Studies on Metastable Heterocycles: 2-Formyl-3-methylene-1-pyrroline

Organic Letters · 2026-03-10

A Staudinger-based synthesis of a stable acylal precursor to 2-formyl-3-methylene-1-pyrroline has been developed. Subsequent acetyl transfer to phenoxide in dry THF generates a mono acetyl potassium hemiacetal that decomposes to the target aldehyde in situ. While the product cannot be concentrated without decomposition, it can be characterized in solution and engaged in diverse reactions. These include nucleophilic substitution, cycloadditions, and an unprecedented Lewis acid-base-mediated dimerization forming pyrrolo-pyrroline scaffolds.

In Vitro and In Vivo Evaluation of Small-Molecule Disassemblers of Pathological Tau Fibrils

ACS Chemical Neuroscience · 2026-01-05 · 2 citations

Aggregation of the microtubule-binding protein tau is the histopathological hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, which are collectively known as tauopathies. Tau aggregation in AD patients is correlated with neuron loss, brain atrophy, and cognitive decline, and pro-aggregation tau mutations are sufficient to cause neurodegeneration and dementia in humans and tauopathy model mice. Thus, reversing tau aggregation is a potential therapeutic avenue for AD. In a previous study, we discovered CNS-11, a small molecule that disaggregates AD patient brain-extracted tau fibrils in vitro. In this study, we identify two chemical analogs of CNS-11, named CNS-11D and CNS-11G, that disaggregate AD patient brain-extracted tau fibrils and prevent seeding in a tau aggregation cell culture model. We also demonstrate that 8 weeks of treatment with either CNS-11D or CNS-11G reduces levels of insoluble tau in a mouse model of tauopathy. Our work defines the properties of two small molecules that diminish aggregation of tau in vivo and provides further support for structure-based methods to target tau for treatment of AD.

Bridging Heterocycle-Mediated Hydrogen Bonding Facilitates Permeability of Polar Macrobicycles

Journal of the American Chemical Society · 2026-04-15

Octafluorocyclopentene engages linear, unprotected peptides in relative-rate-controlled polysubstitution cascades. In one flask at ambient temperature, the reactions generate stable, fluoro-crowned macrobicyclic structures that display dual-loop surfaces. A subset of these molecules was found to have unusually high membrane permeability, as measured by PAMPA. Structures with a bridging imidazole unit were overrepresented in this group. To probe this finding, a larger set of compounds was synthesized wherein peripheral functionality and the bridging residue were incrementally varied. Crystallographic data, NMR studies, and MD simulations indicate the imidazole-bridged structures adopt conformations stabilized by internal H-bonding. The heterocycle further serves to occlude cavity water and allows macrobicycles harboring polar residues, such as serine and aspartate, to retain passive permeability. Calculations reveal a quantity termed ‘desolvation cost efficiency’ that is predictive of PAMPA performance. This parameter may be leveraged for the de novo design of polar peptidomimetics that can enter cells passively.

CCDC 2524526: Experimental Crystal Structure Determination

The Cambridge Structural Database · 2026-04-16

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Origin of Octafluorocyclopentene Polyelectrophilicity

Journal of the American Chemical Society · 2024-02-14 · 6 citations

Octafluorocyclopentene (OFCP) has found utility as a polyelectrophile in substitution cascades that form complex macrocyclic compounds. The Harran group synthesis of macrocyclic polypeptides depends on OFCP as a linker, combining with four different nucleophilic units of a polypeptide. We report a computational investigation of the origins of OFCP reactivity and a rationale for controlled mono-, di-, tri-, and tetrasubstitution of fluoride ions by heteroatomic nucleophiles. The roles of inductive, negative hyperconjugative, and resonance electron-donation by fluoride substituents are explored for the reaction of OFCP, less-fluorinated analogues, and common electrophilic alkenes with several different nucleophiles.

Indolizinylalanine Regioisomers: Tryptophan Isosteres with Bathochromic Fluorescence Emission

The Journal of Organic Chemistry · 2024-09-23 · 3 citations

We have developed a high yielding synthesis of indolizine and directly elaborated the molecule into three optically active indolizinylalanine regioisomers. The protocols exploit metal catalyzed coupling of indolizinyl-halides with organozinc reagents derived from carbamoylated iodoalanine esters. The scalable protocols provide products in a form amenable to solid-phase peptide synthesis (SPPS). When incorporated into peptides, the indolizine heterocycle is more basic and markedly less nucleophilic than tryptophan. Its protonated vinylpyridinium form is deeply colored in solution while the neutral heterocycle is highly fluorescent. The fluorescence quantum yield of indolizine exceeds that of indole and aza-indoles in water, suggesting that indolizinylalanines could be powerful optical probes of protein structure and dynamics, functioning as true tryptophan isosteres.

Supplementary Table 7 from SMAC Mimetic (JP1201) Sensitizes Non–Small Cell Lung Cancers to Multiple Chemotherapy Agents in an IAP-Dependent but TNF-α–Independent Manner

2023-03-30

<p>PDF file - 72K, There are significant negative and positive correlations with various oncogene and tumor suppression gene mutations. * Bold figures identify significant Pearson correlations (p<0.05).</p>

Supplementary Table 1 from SMAC Mimetic (JP1201) Sensitizes Non–Small Cell Lung Cancers to Multiple Chemotherapy Agents in an IAP-Dependent but TNF-α–Independent Manner

2023-03-30

<p>PDF file - 674K, Cells labeled with tumor type of NSCLC have an undetermined histotype. Genes listed in the table have mutations in the tumor lines marked with +, determined by sequencing by the Sanger Center (Forbes et al., 2001). Tumor types are as follows, adenocarcinoma (AC), squamous cell carcinoma (SCC), large cell carcinoma (LCC), tumors with undefined histo-subtype are simply labeled as NSCLC.</p>

Supplementary Figure 4 from SMAC Mimetic (JP1201) Sensitizes Non–Small Cell Lung Cancers to Multiple Chemotherapy Agents in an IAP-Dependent but TNF-α–Independent Manner

2023-03-30

<p>PDF file - 69K, Western blot analysis of activated caspase 4 after chemotherapy treatment. H1395 cells were treated with 500 nM gemcitabine, 100 nM vinorelbine, or 500 nM thapsigargan (a known ER stress inducer), samples were collected as indicated, protein isolated and analyzed by western blot for HSP90 and caspase 4.</p>

Supplementary Table 4 from SMAC Mimetic (JP1201) Sensitizes Non–Small Cell Lung Cancers to Multiple Chemotherapy Agents in an IAP-Dependent but TNF-α–Independent Manner

2023-03-30

<p>PDF file - 45K, Cells were seeded at 500 cells per well in 6 well dishes. The appropriate concentrations of drug were prepared from stock solutions in medium and given to cells for 10-28 days depending on the cell line. At the end of the assay, medium was aspirated and cells were fixed and stained with 0.5% methylene blue in 50% ethanol for 30 minutes. After staining, wells were washed and black and white images of the plates were taken using a ChemiDoc XRS imager and colonies counted (Quantity One software v4.6.5, BioRad, Hercules, CA). Colony counts are averages of triplicate wells done in triplicate over a two week period. - indicates where no drug sensitivity data has been determined.</p>