn Michael addition followed intramolecular aldol reaction. The results in formation advanced intermediate, containing three stereogenic centers, one step which was converted into title compound eight steps.
A synthesis of densely functionalised α-acyloxy enaminals and enaminones<italic>via</italic>a novel homogeneous silver(<sc>i</sc>) catalyzed rearrangement 1-acyloxy-3-azido ketones is reported.
Drug resistance to front-line malarial treatments represents an ongoing threat control malaria, a vector borne infectious disease. The parasite, Plasmodium falciparum has developed genetic variants, conferring the current standard therapeutic artemisinin and its derivatives commonly referred as artemisinin-combination therapies (ACTs). Emergence of multi-drug parasite genotypes is warning potential treatment failure, reaffirming urgent critical need find validate alternate drug targets...
Abstract Despite considerable research on new therapeutics to treat DIPG, a universally fatal grade IV pediatric CNS tumor located in the pons region of brainstem, there has been minimal progress. Somatic missense mutations bone morphogenetic protein (BMP) type I receptor ACVR1 gene encoding activin receptor-like kinase-2 (ALK2) are present approximately 33% children with prompting our initial efforts towards development M4K2009, 3,5-diphenylpyridine ALK2 inhibitor. Looking improve potency,...
ABSTRACT Increased activity of the lysine methyltrans-ferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present first antagonists that block protein-protein interaction between N-terminal PWWP domain H3K36me2. Using virtual screening experimental validation, identified small-molecule antagonist 3f , which binds NSD2-PWWP1 a K d 3.4 μM abrogates...
Abstract PRMT6 catalyzes monomethylation and asymmetric dimethylation of arginine residues in various proteins, plays important roles biological processes is associated with multiple cancers. While there are several reported inhibitors, a highly selective inhibitor has not been to date. Furthermore, allosteric inhibitors protein methyltransferases rare. Here we report the discovery characterization first-in-class, PRMT6, SGC6870. SGC6870 potent (IC 50 = 77 ± 6 nM) outstanding selectivity for...
Abstract RBBP4 is a nuclear WD40 motif-containing protein widely implicated in various cancers and putative drug target. It interacts with multiple proteins within diverse complexes such as nucleosome remodeling deacetylase (NuRD) complex polycomb repressive 2 (PRC2), well histone H3 H4 through two distinct binding sites. B-cell lymphoma/leukemia 11A (BCL11A), friend of GATA-1 (FOG-1), plant homeodomain finger 6 (PHF6) bind to the top donut-shaped seven-bladed β-propeller fold RBBP4, while...