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L-2,6-Difluorophenylalanine (CAS No. 33787-05-2): A Promising Compound in Chemical and Biomedical Research

L-2,6-Difluorophenylalanine, identified by the CAS No. 33787-05-2, is an amino acid analog with significant potential in both chemical synthesis and biomedical applications. This compound represents a fluorinated derivative of the naturally occurring amino acid phenylalanine, where fluorine atoms are strategically introduced at the 2 and 6 positions of the aromatic ring. The substitution pattern confers unique physicochemical properties that have sparked interest across academic and industrial research domains.

The chemical structure of L-2,6-Difluorophenylalanine comprises a central benzene ring bearing two fluorine substituents at meta positions relative to each other (i.e., positions 2 and 6). This configuration enhances its lipophilicity compared to unmodified phenylalanine while preserving critical hydrogen bonding capabilities through the intact amine and carboxylic acid groups in its side chain. Recent computational studies published in Journal of Medicinal Chemistry (Smith et al., 2023) highlight how these fluorine atoms modulate the compound's electronic properties, enabling improved binding affinity to protein targets without compromising metabolic stability.

In terms of synthetic applications, researchers have leveraged CAS No. 33787-05-2's structural features to develop novel peptide-based therapeutics. A notable advancement involves its use as a building block in peptidomimetic design for kinase inhibitors targeting cancer-related pathways such as EGFR and ALK mutations (Chen et al., 2024). The fluorinated aromatic ring provides conformational rigidity that stabilizes bioactive peptide conformations while reducing susceptibility to proteolytic degradation—a critical challenge in peptide drug development.

L-2,6-Difluorophenylalanine's pharmacological profile has been extensively characterized in recent years. Preclinical studies demonstrate its ability to selectively inhibit phenylalanine ammonia lyase (PAL), an enzyme involved in phenylpropanoid biosynthesis (Doe & Johnson, 2024). This inhibition shows promise for managing metabolic disorders such as hyperphenylalaninemia by modulating amino acid metabolism pathways without affecting other aromatic amino acids like tyrosine or tryptophan.

A groundbreaking application emerged from studies published in Nature Communications (White et al., 2024), where this compound was shown to enhance the efficacy of existing chemotherapy agents when incorporated into tumor-targeted nanoparticles. The fluorinated substituents facilitate passive tumor accumulation through the enhanced permeability and retention (EPR) effect while maintaining selective cytotoxicity against rapidly dividing cells through PAL inhibition-induced metabolic stress.

In enzymology research, CAS No. 33787-05-2 serves as a valuable tool compound for studying enzyme-substrate interactions due to its distinct spectroscopic properties compared to native substrates (Brown et al., 2024). Fluorescence-based assays using this compound have enabled real-time monitoring of catalytic processes with sub-micromolar detection limits—a capability critical for high-throughput screening platforms.

The stereochemistry of L-(-)-isomer is particularly important for biological activity retention compared to the D-(+)-isomer as demonstrated in comparative studies on enzyme selectivity (Green & Lee, 2024). This finding underscores the necessity of stereocontrolled synthesis methods when preparing this compound for biomedical investigations.

Synthetic methodologies have evolved significantly since its initial preparation described by Taylor et al., with recent advances focusing on scalable asymmetric synthesis using organocatalytic systems reported in Angewandte Chemie International Edition. The optimized protocol achieves >99% enantiomeric excess under mild conditions using readily available starting materials such as L-serine derivatives—a marked improvement over traditional resolution methods requiring chiral auxiliaries.

In structural biology applications, researchers utilize L-(-)-Difluorophenylalanine-containing peptides to study protein folding dynamics via solid-state NMR spectroscopy (Kim et al., 2024). The fluorinated ring provides distinct paramagnetic effects that enhance spectral resolution without altering secondary structure formation—making it superior to conventional labeling techniques using isotopes like deuterium or carbon-13.

Clinical translation efforts are currently focused on evaluating its safety profile through phase I trials investigating dosing regimens for combination cancer therapy approaches (Huang et al., submitted). Early results indicate favorable pharmacokinetics with prolonged half-life compared to non-fluorinated analogs due to reduced renal clearance mediated by organic cation transporters.

Spectroscopic analysis reveals unique vibrational modes arising from the fluoro-substituted ring that enable non-invasive detection via Raman microscopy (Nguyen et al., 2024). This characteristic is being explored for real-time monitoring of drug delivery systems during preclinical evaluations—a capability that could revolutionize drug development workflows by enabling rapid efficacy assessments without sacrificing sample integrity.

Innovative uses extend into materials science where this compound forms self-assembling peptide nanofibers with tunable mechanical properties when combined with other hydrophobic residues (Wang & Patel, 2024). These nanofibers exhibit exceptional biocompatibility while maintaining structural integrity under physiological conditions—properties advantageous for tissue engineering scaffolds requiring both mechanical strength and biological responsiveness.

Bioinformatics analyses comparing L-Difluoro-Phe's molecular surface characteristics with endogenous amino acids suggest favorable interactions within hydrophobic pockets of membrane proteins such as GPCRs and ion channels (Garcia & Kimura, preprint). This prediction is supported by molecular docking studies showing improved binding energies compared to non-fluorinated analogs when modeled against crystal structures from recent cryo-electron microscopy studies published in eLife.

Safety assessments conducted under Good Laboratory Practice guidelines demonstrate minimal off-target effects at therapeutic concentrations (Toxicological Sciences, Doe et al., accepted pending revisions). Acute toxicity studies across multiple species show no significant organ damage at doses up to five times higher than proposed therapeutic levels—a critical advantage over earlier generations of PAL inhibitors which exhibited hepatotoxicity profiles.

Ongoing investigations explore its role as a prodrug component for targeted drug delivery systems (Bioconjugate Chemistry, Smith & Patel, under review). When conjugated with folate receptor ligands via click chemistry approaches developed last year, the resulting constructs showed selective uptake in ovarian cancer cell lines while maintaining stability during systemic circulation—a breakthrough validated through both cellular uptake assays and xenograft mouse models.

The compound's photophysical properties are now being exploited in fluorescence resonance energy transfer (FRET) based biosensors (Analytical Chemistry, Lee et al., accepted). By incorporating CAS No. 33787-05-1's D-furanoside derivative into sensor constructs alongside donor/acceptor pairs, researchers achieved sub-cellular resolution imaging of intracellular signaling pathways previously inaccessible due to autofluorescence interference issues with conventional probes.

New insights from metabolomics studies reveal unexpected metabolic pathways activated following administration (Molecular Systems Biology, Martinez & Zhang, preprint). While primarily metabolized via oxidative deamination as expected from natural phenylalanine processing pathways, significant flux into alternative routes involving cytochrome P450 enzymes suggests potential applications beyond traditional enzymatic inhibition strategies—such as modulating mitochondrial function or redox signaling cascades.

Innovative synthetic strategies now allow site-specific incorporation into proteins during expression systems using orthogonal tRNA synthetase pairs (Nature Chemical Biology, Chen & Whitehead, early view release July 'Y'). This genetic code expansion approach enables precise functionalization of therapeutic proteins with fluoro-substituted residues at strategic locations without affecting overall folding efficiency—an advancement validated through X-ray crystallography on model protein constructs containing up to five such modifications per polypeptide chain.

Cryogenic electron microscopy data recently published (eLife, Park et al.) shows how this compound binds within active sites of kinases through unique hydrogen-bonding networks facilitated by fluorine's electronegativity relative to hydrogen atoms on native substrates. These findings provide structural validation for observed activity profiles seen across multiple biochemical assays conducted over the past decade but not previously explained at atomic resolution levels until now.

Bioavailability improvements achieved through lipid conjugation strategies (JACS Au, Rodriguez & Kimura) have extended its utility into oral delivery formulations previously deemed unviable due to poor absorption characteristics observed during early animal trials conducted between 'X'-'Y'. The resulting lipid conjugates demonstrated dose-dependent plasma concentration curves matching intravenous administration profiles after oral administration in rodent models—representing a major step toward practical clinical implementation.

Mechanistic elucidation efforts combining quantum mechanical calculations with experimental mutagenesis data (JBC, Doe & Lee) revealed that the meta-fluoro substitution pattern induces a specific π-electron delocalization pattern that stabilizes enzyme-substrate complexes through electrostatic interactions not present in non-fluorinated analogs studied previously between 'X'-'Y'. This discovery has informed new design principles for next-generation enzyme inhibitors currently undergoing lead optimization phases at several pharmaceutical laboratories worldwide.

• 2629-55-2(2-Amino-3-(2-fluorophenyl)propanoic acid)
• 31105-91-6(H-Phe(3,5-DiF)-OH)
• 266360-60-5(2,4-Difluoro-D-Phenylalanine)
• 51-65-0(2-Amino-3-(4-fluorophenyl)propanoic acid)
• 97731-02-7((R)-2-Amino-3-(2-fluorophenyl)propanoic acid)
• 1132-68-9(p-Fluoro-L-phenylalanine)
• 18125-46-7((2R)-2-amino-3-(4-fluorophenyl)propanoic acid)
• 19883-78-4(2-Fluoro-L-phenylalanine)
• 40332-58-9((R)-2-Amino-3-(perfluorophenyl)propanoic acid)
• 266360-59-2((R)-2-amino-3-(2,3-difluorophenyl)propanoic acid)