Configurationally restricted bis-tetraazamacrocyclic complexes: chemokine receptor antagonists

The chemokine receptor CXCR4 is a trans-membrane protein which has been implicated in many physiological and pathological processes including cancer, rheumatoid arthritis and most significantly HIV replication. CXCR4 plays a vital role in embryonic development but is not essential at the post-development stage; therefore, it has been identified as a potential therapeutic target.Bis-macrocyclic drugs (e.g. AMDS 100) bind to aspartate residues on the CXCR4 surface and inhibit HIV replication by blocking the interaction of gp!20/gp41 with the protein. The incorporation of transition metals (e.g. zinc(II) and copper(II)) into the macrocyclic cavity increases anti-viral potency. The addition of a bridging ethylene unit to the macrocyclic framework locks the complex into a single configuration, potentially optimising the interaction with the receptor.A series of configurationally restricted macrocyclic compounds have been prepared utilising bis-aminal chemistry. Characterisation by X-ray crystallography and X-ray absorption spectroscopy has confirmed that the complexes possessing an ethylene bridge between adjacent nitrogen atoms are fixed in the trans-II configuration and that complexes containing an ethylene bridge between non-adjacent nitrogen atoms adopt the cis-V configuration. In addition, solution EXAFS has been used as a model to probe the binding of the complexes to aspartate residues on the receptor surface.The zinc(II) trans-II and copper(II) cis-V complexes reported here are more potent against HIV replication than AMDS 100 (IC₅₀ values against IIIB ; 0.00208 µM, 0.00491 µM and 0.018 µM respectively), confirming the importance of coordination interactions for potent binding to CXCR4 and also validating the strategy of configurationally fixing the macrocyclic unit for optimising receptor binding. It is believed that both thermodynamic and kinetic properties are important for effective binding to CXCR4

One-pot radioiodination of aryl amines via stable diazonium salts: preparation of 125I-imaging agents

An operationally simple, one-pot, two-step tandem procedure that allows the incorporation of radioactive iodine into aryl amines via stable diazonium salts is described. The mild conditions are tolerant of various functional groups and substitution patterns, allowing late-stage, rapid access to a wide range of 125I-labelled aryl compounds and SPECT radiotracers

Late stage iodination of biologically active agents using a one-pot process from aryl amines

A simple and effective one-pot tandem procedure that generates aryl iodides from readily available aryl amines via stable diazonium salts has been developed. The operationally simple procedure and mild conditions allow late-stage iodination of a wide range of aryl compounds bearing various functional groups and substitution patterns. A novel synthetic strategy involving the preparation of nitroaryl compounds followed by a chemoselective tin(II) dichloride reduction and the use of the one-pot diazotisation–iodination transformation was also developed. The general applicability of this approach was demonstrated with the preparation of a number of medicinally important compounds including CNS1261, a SPECT imaging agent of the N-methyl-D-aspartate (NMDA) receptor and IBOX, a compound used to detect amyloid plaques in the brain

Triaza-macrocyclic complexes of aluminium, gallium and indium halides: fast 18F and 19F incorporation via halide exchange under mild conditions in aqueous solution

Rapid and complete fluorination of the complexes [MCl3(L)] (L = Me3-tacn, BzMe2-tacn, M = Al, Ga, In) occurs at room temperature via reaction of a MeCN solution of the complex with 3 mol. equivs. of KF in water. The Ga and In complexes are also readily fluorinated using R4NF (R = Me or nBu) in MeCN solution, whereas no reaction occurs with the Al species under these conditions. The distorted octahedral fac-trifluoride coordination at M is confirmed in solution by multinuclear (19F, 27Al, 71Ga and 115In) NMR spectroscopic studies, leading to sharp resonances with 19F-71Ga and 19F-115In couplings evident. The [MF3(L)] are extremely stable in aqueous solution and at low pH; they crystallise as tetrahydrates, [MF3(Me3-tacn)]·4H2O, with extended H-bonding networks formed through both F···H-O and O···H-O contacts. [InF3(BzMe2-tacn)]·1.2H2O also shows intermolecular F···H-O hydrogen bonding contacts. The prospects for developing this coordination chemistry further to take advantage of the high metal-fluoride bond energies to enable rapid, late-stage fluorination of large macromolecules under mild conditions for PET imaging applications in nuclear medicine are discussed. This work also demonstrates that F-18 radiolabelling to form [F-18] [GaF3(BzMe2-tacn)] is effected readily at room temperature in aqueous MeCN over 30-60 mins on addition of 2.99 mol equivs. of [19F]-KFaq and 0.4 mL [18F]-KFaq (100 – 400 MBq) to [GaCl3(BzMe2-tacn)] with ca. 30% incorporation

Nicotine patch preloading for smoking cessation (the preloading trial): study protocol for a randomized controlled trial

Background: The use of nicotine replacement therapy before quitting smoking is called nicotine preloading. Standard smoking cessation protocols suggest commencing nicotine replacement therapy only on the first day of quitting smoking (quit day) aiming to reduce withdrawal symptoms and craving. However, other, more successful smoking cessation pharmacotherapies are used prior to the quit day as well as after. Nicotine preloading could improve quit rates by reducing satisfaction from smoking prior to quitting and breaking the association between smoking and reward. A systematic literature review suggests that evidence for the effectiveness of preloading is inconclusive and further trials are needed. Methods/Design: This is a study protocol for a multicenter, non-blinded, randomized controlled trial based in the United Kingdom, enrolling 1786 smokers who want to quit, funded by the National Institute for Health Research, Health Technology Assessment program, and sponsored by the University of Oxford. Participants will primarily be recruited through general practices and smoking cessation clinics, and randomized (1:1) either to use 21 mg nicotine patches, or not, for four weeks before quitting, whilst smoking as normal. All participants will be referred to receive standard smoking cessation service support. Follow-ups will take place at one week, four weeks, six months and 12 months after quit day. The primary outcome will be prolonged, biochemically verified six-month abstinence. Additional outcomes will include point prevalence abstinence and abstinence of four-week and 12-month duration, side effects, costs of treatment, and markers of potential mediators and moderators of the preloading effect. Discussion: This large trial will add substantially to evidence on the effectiveness of nicotine preloading, but also on its cost effectiveness and potential mediators, which have not been investigated in detail previously. A range of recruitment strategies have been considered to try and compensate for any challenges encountered in recruiting the large sample, and the multicentre design means that knowledge can be shared between recruitment teams. The pragmatic study design means that results will give a realistic estimate of the success of the intervention if it were to be rolled out as part of standard smoking cessation service practice. Trial registration: Current Controlled Trials ISRCTN33031001. Registered 27 April 2012

Configurationally restricted bis-tetraazamacrocyclic complexes: chemokine receptor antagonists

The chemokine receptor CXCR4 is a trans-membrane protein which has been implicated in many physiological and pathological processes including cancer, rheumatoid arthritis and most significantly HIV replication. CXCR4 plays a vital role in embryonic development but is not essential at the post-development stage; therefore, it has been identified as a potential therapeutic target. Bis-macrocyclic drugs (e.g. AMDS 100) bind to aspartate residues on the CXCR4 surface and inhibit HIV replication by blocking the interaction of gp!20/gp41 with the protein. The incorporation of transition metals (e.g. zinc(II) and copper(II)) into the macrocyclic cavity increases anti-viral potency. The addition of a bridging ethylene unit to the macrocyclic framework locks the complex into a single configuration, potentially optimising the interaction with the receptor. A series of configurationally restricted macrocyclic compounds have been prepared utilising bis-aminal chemistry. Characterisation by X-ray crystallography and X-ray absorption spectroscopy has confirmed that the complexes possessing an ethylene bridge between adjacent nitrogen atoms are fixed in the trans-II configuration and that complexes containing an ethylene bridge between non-adjacent nitrogen atoms adopt the cis-V configuration. In addition, solution EXAFS has been used as a model to probe the binding of the complexes to aspartate residues on the receptor surface. The zinc(II) trans-II and copper(II) cis-V complexes reported here are more potent against HIV replication than AMDS 100 (IC₅₀ values against IIIB ; 0.00208 µM, 0.00491 µM and 0.018 µM respectively), confirming the importance of coordination interactions for potent binding to CXCR4 and also validating the strategy of configurationally fixing the macrocyclic unit for optimising receptor binding. It is believed that both thermodynamic and kinetic properties are important for effective binding to CXCR4