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FMOC-L-4-Fluorophe is a non-natural amino acid derivative that plays a crucial role in peptide engineering and drug design. Its molecular structure precisely integrates the natural backbone of L-phenylalanine, the precise modification of the ortho-fluorine atom, and the protection strategy of the fluorene methoxycarbonyl group:
The fluorine atom introduced at the position of the benzene ring can not only subtly regulate the electronic distribution and lipophilicity of the amino acid, but also serve as a sensitive probe for 19F nuclear magnetic resonance to real-time trace the folding, localization and metabolic processes of the peptide in the body; while its Fmoc protecting group ensures its perfect compatibility with the standard process in solid-phase synthesis, and can be efficiently removed through mild alkaline treatment. This characteristic makes it a core tool for optimizing the pharmacokinetic properties of therapeutic peptides.
By systematically replacing the natural phenylalanine, it can significantly enhance the affinity of the peptide to the target protein, improve membrane permeability and resist enzymatic degradation, and is widely used in the construction of new GPCR ligands, enzyme inhibitors and antibody-drug conjugates, providing a powerful chemical basis for the rational design of highly active biological agents.
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Chemical Formula |
C30H25NO4 |
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Exact Mass |
463 |
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Molecular Weight |
464 |
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m/z |
463 (100.0%), 464 (32.4%), 465 (2.7%), 465 (2.4%) |
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Elemental Analysis |
C, 77.74; H, 5.44; N, 3.02; O, 13.81 |
FMOC-L-4-Fluorophe,The full name is N - (9-fluorenylmethoxycarbonyl) - L-4-fluorophenylalanine (Fmoc-L-4-fluorophenylalanine, abbreviated as Fmoc-Phe (4-F) - OH), CAS number 169243-86-1, molecular formula C24H20FNO4, molecular weight 405.42, it is an alpha aminofluorenylmethoxycarbonyl (Fmoc) protected derivative of L-4-fluorophenylalanine, belonging to the core monomer of fluorinated non natural amino acid and solid-phase peptide synthesis (SPPS).
Core applications in the field of peptide drug synthesis
Fmoc Phe (4-F) - OH is a key non natural amino acid monomer for the development and production of peptide drugs. By accurately introducing 4-fluorophenylalanine residues into the peptide sequence, it significantly optimizes the drug properties, activity, stability, and pharmacokinetics (ADME) of peptide drugs. It is the core building block for anti-tumor, anti infection, metabolic disease, and central nervous system peptide drugs.
Natural phenylalanine (Phe) is easily hydrolyzed by proteases such as trypsin, chymotrypsin, and protease, resulting in a short half-life of peptide drugs in the body and requiring frequent administration. The 4-fluoro atom introduced by Fmoc Phe (4-F) - OH inhibits protease recognition and hydrolysis through both steric hindrance and electronic effects
Space shielding effect: The radius of fluorine atoms (0.147 nm) is close to that of hydrogen atoms (0.120 nm), but the electronegativity is extremely strong, forming an electron cloud shielding layer at the 4-position of the benzene ring, which hinders the binding of protease active centers.
Electronic effect: The strong electron withdrawing effect of fluorine reduces the electron cloud density of the benzene ring, weakens the conjugation of amide bond electron clouds, and reduces the hydrolytic activity of proteases on peptide bonds.
Application effect: Peptides containing 4-fluorophenylalanine have an in vivo half-life extended by 2-10 times, significantly reducing the frequency of administration. For example:
Anti tumor peptides: modify RGD peptides, octreotide, and somatostatin analogs to enhance targeting and retention time towards tumor tissues.
Antimicrobial peptides: modify defense factors and lactoferrin peptides to enhance bactericidal activity and serum stability against drug-resistant bacteria.
Hypoglycemic peptides: modify GLP-1 and glucagon like peptide analogs to prolong in vivo action time and reduce injection frequency.
Regulating the biological activity and receptor selectivity of peptide drugs
Fluorine atoms precisely regulate the binding affinity and selectivity of peptides with G protein coupled receptors (GPCRs), enzymes, ion channels, and antigen epitopes by altering molecular electrical properties, lipophilicity, and conformation
Enhancing receptor affinity: The dipole moment and hydrophobic interaction of 4-fluorophenylalanine optimize the binding between peptides and receptor hydrophobic pockets, increasing activity by 10-100 times. For example:
Neuropeptide Y (NPY) receptor ligand: Introducing Fmoc-L-4-Fluorophe increases the selectivity of Y1/Y5 receptors by 50 times, used for the treatment of obesity and anxiety.
Opioid receptor agonists: modify enkephalins and endorphins analogs to enhance analgesic activity and reduce addiction.
Optimize enzyme inhibition activity: Used for peptide synthesis of proteasome inhibitors, angiotensin-converting enzyme (ACE) inhibitors, and thrombin inhibitors. Fluorine atoms enhance hydrogen bonding and hydrophobic interactions with enzyme active centers, thereby increasing the inhibition constant (Ki).
Regulating peptide conformation: Fluorine atoms induce the formation of stable alpha helices and beta folds in peptides, reducing random curling and enhancing bioavailability and target binding specificity.
Improving the pharmacokinetic (ADME) properties of peptide drugs
Fmoc Phe (4-F) - OH comprehensively optimizes the ADME properties of peptides by regulating lipid solubility (LogP), membrane permeability, and plasma protein binding rate
Enhancing membrane permeability: Moderate increase in lipid solubility (LogP increase of 0.5-1.0) with 4-fluoro substitution, improving intestinal and blood-brain barrier (BBB) penetration, suitable for oral administration and central nervous system peptide drugs.
Optimize plasma binding: Fluorinated benzene ring enhances hydrophobic binding with albumin and lipoprotein, prolongs circulation time, and reduces renal clearance.
Reduce immunogenicity: Fluoride atoms mask antigenic epitopes, reduce the immunogenicity of peptide drugs, and lower the risk of allergic reactions.
Used for the synthesis of long-acting, targeted, and conjugated peptide drugs
Long acting peptides: Conjugated with polyethylene glycol (PEG), fatty acids, and albumin binding peptides, 4-fluorophenylalanine serves as the connecting site and stabilizing unit to prepare ultra long acting peptide drugs.
Targeted peptides: Introduced into tumor targeting, inflammation targeting, and tissue-specific peptides to enhance targeting affinity and stability.
Peptide drug conjugate (PDC): As a connecting arm and stabilizing module, it couples cytotoxic drugs and fluorescent probes to peptide carriers for precise tumor treatment and imaging.
Fmoc Phe (4-F) - OH is widely used in the synthesis and optimization of peptide drugs in Phase I-III clinical practice
Antitumor: Synthesize fluorooctreotide, fluoroRGD peptide, and fluoroapoptotic peptide for the treatment of neuroendocrine tumors and solid tumors.
Metabolic disease: fluoro GLP-1 analog, fluoro amylin analog, used for type 2 diabetes and obesity.
Anti infection: Fluorinated antimicrobial peptides and antifungal peptides are used to deal with multidrug-resistant bacterial infections.
Central nervous system: Fluoroneuropeptides, antiepileptic peptides, used for depression, epilepsy, and neuropathic pain.
This section mainly refers to sources:
- BenchChem. Step-by-step guide to 4-fluoro-L-phenylalanine solid-phase peptide synthesis. 2026.
- Application of MolAid. FMOC-L-4-FluoroPhe in Peptide Drug Metabolic Stabilization two thousand and twenty-five
- TCI Chemicals. Fmoc-Phe(4-F)-OH for Peptide Drug Discovery. 2025.
- PubMed. Fluorinated phenylalanines: Tools for modulating peptide stability and activity. 2024.
- MarketPublishers. Global Fmoc-4-fluoro-L-phenylalanine Market Report 2024–2030. 2024.
Basic Applications in Solid Phase Peptide Synthesis (SPPS) and Peptide Chemistry Research
FMOC-L-4-Fluorophe is a standard non natural amino acid monomer for Fmoc solid-phase peptide synthesis technology, suitable for manual/automatic SPPS, liquid-phase peptide synthesis, fragment condensation, and cyclic peptide synthesis. It is a core reagent for peptide chemistry research and industrial production.
Synthesis of linear peptides: coupling and deprotection with other Fmoc amino acids (Fmoc Gly OH, Fmoc Ala OH, Fmoc Lys (Boc) - OH, etc.) in sequence to synthesize the target peptide containing 4-fluorophenylalanine.
Coupling conditions: HATU/HOBt/DIPEA and DIC/Oxyma are commonly used as condensation reagents, DMF is used as the solvent, and the reaction time is 1-3 hours at room temperature. The coupling rate is>95%.
Deprotection conditions: 20% piperidine/DMF, room temperature for 5-20 minutes, quantitative removal of Fmoc groups.
Cutting conditions: TFA/TIS/water (95:2.5:2.5), room temperature 2-4 hours, removal of side chain protecting groups and resin cracking.
Synthesis of cyclic peptides: cyclic peptides and mimetic peptides are prepared by side chain amino/carboxyl/thiol cyclization, disulfide bond cyclization, and amide bond cyclization. Fluorine atoms enhance the stability and membrane permeability of cyclic peptides.
Synthetic modified peptides: used for phosphorylation, glycosylation, cardamoylation, biotinylation, and fluorescence labeling peptide synthesis, with 4-fluorophenylalanine as a stable backbone that does not interfere with the modification reaction.
Fmoc Phe (4-F) - OH is a classic fluorinated probe for peptide SAR research. By point by point substitution and comparison with natural phenylalanine, the active site, binding mode, and structure-activity relationship of peptides are analyzed
Localization of active residues: Replace the key phenylalanine residue in the polypeptide with 4-fluorophenylalanine, detect changes in activity, and determine whether the residue is a receptor binding core site.
Optimization of Combined Pocket: By comparing the substitution of phenylalanine with fluorine, chlorine, bromine, methyl, and methoxy groups, the optimal substituent is screened to enhance peptide affinity and selectivity.
Conformation activity correlation: Fluorine atoms induce conformational changes in peptides, combined with circular dichroism (CD) and nuclear magnetic resonance (NMR), to analyze the quantitative relationship between conformation and activity.
Combination peptide library: used for parallel synthesis, phage display, mRNA display peptide libraries, constructing fluorinated peptide libraries, high-throughput screening of highly active, stable, and selective lead compounds.
Targeted library: Construct fluorinated peptide libraries targeting GPCRs, kinases, and proteases to accelerate drug target discovery and lead optimization.
Peptide Purification, Identification, and Quality Control
Purification assistance: 4-fluorophenylalanine moderately increases peptide hydrophobicity, improves the separation efficiency of reverse phase high performance liquid chromatography (RP-HPLC), and enhances purification efficiency and purity.
Identification mark: Fmoc group with strong UV absorption (301 nm), capable of real-time monitoring of coupling and deprotection efficiency; Fluorine atoms provide ¹⁹ F NMR exclusive signals without ¹ H background interference, accurately identifying peptide structures.
This section mainly refers to sources:
- BenchChem. Application Notes for Fmoc-4-F-Phe-OH in Solid-Phase Peptide Synthesis. 2026.
- Chemical Book. Synthesis Method and Process of FMOC-L-4-Fluorophenylalanine Peptide two thousand and twenty-five
- Huayuan Network Application of Fmoc Amino Acid in Peptide Library Synthesis two thousand and twenty-five
- Fmoc Solid-Phase Peptide Synthesis: A Practical Approach. Oxford University Press. 2023.
Frequently Asked Questions
Q: Why does FMOC-L-4-Fluorophe sometimes show lower coupling efficiency in solid-phase peptide synthesis (SPPS) compared to unfluorinated FMOC-Phe?
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A: The electron‑withdrawing fluorine at the para position slightly reduces the nucleophilicity of the α‑amino group and increases steric hindrance of the aromatic ring. This can slow down acylation during coupling, leading to slightly lower conversion and more difficult condensation with bulky C‑terminal residues.
Q: Does the fluorine substituent affect the stability of the FMOC carbamate group during deprotection?
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A: Yes. The electron‑withdrawing effect of fluorine slightly increases the acidity of the N–H bond and marginally weakens the carbamate linkage. This can lead to a small amount of premature FMOC cleavage under prolonged basic washing conditions, though it does not significantly affect standard piperidine Fmoc removal protocols.
Q: Can FMOC-L-4-Fluorophe cause racemization more easily during coupling than other FMOC amino acids?
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A: Relatively more easily. The fluorine stabilizes the enolate intermediate formed at the α‑carbon during base‑mediated activation. Under strong base or prolonged coupling time, minor epimerization may occur, especially when using HOBt‑free coupling reagents or high‑pH conditions.
Q: How does para‑fluorine influence the hydrophobicity and retention behavior of FMOC-L-4-Fluorophe in HPLC?
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A: Fluorine increases lipophilicity but introduces weak polar interactions. Compared to FMOC‑Phe, it typically shows slightly longer retention on reversed‑phase C18 columns and is less prone to peak co‑elution with certain hydrophobic impurities. Fluorine‑specific dipole interactions also cause subtle changes in elution order in mixed peptide systems.
Q: Does FMOC-L-4-Fluorophe exhibit unusual solubility behavior in common SPFS solvents?
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A: Yes. It has lower solubility in pure DMF than FMOC-Phe but better solubility in DMF–DCM mixtures. The fluorine atom reduces crystal packing efficiency but increases polarity mismatch with highly polar aprotic solvents, leading to precipitation during long‑term storage in concentrated DMF solutions.
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