O4‐Alkylated‐2‐Deoxyuridine Repair by O6‐Alkylguanine DNA Alkyltransferase is Augmented by a C5‐Fluorine Modification

Oligonucleotides containing various adducts, including ethyl, benzyl, 4‐hydroxybutyl and 7‐hydroxyheptyl groups, at the O⁴ atom of 5‐fluoro‐O⁴‐alkyl‐2′‐deoxyuridine were prepared by solid‐phase synthesis. UV thermal denaturation studies demonstrated that these modifications destabilised the duplex by approximately 10 °C, relative to the control containing 5‐fluoro‐2′‐deoxyuridine. Circular dichroism spectroscopy revealed that these modified duplexes all adopted a B‐form DNA structure. O⁶‐Alkylguanine DNA alkyltransferase (AGT) from humans (hAGT) was most efficient at repair of the 5‐fluoro‐O⁴‐benzyl‐2′‐deoxyuridine adduct, whereas the thymidine analogue was refractory to repair. The Escherichia coli AGT variant (OGT) was also efficient at removing O⁴‐ethyl and benzyl adducts of 5‐fluoro‐2‐deoxyuridine. Computational assessment of N1‐methyl analogues of the O⁴‐alkylated nucleobases revealed that the C5‐fluorine modification had an influence on reducing the electron density of the O⁴?C_α bond, relative to thymine (C5‐methyl) and uracil (C5‐hydrogen). These results reveal the positive influence of the C5‐fluorine atom on the repair of larger O⁴‐alkyl adducts to expand knowledge of the range of substrates able to be repaired by AGT.     

Isotactic poly(1‐hexene sulfone)s by stereoselective anionic ring‐opening polymerisation

Background: Poly(olefin sulfone)s have been shown to form helical regions and to display main‐chain liquid‐crystalline behaviour in the bulk when they possess long side‐chains. It is believed that increasing the tacticity of the backbone could enhance their liquid‐crystalline behaviour. This study aims to produce tactic poly(olefin sulfone)s by stereospecific ring‐opening polymerisation. Results: T actic polythiranes were successfully obtained from a racemic mixture of thirane monomers using a series of chiral catalyst systems. The isotactic placement (P_i) was determined using ¹³C NMR analysis of carbons in or near the backbone. The polysulfides were oxidised by peracetic acid to their corresponding polysulfones. Powder X‐ray diffraction studies showed that the isotactic polysulfones formed more ordered structures than their atactic analogues, an effect attributed to a tightening of the helical pitch. Conclusions: Tactic poly(1‐hexene sulfone)s have been prepared for the first time by stereoselective ring‐opening polymerisation. Copyright © 2007 Society of Chemical Industry     

Discovery,Synthesis, and Optimization of Diarylisoxazole‐3‐carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore

The mitochondrial permeability transition pore (mtPTP) is a Ca²⁺‐requiring mega‐channel which, under pathological conditions, leads to the deregulated release of Ca²⁺ and mitochondrial dysfunction, ultimately resulting in cell death. Although the mtPTP is a potential therapeutic target for many human pathologies, its potential as a drug target is currently unrealized. Herein we describe an optimization effort initiated around hit 1 , 5‐(3‐hydroxyphenyl)‐N‐(3,4,5‐trimethoxyphenyl)isoxazole‐3‐carboxamide, which was found to possess promising inhibitory activity against mitochondrial swelling (EC₅₀<0.39 μM ) and showed no interference on the inner mitochondrial membrane potential (rhodamine 123 uptake EC₅₀>100 μM ). This enabled the construction of a series of picomolar mtPTP inhibitors that also potently increase the calcium retention capacity of the mitochondria. Finally, the therapeutic potential and in vivo efficacy of one of the most potent analogues, N‐(3‐chloro‐2‐methylphenyl)‐5‐(4‐fluoro‐3‐hydroxyphenyl)isoxazole‐3‐carboxamide ( 60 ), was validated in a biologically relevant zebrafish model of collagen VI congenital muscular dystrophies.     

Synthesis and Biological Evaluation of Purine 2′‐Fluoro‐2′‐deoxyriboside ProTides as Anti‐influenza Virus Agents

2′‐Fluoro‐2′‐deoxyguanosine has been reported to have potent anti‐influenza virus activity in vitro and in vivo. Herein we describe the synthesis and biological evaluation of 6‐modified 2′‐fluoro‐2′‐deoxyguanosine analogues and their corresponding phosphoramidate ProTides as potential anti‐influenza virus agents. Whereas the parent nucleosides were devoid of antiviral activity in two different cellular assays, the 5′‐O‐naphthyl(methoxy‐L ‐alaninyl) ProTide derivatives of 6‐O‐methyl‐2′‐fluoro‐2′‐deoxyguanosine, 6‐O‐ethyl‐2′‐fluoro‐2′‐deoxyguanosine, and 2′‐deoxy‐2′‐fluoro‐6‐chloroguanosine, and the 5′‐O‐naphthyl(ethoxy‐L ‐alaninyl) ProTide of 6‐O‐ethyl‐2′‐fluoro‐2′‐deoxyguanosine displayed antiviral EC₉₉ values of ～12 μM . The antiviral results are supported by metabolism studies. Rapid conversion into the L ‐alaninyl metabolite and then 6‐modified 2′‐fluoro‐2′‐deoxyguanosine 5′‐monophosphate was observed in enzymatic assays with yeast carboxypeptidase Y or crude cell lysate. Evidence for efficient removal of the 6‐substituent on the guanine part was provided by enzymatic studies with adenosine deaminase, and by molecular modeling of the nucleoside 5′‐monophosphates in the catalytic site of a model of ADAL1, thus indicating the utility of the double prodrug concept.     

Chemical Synthesis of the Epimeric (23R)‐ and (23S)‐Fluoro Derivatives of Bile Acids via Horner–Wadsworth–Emmons Reaction

A method for the synthesis of two (23R)‐ and (23S)‐epimeric pairs of 23‐fluoro‐3α,7α,12α‐trihydroxy‐5β‐cholan‐24‐oic acid and 23‐fluoro‐3α,7α‐dihydroxy‐5β‐cholan‐24‐oic acid is described. The key intermediates, 23,24‐dinor‐22‐aldehyde peracetates were prepared from cholic and chenodeoxycholic acids via the 24‐nor‐22‐ene, 24‐nor‐22ξ,23‐epoxy, and 23,24‐dinor‐22‐aldehyde derivatives. The Horner–Wadsworth–Emmons reaction of the 23,24‐dinor‐22‐aldehydes using triethyl 2‐fluoro‐2‐phosphonoacetate in the presence of LiCl and 1,8‐diazabicyclo[5,4,0]undec‐7‐ene (DBU), and subsequent hydrogenation of the resulting 23ξ‐fluoro‐22‐ene ethyl esters, followed by hydrolysis, gave a mixture of the epimeric (23R)‐ and (23S)‐fluorinated bile acids which were resolved efficiently by preparative RP‐HPLC. The stereochemical configuration of the fluorine atom at C‐23 in the newly synthesized compounds was confirmed directly by the X‐ray crystallographic data. The ¹H and ¹³C NMR spectral differences between the (23R)‐ and (23S)‐epimers were also discussed.     

Synthesis and Characterization of Octapeptide Somatostatin Analogues with Backbone Cyclization: Comparison of Different Strategies,Biological Activities and Enzymatic Stabilities

Somatostatin octapeptide analogues of the general sequence DPhe⁵‐Phe ⁶‐Tyr⁷‐DTrp⁸‐Lys⁹‐Val¹⁰‐Ph ¹¹‐Thr¹²‐NH₂ containing two types of backbone cyclization have been synthesized by the solid phase methodology. Backbone cyclization in these peptides was achieved via N‐modified phenylalanines in position 6 and 11. The N‐modified amino acids were incorporated as dipeptide building units which have been prepared in solution prior to the solid phase synthesis. Two dipeptide units of structure a) Fmoc‐aa ₁ ψ[CO—N((CH₂)_n‐X)]Phe—OH or b) Fmoc‐aa₁ ψ[CH₂—N(COlpar;CH₂)_n‐X)]Phe—OH have been introduced into the peptide sequence. Different resins and linkers were examined for an optimized peptide assembly and monitoring. The synthesized somatostatin analogues are highly resistant against enzymatic degradation as determined in vitro by incubation with rat liver homogenate. The biological activity was determined in binding experiments to the somatostatin receptors expressed in CHO‐ or BON‐1 cells. Most analogues show moderate activity without differentiation between the receptor subtypes.     

Pro‐oxidant Properties of AZT and other Thymidine Analogues in Macrophages: Implication of the Azido Moiety in Oxidative Stress

Zidovudine (azidothymidine, AZT) was the first drug approved for human immunodeficiency virus (HIV) treatment. Unfortunately, AZT is known to lead to severe side effects, many of which are generally thought to result from increased reactive oxygen species (ROS) production. In this work, the pro‐oxidative properties of AZT and other thymidine analogues were investigated electrochemically at microelectrodes. Macrophages pre‐incubated with AZT were found to release significant amounts of reactive species, including H₂O₂, ONOO^?, NO^. and NO₂^?. Interestingly, the total amounts of released species were the greatest when cells were incubated with azido‐containing analogues. The pro‐oxidative effect of these compounds decreased significantly when the free azide terminal group was modified by reaction with a triosmium cluster. As expected, thymidine incubation did not lead to any increase in overall ROS levels. This work implicates the azido moiety in AZT‐induced oxidative stress.     

Synthesis and characterization of novel poly(arylene ether)s based on 9,10‐bis‐(4‐fluoro‐3‐trifluoromethylphenyl) anthracene and 2,7‐bis‐(4‐fluoro‐3‐trifluoromethylphenyl) fluorene

Two new bisfluoro monomers 9,10‐bis‐(4‐fluoro‐3‐trifluoromethylphenyl) anthracene and 2,7‐bis‐(4‐fluoro‐3‐trifluoromethylphenyl) fluorene have been synthesized by the cross‐coupling reaction of 2‐fluoro‐3‐trifluoromethyl phenyl boronic acid with 9,10‐dibromo anthracene and 2,7‐dibromo fluorine, respectively. These two bisfluoro compounds were used to prepare several poly(arylene ether)s by aromatic nucleophilic displacement of fluorine with various bisphenols; such as bisphenol‐A, bisphenol‐6F, bishydroxy biphenyl, and 9,9‐bis‐(4‐hydroxyphenyl)‐fluorene. The products obtained by displacement of the fluorine atoms exhibits weight‐average molar masses up to 1.5 ×10⁵ g mol^?1 and number average molecular weight up to 6.8 × 10⁴ g mol^?1 in GPC. These poly(arylene ether)s show very high thermal stability even up to 490°C for 5% weight loss occurring at this temperature in TGA in synthetic air and showed glass transition temperature observed up to 310°C. All the polymers are soluble in a wide range of organic solvents, e.g., CHCl₃, THF, NMP, and DMF. Films cast from DMF solution are brittle in nature. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007     

Synthesis and Pharmacological Evaluation of Fluorinated Quinoxaline-Based κ-Opioid Receptor (KOR) Agonists Designed for PET Studies

κ-Opioid receptors (KORs) play a predominant role in pain alleviation, itching skin diseases, depression and neurodegenerative disorders such as multiple sclerosis. Therefore, imaging of KOR by a fluorinated PET tracer was envisaged. Two strategies were followed to introduce a F atom into the very potent class of cis,trans-configured perhydroquinoxalines. Whereas the synthesis of fluoroethyltriazole 2 has already been reported, fluoropyrrolidines 14 (1-[2-(3,4-dichlorophenyl)acetyl]-8-[(R)-3-fluoropyrrolidin-1-yl]-perhydroquinoxalines) were prepared by S_N2 substitution of a cyclic sulfuric acid derivative with hydroxypyrrolidine and subsequent transformation of the OH moiety into a F substituent. Fluoropyrrolidines 14 showed similar low-nanomolar KOR affinity and selectivity to the corresponding pyrrolidines, but the corresponding alcohols were slightly less active. In the cAMP and β-arrestin assay, 14b (proton at the 4-position) exhibited similar KOR agonistic activity as U-50,488. The fluoro derivatives 14b and 14c (CO₂CH₃ at the 4-position) revealed KOR-mediated anti-inflammatory activity as CD11c and the IFN-γ production were reduced significantly in mouse and human dendritic cells. Compounds 14b and 14-c also displayed anti-inflammatory and immunomodulatory activity in mouse and human T cells. The PET tracer [¹⁸F]- 2 was prepared by 1,3-dipolar cycloaddition. In vivo, [¹⁸F]- 2 did not label KOR due to very fast elimination kinetics. Nucleophilic substitution of a mesylate precursor provided [¹⁸F]- 14c . Unfortunately, defluorination of [¹⁸F]- 14c occurred in vivo, which was analyzed in detail by in vitro studies.     

FI Catalysts: A New Family of High Performance Catalysts for Olefin Polymerization

This paper reviews a new family of olefin polymerization catalysts. The catalysts, named FI catalysts, are based on non‐symmetrical phenoxyimine chelate ligands combined with group 4 transition metals and were developed using “ligand‐oriented catalyst design”. FI catalysts display very high ethylene polymerization activities under mild conditions. The highest activity exhibited by a zirconium FI catalyst reached an astonishing catalyst turnover frequency (TOF) of 64,900 s ^–1 atm ^–1, which is two orders of magnitude greater than that seen with Cp₂ZrCl₂ under the same conditions. In addition, titanium FI catalysts with fluorinated ligands promote exceptionally high‐speed, living ethylene polymerization and can produce monodisperse high molecular weight polyethylenes (M_w/M_n<1.2, max. M_n>400,000) at 50 °C. The maximum TOF, 24,500 min ^–1 atm ^–1, is three orders of magnitude greater than those for known living ethylene polymerization catalysts. Moreover, the fluorinated FI catalysts promote stereospecific room‐temperature living polymerization of propylene to provide highly syndiotactic monodisperse polypropylene (max. [rr] 98%). The versatility of the FI catalysts allows for the creation of new polymers which are difficult or impossible to prepare using group 4 metallocene catalysts. For example, it is possible to prepare low molecular weight (M_v∼10³) polyethylene or poly(ethylene‐co‐propylene) with olefinic end groups, ultra‐high molecular weight polyethylene or poly(ethylene‐co‐propylene), high molecular weight poly(1‐hexene) with atactic structures including frequent regioerrors, monodisperse poly(ethylene‐co‐propylene) with various propylene contents, and a number of polyolefin block copolymers [e.g., polyethylene‐b‐poly(ethylene‐co‐propylene), syndiotactic polypropylene‐b‐poly(ethylene‐co‐propylene), polyethylene‐b‐poly(ethylene‐co‐propylene)‐b‐syndiotactic polypropylene]. These unique polymers are anticipated to possess novel material properties and uses.     

Synthesis and characterization of pendent hydroxy fluoroesters of secondary high molecular weight guayule rubber

The epoxidation of secondary high molecular weight guayule rubber (SHMWGR) and subsequent ring opening with fluoroacids to give hydroxyfluoroesters (FGR) is reported. Structural characterization was performed with FTIR; ¹H-, ¹³C-, and ¹⁹F-NMR; and DSC. The percent epoxidation was quantitatively determined by ¹H-NMR. It was noted that the glass transition temperatures (T_g) of the FGR polymers increased with increasing fluoro acid content; however, reactions with longer chain, highly fluorinated acids lowered the T_g. © 1997 John Wiley & Sons, Inc. J Appl Polym Sci 63: 1077–1089, 1997     

Potent Fluoro‐oligosaccharide Probes of Adhesion in Toxoplasmosis

Unnatural, NMR‐ and MRI‐active fluorinated sugar probes, designed and synthesised to bind to the pathogenic protein TgMIC1 from Toxoplasma gondii, were found to display binding potency equal to and above that of the natural ligand. Dissection of the binding mechanism and modes, including the first X‐ray crystal structures of a fluoro‐oligosaccharide bound to a lectin, demonstrate that it is possible to create effective fluorinated probe ligands for the study of, and perhaps intervention in, sugar–protein binding events.     

Synthesis, receptor binding, and CNS pharmacological studies of new thyrotropin-releasing hormone (TRH) analogues

As part of our search for selective and CNS‐active thyrotropin‐releasing hormone (TRH) analogues, we synthesized a set of 44 new analogues in which His and pGlu residues were modified or replaced. The analogues were evaluated as agonists at TRH‐R1 and TRH‐R2 in cells in vitro, and in vivo in mice for analeptic and anticonvulsant activities. Several analogues bound to TRH‐R1 and TRH‐R2 with good to moderate affinities, and are full agonists at both receptor subtypes. Specifically, analogue 21 a (R=CH₃) exhibited binding affinities (K_i values) of 0.17 μM for TRH‐R1 and 0.016 μM for TRH‐R2; it is 10‐fold less potent than TRH in binding to TRH‐R1 and equipotent with TRH in binding to TRH‐R2. Compound 21 a , the most selective agonist, activated TRH‐R2 with a potency (EC₅₀ value) of 0.0021 μM , but activated TRH‐R1 at EC₅₀=0.05 μM , and exhibited 24‐fold selectivity for TRH‐R2 over TRH‐R1. The newly synthesized TRH analogues were also evaluated in vivo to assess their potencies in antagonism of barbiturate‐induced sleeping time, and several analogues displayed potent analeptic activity. Specifically, analogues 21 a , b and 22 a , b decreased sleeping time by nearly 50 % more than TRH. These analogues also displayed potent anticonvulsant activity and provided significant protection against PTZ‐induced seizures, but failed to provide any protection in MES‐induced seizures at 10 μmol kg^?1. The results of this study provide evidence that TRH analogues that show selectivity for TRH‐R2 over TRH‐R1 possess potent CNS activity.     

Highly fluorinated poly(ether‐imide)s derived from 2,2′‐bis(3,4,5‐trifluorophenyl)‐4,4′‐diaminodiphenyl ether and aromatic dianhydrides

A new diamine, 2,2′‐bis(3,4,5‐trifluorophenyl)‐4,4′‐diaminodiphenyl ether (FPAPE) was synthesized through the Suzuki coupling reaction of 2,2′‐diiodo‐4,4′‐dinitrodiphenyl ether with 3,4,5‐trifluorophenylboronic acid to produce 2,2′‐bis(3,4,5‐trifluorophenyl)‐4,4′‐dinitrodiphenyl ether (FPNPE), followed by palladium‐catalyzed hydrazine reduction of FPNPE. FPAPE was then utilized to prepare a novel class of highly fluorinated all‐aromatic poly(ether‐imide)s. The chemical structure of the resulting polymers is well confirmed by infrared and nuclear magnetic resonance spectroscopic methods. Limiting viscosity numbers of the polymer solutions at 25 °C were measured through the extrapolation of the concentrations used to zero. M_n and M_w of these polymers were about 10 000 and 25 000 g mol^?1, respectively. The polymers showed a good film‐forming ability, and some characteristics of their thin films including color and flexibility were investigated qualitatively. An excellent solubility in polar organic solvents was observed. X‐ray diffraction measurements showed that the fluoro‐containing polymers have a nearly amorphous nature. The resulting polymers had T_g values higher than 340 °C and were thermally stable, with 10% weight loss temperatures being recorded above 550 °C. Based on the results obtained, FPAPE can be considered as a promising design to prepare the related high performance polymeric materials. Copyright © 2011 Society of Chemical Industry     

Preparation,surface wetting properties,and protein adsorption resistance of well‐defined amphiphilic fluorinated diblock copolymers

Novel well‐defined amphiphilic fluorinated diblock copolymers P(PEGMA‐co‐MMA)‐b‐PC₆SMA were synthesized successfully by RAFT polymerization and characterized by FTIR, ¹HNMR and GPC. For copolymer coatings, static contact angles, θ, with water (θ_water ≥ 109.5^°) and n‐hexadecane (θ_hexadecane ≥ 68.9^°) pointed to the simultaneous hydrophobic and lipophobic characteristics of the copolymer surfaces. Dynamic contact angle measurements indirectly demonstrated that copolymer films underwent surface reconstruction upon contact with water, which results in a surface with surface coverage of polar PEG units. Moreover, the distinct nanoscale microphase segregation structures were proved by atomic force microscopy (AFM) images. Finally, using bovine serum albumin (BSA–FITC) as the model protein, copolymers exhibited excellent protein adsorption resistance. It is believed that the combination of surface reorganization and nanometer‐scale microphase segregation structure endows the excellent protein resistance for amphiphilic fluorinated copolymers. These results provide deeper insight of the effect of surface reconstruction and microphase segregation on the protein adsorption behaviors, and these amphiphilic fluoropolymers can expect to have potential applications as antifouling coatings in the field of marine and biomedical. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 41167.     

Synthesis and properties of fluoro‐polyetherimides

A series of amorphous fluoro‐polyetherimides based on 2,2′‐bis(3,4‐dicarboxyphenyl) hexafluropropane dianhydride (6FDA) and di‐ether‐containing diamines 4,4′‐bis(3‐aminophenoxy)diphenyl sulfone (m‐SED), 4,4′‐bis(4‐aminophenoxy)diphenyl sulfone (p‐SED), 4,4′‐bis(4‐aminophenoxy)diphenyl propane (BPADE) were synthesized. These melt processable polyetherimide polymers from p‐SED and BPADE showed excellent electrical properties. The dielectric constants, 2.74 and 2.65 at 10 MHz respectively, are lower than commercially available polyetherimide ULTEM® 1000, and polyimide Kapton® H films. In addition, we found that trifluoromethyl groups‐containing polyimides not only show extraordinary electrical properties, but they also exhibit excellent long‐term thermo‐oxidative stability and reduced water absorption relative to non‐fluorinated polyimides. The weight retention of these fluoro‐polyetherimides at 315°C for 300 h in air varies from 93% to 98%. Whereas, their moisture absorption at 100 RH at 50°C was in the range of 0.3% to 1.05%, which is much lower than those of Ultem 1000 and Kapton H. In the case of fluoro‐polyetherimides from p‐SED and m‐SED (para and meta isomers) diamines with ‘ether’ and sulfonyl (‐SO₂‐) spacer groups, the d‐spacing and T_g values decreased from 4.72Å to 4.56Å and 293°C to 244°C respectively. Similarly, the transparency of these polymer films (in the range of 80% to 90%) at 500 nm solar wavelength was higher than Ultem 1000 and Kapton H.     

Two pathways for pyrrole formation in coumermycin A(1) biosynthesis: the central pyrrole moiety is formed from L-threonine

Coumermycin A₁ is an aminocoumarin antibiotic produced by Streptomyces rishiriensis. It contains three pyrrole rings, that is, two terminal 5‐methyl‐pyrrole‐2‐carboxyl moieties and a central 3‐methylpyrrole‐2,4‐dicarboxylic acid moiety. The biosynthesis of the terminal pyrrole moieties has been elucidated previously. However, the biosynthetic precursors of the central pyrrole moiety have remained unknown, and none of the genes or enzymes involved in its formation has been identified. We now show that five genes, contained in a contiguous 4.7 kb region within the coumermycin biosynthetic gene cluster, are required for the biosynthesis of this central pyrrole moiety. Each of these genes was deleted individually, resulting in a strong reduction or an abolishment of coumermycin production. External feeding of the central pyrrole moiety restored coumermycin production. One of these genes shows similarity to L ‐threonine kinase genes. Feeding of [U‐¹³C,¹⁵N]L ‐threonine and ¹³C NMR analysis of the resulting compound unequivocally proved that threonine was incorporated intact into the central pyrrole (19 % enrichment) to provide the heterocyclic nitrogen as well as four of the seven carbons of this moiety. Therefore, this pyrrole is formed via a new, hitherto unknown biosynthetic pathway. A hypothesis for the reaction sequence leading to the central pyrrole moiety of coumermycin A₁ is presented.     

Superhydrophobic films of UV‐curable fluorinated epoxy acrylate resins

Photopolymerization processes are often used in industrial applications because of their solvent‐free formulations and various advantages over conventional thermal processes. Fluorinated monomers and oligomers yield coatings of great interest because of the peculiar characteristics of fluorine atoms: these coatings show hydrophobicity, chemical stability, weathering resistance, etc. Novel UV‐curable fluorinated epoxy acrylate oligomers were synthesized from 1H,1H‐perfluorohexan‐1‐ol, 1,6‐hexamethylene diisocyanate (HDI) and epoxy acrylate (EA). The HDI plays the role of a spacer group in the side chain between the EA backbone chain and the fluorinated segment. This new spacer containing a urethane moiety with long alkyl groups can exhibit a self‐organization effect through the formation of strong hydrogen bonding. This resulted in a stiffening of the whole HDI urethane–perfluoalkyl chain to form nanostructure surface segregation. The designed fluorinated EA with fluoroalkyl (C₅F₁₁) units in the side chain exhibited a contact angle of about 151°, which is in the superhydrophobic range. Copyright © 2010 Society of Chemical Industry     

Probing the Outstanding Local Hydrophobicity Increases in Peptide Sequences Induced by Incorporation of Trifluoromethylated Amino Acids

In order to achieve accurate determination of the local hydrophobicity increases in peptide sequences produced by incorporation of trifluoromethylated amino acids (TfmAAs), the chromatographic hydrophobicity indexes (?₀) of three series of tripeptides containing three unnatural trifluoromethylated amino acids have been measured and compared with those of their non‐fluorinated analogues. The hydrophobic contribution of each fluorinated amino acid was quantified by varying the position and the protection of (R)‐ and (S)‐α‐trifluoromethylalanine (TfmAla), (R)‐trifluoromethylcysteine (TfmCys), and (S)‐trifluoromethionine (TFM) in a short peptide sequence. As a general trend, strong increases in hydrophobicity were precisely measured, even exceeding the high hydrophobic contribution of the natural amino acid isoleucine. This study validates the incorporation of trifluoromethylated amino acids into peptide sequences as a rational strategy for the fine‐tuning of hydrophobic peptide–protein interactions.     

Synthesis and application of the first radioligand targeting the allosteric binding pocket of chemokine receptor CXCR3

Strategies for the identification of allosteric modulators of chemokine receptors largely rely on various cell‐based functional assays. Radioligand binding assays are typically not available for allosteric binding sites. We synthesized, purified, and applied the first tritium‐labeled allosteric modulator of the human chemokine receptor CXCR3 (RAMX3, [³H]N‐{1‐[3‐(4‐ethoxyphenyl)‐4‐oxo‐3,4‐dihydropyrido[2,3‐d]pyrimidin‐2‐yl]ethyl}‐2‐[4‐fluoro‐3‐(trifluoromethyl)phenyl]‐N‐[(1‐methylpiperidin‐4‐yl)methyl]acetamide). RAMX3 is chemically derived from 8‐azaquinazolinone‐type allosteric modulators and binds to the CXCR3 receptor with a K_d value of 1.08 nM (specific activity: 80.4 Ci mmol^?1). Radioligand displacement assays showed potent negative cooperativity between RAMX3 and chemokine CXCL11, providing a basis for the use of RAMX3 to investigate other potential allosteric modulators. Additionally, the synthesis and characterization of a number of other full and truncated 8‐azaquinazoline analogues were used to validate the binding properties of RAMX3. We demonstrate that RAMX3 can be efficiently used to facilitate the discovery and characterization of small molecules as allosteric modulators of the CXCR3 receptor.