The small and highly electronegative fluorine atom can play a remarkable role in medicinal chemistry. Selective installation of fluorine into a therapeutic or diagnostic small molecule candidate can enhance a number of pharmacokinetic and physicochemical properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to target protein has also been documented in a number of cases. A further emerging application of the fluorine atom is the use of 18 F as a radiolabel tracer atom in the exquisitely sensitive technique of Positron Emission Tomography (PET) imaging. This short review aims to bring together these various aspects of the use of fluorine in medicinal chemistry applications, citing selected examples from across a variety of therapeutic and diagnostic settings. The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development. A major challenge moving forward will be how and where to install fluorine in a rational sense to best optimise molecular properties.

The synthesis of some ebselen analogues and diaryl diselenides, which have amino acid functions as an intramolecularly coordinating group (Se···O) has been achieved by the DCC coupling procedure. The reaction of 2,2'-diselanediylbis(5-tert-butylisophthalic acid) or the activated ester tetrakis(2,5-dioxopyrrolidin-1-yl) 2,2'-diselanediylbis(5-tert-butylisophthalate) with different C-protected amino acids (Gly, L-Phe, L-Ala, and L-Trp) afforded the corresponding ebselen analogues. The used precursor diselenides have been found to undergo facile intramolecular cyclization during the amide bond formation reaction. In contrast, the DCC coupling of 2,2'-diselanediyldibenzoic acid with C-protected amino acids (Gly, L/D-Ala and L-Phe) affords the corresponding amide derivatives and not the ebselen analogues. Some of the representative compounds have been structurally characterized by single-crystal X-ray crystallography. The glutathione peroxidase (GPx)-like activities of the ebselen analogues and the diaryl diselenides have been evaluated by using the coupled reductase assay method. Intramolecularly stabilized ebselen analogues show slightly higher maximal velocity (V(max)) than ebselen. However, they do not show any GPx-like activity at low GSH concentrations at which ebselen and related diselenides are active. This could be attributed to the peroxide-mediated intramolecular cyclization of the corresponding selenenyl sulfide and diaryl diselenide intermediates generated during the catalytic cycle. Interestingly, the diaryl diselenides with alanine (L,L or D,D) amide moieties showed excellent catalytic efficiency (k(cat)/K(M)) with low K(M) values in comparison to the other compounds.

The isolation of pure [2-(phenylazo)phenyl-C,N 0 ]tellurium(IV) tribromide ( 6) has been achieved by modifying the reported procedure, which involved transmetalation of [2-(phenylazo)phenyl-C, N 0 ]mercury(II) chloride (7) with TeBr 4 . The mixed-valent derivative bis[2-(phenylazo)phenyl-C, N 0 ]ditellurium dichloride (19), incorporating both a divalent and a tetravalent tellurium, was obtained serendipitously during the reduction of [2-(phenylazo)phenyl-C,N 0 ]tellurium(IV) trichloride (16) with hydrazine hydrate. Bis[2-(phenylazo)phenyl-C,N 0 ]telluride (10) has been synthesized by the ortholithiation route. Telluride 10, on treatment with SO 2 Cl 2 and Br 2 , underwent oxidative addition to give the expected Te(IV) halogenated products bis[2-(phenylazo)phenyl-C,N 0 ]tellurium(IV) dichloride (13) and bis[2-(phenylazo)phenyl-C,N 0 ]tellurium(IV) dibromide (11), respectively. However, a similar reaction of 10 with I 2 resulted in the formation of an unexpected telluronium cation, iodobis[2-(phenylazo)phenyl-C,N 0 ]telluronium triiodide (14), and [2-(phenylazo)phenyl-C,N 0 ]tellurenenyl(II) iodide (12). Alkaline hydrolysis of 16 under reflux conditions resulted in the formation of monomeric [2-(phenylazo)phenyl-C,N 0 ]tellurinic acid (20) and its sodium salt (21) as a cocrystal. Bis[[2-(phenylazo)phenyl-C,N 0 ]tellurium]oxide (22) was obtained from the hydrolysis of [2-(phenylazo)phenyl-C,N 0 ]tellurium(II) chloride (17). The reaction of 13 with an alkaline solution resulted in the formation of the corresponding bis[2-(phenylazo)phenyl-C,N 0 ]tellurium(IV) oxide (23) and dichlorobis[2-(phenylazo)phenyl-C,N 0 ]tellurium(IV) oxide ( 24). The identity of all the derivatives was confirmed by multinuclear NMR ( 1 H, 13 C, 125 Te) and FT-IR spectroscopy, elemental analysis, and ESI-MS. The structures for tellurium derivatives 6, 10-14, 17, 19, 20-23, and 23A were also confirmed by X-ray crystallography. Density functional theory (DFT) was utilized for optimizing the geometries of 11, 13, and 14 to examine the possibility of a four-membered intramolecular Te 3 3 3 N interaction.

Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate. In human cell cultures, compound 32 resulted in suppression of Th2 cytokine responses to allergens, while in vivo intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of 32 of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals.

No abstract