Fluorine-containing pharmaceuticals approved by the FDA in 2020: Synthesis and biological activity

Thirteen new fluorine-containing drugs, which have been granted approval by the US Food and Drug Administration (FDA) in 2020, are profiled in this review. Therapeutic areas of these new fluorinated pharmaceuticals include medicines and diagnostic agents for Cushing's disease, neurofibromatosis, migraine, Alzheimer's disease, myelodysplastic syndromes, hereditary angioedema attacks, and various cancers. Molecules of these approved drugs feature aromatic fluorine (Ar-F) (11 compounds), aromatic Ar-CF₃ (1), aliphatic CHF (1) and CF₂ (1) groups. For each compound, we provide a spectrum of biological activity, medicinal chemistry discovery, and synthetic approaches.     

Fluorinated amino acids: compatibility with native protein structures and effects on protein-protein interactions

Fluorinated analogues of the canonical α-L-amino acids have gained widespread attention as building blocks that may endow peptides and proteins with advantageous biophysical, chemical and biological properties. This critical review covers the literature dealing with investigations of peptides and proteins containing fluorinated analogues of the canonical amino acids published over the course of the past decade including the late nineties. It focuses on side-chain fluorinated amino acids, the carbon backbone of which is identical to their natural analogues. Each class of amino acids--aliphatic, aromatic, charged and polar as well as proline--is presented in a separate section. General effects of fluorine on essential properties such as hydrophobicity, acidity/basicity and conformation of the specific side chains and the impact of these altered properties on stability, folding kinetics and activity of peptides and proteins are discussed (245 references).     

Nucleophilic displacement of aromatic nitro groups

The relative nucleofugicity of the nitro group in many aromatic nucleophilic substitution reactions rivals, and in some cases surpasses, that of the fluorine atom. The use of the nitro function as a leaving group in such reactions facilitates the synthesis of novel substituted benzene derivatives and simplifies the synthesis of a wide variety of heterocycles.     

The Synthesis and Herbicidal Evaluation of Fluorine-Containing Phenoxyacetoxyalkylphosphonate Derivatives

To investigate the influence of a fluorine moiety on the biological activity of phenoxyacetoxyalkylphosphonates, a series of fluorine-containing phenoxyacetoxyalkylphosphonates were synthesized and screened for herbicidal activity in a greenhouse. The majority of the title compounds showed better preemergence activity than postemergence activity against the test plants, especially on monocotyledon. Compound 5l exhibited notable activity. Results showed that by introducing a fluorine moiety to the parent structure of phenoxyacetoxyalkylphosphonates, a series of new compounds with satisfactory herbicidal activity could be synthesized. A reasonable combination of a fluorine moiety and other substituents on the benzene ring had a great influence on the herbicidal activity.     

Oxidized metabolites from benzo[a]pyrene, benzo[e]pyrene, and aza-benzo[a]pyrenes. A computational study of their carbocations formed by epoxide ring opening reactions

A DFT study aimed at understanding structure-reactivity relationships and fluorine substitution effects on carbocation stability in benzo[a]pyrene (BaP), benzo[e]pyrene (BeP), and aza-benzo[a]pyrene (aza-BaP) derivatives are reported. The relative energies of the resulting carbocations are examined and compared, taking into account the available biological activity data on these compounds. O-Protonation of the epoxides and diol epoxides leads to carbocation formation by barrierless processes. Charge delocalization modes in the resulting carbocations were deduced via NPA-derived changes in charges, and fluorine substitution effects were analyzed on the basis of charge density at different carbocation positions. Thus, fluorine substitution at sites bearing negative charge generated inductive destabilization of the carbocation, whereas a fluorine atom at a ring position which presented significant positive charge density produced a less pronounced destabilization due to fluorine p-pi back-bonding. Protonation reactions were also studied for the azaBaPs. In selected cases, the covalent adducts generated via bond formation with the exocyclic nitrogen of cytosine were computed and relative energies and geometries of the resulting adducts were examined.     

A step toward direct fullerene synthesis: C60 fullerene precursors with fluorine in key positions

Several fluorine containing polycyclic aromatic hydrocarbons with exact carbon atom topology of the C₆₀ fullerene have been synthesized. Different numbers of fluorine atoms were introduced in the key positions, as needed for an efficient intramolecular condensation to the fullerene molecule. The polycyclic aromatic compounds obtained represent attractive precursors for rational, high-yield fullerene synthesis by flash vacuum pyrolysis.     

The reaction of direct phenylation by nucleogenic cations as a method of synthesis of unknown or complicated tritium labeled compounds

As a result of ion-molecular reactions of nucleogenic phenyl cations, generated by tritium β-decay in polytritiated benzene, with nucleophilic centers of investigated substrates the direct phenylation has been realized at first time and unknown tritium labeled aromatic derivatives of polyvalent fluorine together with the different N-phenyl substituted pyridinium compounds which are important syntones for biological and medical investigations have been synthesized.     

New Cyanoarylporphyrazines with High Sensitivity of Photophysical Parameters to Viscosity as Promising Agents for Photodynamic Therapy

Photophysical properties and photodynamic activity for a series of cyanoarylporphyrazine pigments have been analyzed depending on the nature of the substituents and their position in the aromatic ring. Replacement of the fluorine atom in the para-position with the methoxy group leads to significant increase in the ratio of the dark and photoinduced cytotoxicities, i.e. potential therapeutic index of porphyrazine as photosensitizer in photodynamic cancer therapy.     

Recent Progress Toward Trifluoromethylselenolation Reactions

Recently, a great deal of work has been done in the construction of C–CF₃ or C–SCF₃ bonds, because these fluorine groups display remarkable biological properties. Despite a trifluoromethylseleno group like CF₃ or SCF₃ may also have potential biological activity, the work on the construction of the C–SeCF₃ bond is rarely reported. This mini‐review highlights recent developments in trifluoromethylselenolation reactions using fluorine reagents, such as (Me₄N )SeCF₃ , ClSeCF₃ , [(bpy)Cu(SeCF₃ )]₂, Me₃SiCF₃ , and HCF₃ . Five approaches to the trifluoromethylselenolation of organic compounds are summarized: (1) trifluoromethylselenolation of aryl, alkyl, and heteroaryl halides, aromatic compounds, and boronic acids; (2) trifluoromethylselenolation of terminal alkynes and propargylic chlorides; (3) trifluoromethylselenolation of allylic bromides, vinyl halides, α‐bromo‐α,β‐unsaturated carbonyl compounds, and acyl chlorides; (4) trifluoromethylselenolation of diazo compounds; and (5) synthesis of trifluoromethyl selenides from selenocyanates and fluoroform.     

Detection of primary and secondary amines in energy-related materials using an element-selective glow-discharge detector

Mutagenic primary polycyclic aromatic amines present in shale oil and synthetic crudes may be readily detected by a simple derivatization and Chromatographic procedure. Nitrogenous bases and amines are extracted from the sample with dilute mineral acid and derivatized with trifluoroacetic anhydride. The derivatized amines are separated by gas chromatography and specifically detected using a glow-discharge detector tuned to an emission wavelength of fluorine. Under these conditions, the aromatic nitrogenous bases, such as acridine, are not detected even though they are present in the sample. As little as 14 ng of fluorine, arising from the derivative of 33 ng of 2,4,6-trimethylaniline, can be detected. The selectivity of the glow-discharge detector for derivatized amines vs. nonderivatized aromatic nitrogenous bases was estimated to be a minimum of 200:1.     

Do Docking Sites Persist Upon Fluorination? The Diadamantyl Ether-Aromatics Challenge for Rotational Spectroscopy and Theory

Fluorinated derivatives of biological molecules have proven to be highly efficient at modifying the biological activity of a given protein through changes in the stability and the kind of docking interactions. These interactions can be hindered or facilitated based on the hydrophilic/hydrophobic character of a particular protein region. Diadamantyl ether (C₂₀H₃₀O) possesses both kinds of docking sites, serving as a good template to model these important contacts with aromatic fluorinated counterparts. In this work, an experimental study on the structures of several complexes between diadamantyl ether and benzene as well as a series of fluorinated benzenes is reported to analyze the effect of H→F substitution on the interaction and structure of the resulting molecular clusters using rotational spectroscopy. All experimentally observed complexes are largely dominated by London dispersion interactions with the hydrogen-terminated surface areas of diadamantyl ether. Already single substitution of one hydrogen atom with fluorine changes the preferred docking site of the complexes. However, the overall contributions of the different intermolecular interactions are similar for the different complexes, contrary to previous studies focusing on the difference in interactions using fluorinated and non-fluorinated molecules.     

Spontaneous Mirror‐Symmetry Breaking in Isotropic Liquid Phases of Photoisomerizable Achiral Molecules

Spontaneous mirror‐symmetry breaking is of fundamental importance in science as it contributes to the development of chiral superstructures and new materials and has a major impact on the discussion around the emergence of uniform chirality in biological systems. Herein we report chirality synchronization, leading to spontaneous chiral conglomerate formation in isotropic liquids of achiral and photoisomerizable azobenzene‐based rod‐like molecules. The position of fluorine substituents at the aromatic core is found to have a significant effect on the stability and the temperature range of these chiral liquids. Moreover, these liquid conglomerates occur in a new phase sequence adjacent to a 3D tetragonal mesophase.     

Hydrogen Bonds with Fluorine in Ligand–Protein Complexes-the PDB Analysis and Energy Calculations

Fluorine is a common substituent in medicinal chemistry and is found in up to 50% of the most profitable drugs. In this study, a statistical analysis of the nature, geometry, and frequency of hydrogen bonds (HBs) formed between the aromatic and aliphatic C–F groups of small molecules and biological targets found in the Protein Data Bank (PDB) repository was presented. Interaction energies were calculated for those complexes using three different approaches. The obtained results indicated that the interaction energy of F-containing HBs is determined by the donor–acceptor distance and not by the angles. Moreover, no significant relationship between the energies of HBs with fluorine and the donor type was found, implying that fluorine is a weak HB acceptor for all types of HB donors. However, the statistical analysis of the PDB repository revealed that the most populated geometric parameters of HBs did not match the calculated energetic optima. In a nutshell, HBs containing fluorine are forced to form due to the stronger ligand–receptor neighboring interactions, which make fluorine the “donor’s last resort”.     

Fluoroalkene chemistry: Part 1. Highly-toxic fluorobutenes and their mode of toxicity: reactions of perfluoroisobutene and polyfluorinated cyclobutenes with thiols

The reactions of four highly-toxic fluorobutenes - perfluoroisobutene (PFIB), 1-hydropentafluorocyclobutene (1-H), hexafluorocyclobutene (HFCB) and 3-chloropentafluorocyclobutene (3-Cl)—with propanethiol, 2,6-dimethoxybenzenethiol and N-acetylcysteine isopropyl ester were studied. PFIB and HFCB reacted with two molar equivalents of the aliphatic thiols, but with only one molar equivalent of the aromatic thiol (presumably due to steric hindrance) and resembled phosgene in their reactivity. The fluorocyclobutenes 1-H and 3-Cl reacted with one and up to three molar equivalents of the aliphatic thiols, respectively, but with only one molar equivalent of the aromatic thiol. The products of allyl and vinyl substitution were isolated and characterised as fully as possible. The inhalation toxicities of the fluorocyclobutenes to rodents correlated with the number of easily-displaceable fluorine substituents, supporting the contention that toxicity is due to reaction with biological thiols in the lung.     

Synthesis and features of thermolysis of fluorine-containing aromatic 1-hydroxy-1-hydroperoxides and 1,1′-dihydroperoxides

Aromatic fluorine-containing 1-hydroxy-1-hydroperoxides and 1,1′-dihydroxyperoxides were obtained and their thermolysis features were studied. The fluorine atoms incorporation into the aromatic ring of 1-hydroxy-1-hydroperoxides was found to lead to their thermal stability increase. 1,1′-Dihydroxyperoxides are the less thermal stable than 1-hydroxy-1-hydroperoxides. Compared to the fluorine atoms, incorporation of fluoroalkyl groups into the aromatic ring exerts greater effect on the stability of the peroxide.     

Dipole-induced structure in aromatic-terminated self-assembled monolayers: a study by near edge x-ray absorption fine structure spectroscopy

The structure of self-assembled monolayers presenting aromatic rings at a surface is studied by near edge x-ray absorption fine structure spectroscopy (NEXAFS). Fluorine substitution at asymmetric positions in the aromatic rings is used to generate a layer of dipoles at the surface of the monolayer. We find that fluorine substituted aromatic rings are more ordered than unsubstituted aromatic rings by a factor of two based on the polarization dependence of the lowest C 1s to pi* transition, which is associated with transitions from phenyl carbons attached to hydrogens. This result is consistent with the influence of dipole-dipole interactions and quadrupolar interactions between the aromatic groups due to the substitution of fluorine atoms. The work also serves to illustrate how subtle variations in the orientation of an end group of a self-assembled monolayer can be determined by using NEXAFS.     

2-Fluoro-5-nitrophenyldiazonium: A Novel Sanger-Type Reagent for the Versatile Functionalization of Alcohols

As a novel Sanger-type reagent, 2-fluoro-5-nitrophenyldiazonium tetrafluoroborate enabled the versatile functionalization of primary and secondary aliphatic alcohols. Based on a mild nucleophilic aromatic substitution of the fluorine atom under unprecedented, base-free conditions, the diazonium unit on the aromatic core of the resulting aryl-alkyl ether could be employed for such diverse transformations as radical C−H activation and cyclization, as well as palladium catalyzed cross-coupling reactions.     

Aromatic hydroxyl group plays a critical role in antibacterial activity of the curcumin analogues

The aim of this study was to investigate the role of the aromatic substituents of the curcumin scaffold on the antibacterial activity of the resulting curcumin analogues. Six curcumin analogues with different aromatic substituents were prepared and their antibacterial activities were evaluated against two Gram-positive and four Gram-negative bacteria. The structure-activity relationship study demonstrated that antibacterial activity of the curcumin analogues was critically dependent upon the aromatic hydroxyl group. Thus, hydroxycurcumin with an additional aromatic hydroxyl group on the curcumin scaffold showed antibacterial activity against all six pathogens tested and it remained effective even against ampicillin-resistant Enterobacter cloacae. Along with the previously reported antioxidative effect, the broad-spectrum antibacterial activity of the hydroxycurcumin warrants further investigation of its biological activity as well as extensive structure-activity relationship study of the curcumin analogues with various aromatic substituents.     

Positioning a Carbon–Fluorine Bond over the π Cloud of an Aromatic Ring: A Different Type of Arene Activation

It is known that the fluoro group has only a small effect on the rates of electrophilic aromatic substitutions. Imagine instead a carbon–fluorine (C?F) bond positioned tightly over the π cloud of an aryl ring—such an orthogonal, noncovalent arrangement could instead stabilize a positively charged arene intermediate or transition state, giving rise to novel electrophilic aromatic substitution chemistry. Herein, we report the synthesis and study of molecule 1 , containing a rigid C?F???Ar interaction that plays a prominent role in both its reaction chemistry and spectroscopy. For example, we established that the C?F???Ar interaction can bring about a >1500 fold increase in the relative rate of an aromatic nitration reaction, affording functionalization on the activated ring exclusively. Overall, these results establish fluoro as a through‐space directing/activating group that complements the traditional role of fluorine as a slightly deactivating aryl substituent in nitrations.     

Fluorine nuclear spin coupling constants in fluoro-substituted furans

In order to assist experimental assignments in olefinic and aromatic fluorine compounds, fluorine nuclear coupling constants have been obtained from the first-order self-consistent perturbation theory equation with the INDO molecular orbital approximation in a series of fluoro-substituted furans. There is a clear distinction between the magnitudes and signs for the four fluorine coupling positions; the importance of the orbital and spin-dipolar contributions is very clear. Tentative signs are suggested for all the coupling constants.