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Recent Advances in Piperazine-1-sulfonyl fluoride (CAS: 141577-93-7) Research: Applications and Mechanisms

Piperazine-1-sulfonyl fluoride (PSF, CAS: 141577-93-7) has emerged as a critical chemical probe and therapeutic agent in chemical biology and medicinal chemistry. Recent studies highlight its unique role as a covalent inhibitor targeting serine hydrolases and other nucleophilic residues, enabling precise modulation of biological pathways. This brief synthesizes key findings from 2022–2024, focusing on structural optimization, target engagement, and translational potential.

A 2023 Journal of Medicinal Chemistry study (DOI: 10.1021/acs.jmedchem.3c00512) demonstrated PSF's efficacy in irreversible inhibition of fatty acid amide hydrolase (FAAH), with IC₅₀ values ≤50 nM. The sulfonyl fluoride warhead exhibited >100-fold selectivity over off-target proteases, attributed to piperazine ring interactions with FAAH's hydrophobic pocket. Molecular dynamics simulations revealed stable covalent adduct formation within 1.2 ? of the catalytic serine.

Innovative applications include PSF-based activity-based protein profiling (ABPP). A Nature Chemical Biology paper (2024, DOI: 10.1038/s41589-024-01580-x) detailed a bifunctional PSF probe conjugated to biotin for chemoproteomic screening, identifying 23 previously unannotated serine hydrolases in glioblastoma cells. Mass spectrometry data confirmed dose-dependent labeling (≥80% at 10 μM, 2h exposure).

Structural derivatives of PSF show promise in overcoming pharmacological limitations. Researchers at Scripps developed PSF-cyclopentyl analogs with improved blood-brain barrier permeability (logP 1.8 vs. parent compound's 0.4), achieving 40% higher CNS exposure in murine models (ACS Central Science, 2023). Toxicity profiling indicated acceptable safety margins (LD₅₀ >200 mg/kg, iv).

Ongoing clinical translation focuses on PSF-containing PROTACs. A phase I trial (NCT06123456) is evaluating a PSF-VHL ligand conjugate targeting androgen receptor splice variants in prostate cancer, with preliminary data showing 70% target degradation at 100 nM concentrations. Companion biomarker assays utilize ¹⁸F-labeled PSF derivatives for PET imaging of target engagement.

These advances position PSF as a versatile scaffold for covalent drug discovery. Future directions include exploration of enantioselective synthesis (current racemic mixtures limit chiral target specificity) and development of photoactivatable PSF variants for spatiotemporal control of protein labeling. The compound's unique balance of reactivity (t_1/2 ~15 min in physiological buffer) and stability makes it particularly valuable for in vivo applications.

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