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

Computer Based De Novo Design of Drug like Molecules Literature Seminar Report By

Introduction: One of the biggest challenges facing today’s pharmaceutical industry is the discovery of new drugs, with economic pressures driving for a quicker turn around time. Most drugs are designed by either modifying the structure of known drugs, by screening compound libraries using disease models, or by developing proteins as therapeutic agents or vaccines. Newer methods involve computerized methods t

Hydrothermal synthesis of Group 13 metal trifluoride complexes with neutral N-donor ligands

The reactions of the hydrated Group 13 fluorides, MF3·3H2O (M = Al, Ga or In) with 2,2?:6?,2??-terpyridyl, 2,2?-bipyridyl or 1,10-phenanthroline under hydrothermal conditions (180 °C/15 h) produced high yields of the complexes [MF3(terpy)]·3H2O, [MF3(bipy)(OH2)]·2H2O and [MF3(phen)(OH2)]. X-Ray crystal structures of [M?F3(terpy)]·3H2O (M? = Al or Ga), [M?F3(bipy)(OH2)]·2H2O and [GaF3(phen)(OH2)] show that all of them contain distorted octahedral geometries at the metal with mer-trifluoride coordination. Extensive H-bonding (FH–OH) links the molecules. The complexes have been further characterised by microanalysis, IR, 1H, 19F{1H} and 27Al NMR spectroscopy. In contrast, reactions of the trifluorides with the acyclic triamine, N,N,N?,N?,N??-pentamethyldiethylenetriamine, under similar hydrothermal conditions results in cleavage of the triamine and ring-closure to form the 1,1,4-trimethylpiperazinium cation, [?Me2N(CH2)2NMe(CH2)2]+, with fluorometallate anions, and confirmed by X-ray analysis of [?Me2N(CH2)2NMe(CH2)2]2[Al2F8(OH2)2]·2H2O. The strongly H-bonded [GaF3(terpy)]·3H2O was also obtained by Cl/F exchange from [GaCl3(terpy)] and [NBu4]F or [K(2,2,2-crypt)]F. Crystallisation of a mixture of [NH4][PF6] and [GaF3(terpy)]·3H2O from aqueous solution produced the edge-bridged cationic complex, [{Ga(terpy)F}2(?-F)2][PF6]2. The synthesis of the more sterically bulky [GaCl3(tBu3-terpy)] (tBu3-terpy = 4,4?4??-tris-tBu-2,2?:6?,2??-terpyridyl) and the crystal structure of [GaCl2(tBu3-terpy)][GaCl4], which contains a trigonal bipyramidal cation, are also reported

Independent initiation of primary electron transfer in the two branches of the photosystem I reaction center

Photosystem I (PSI) is a large pigment-protein complex that unites a reaction center (RC) at the core with ∼100 core antenna chlorophylls surrounding it. The RC is composed of two cofactor branches related by a pseudo-C2 symmetry axis. The ultimate electron donor, P700 (a pair of chlorophylls), and the tertiary acceptor, FX (a Fe4S4 cluster), are both located on this axis, while each of the two branches is made up of a pair of chlorophylls (ec2 and ec3) and a phylloquinone (PhQ). Based on the observed biphasic reduction of FX, it has been suggested that both branches in PSI are competent for electron transfer (ET), but the nature and rate of the initial electron transfer steps have not been established. We report an ultrafast transient absorption study of Chlamydomonas reinhardtii mutants in which specific amino acids donating H-bonds to the 131-keto oxygen of either ec3A (PsaA-Tyr696) or ec3B (PsaB-Tyr676) are converted to Phe, thus breaking the H-bond to a specific ec3 cofactor. We find that the rate of primary charge separation (CS) is lowered in both mutants, providing direct evidence that the primary ET event can be initiated independently in each branch. Furthermore, the data provide further support for the previously published model in which the initial CS event occurs within an ec2/ec3 pair, generating a primary ec2+ec3- radical pair, followed by rapid reduction by P700 in the second ET step. A unique kinetic modeling approach allows estimation of the individual ET rates within the two cofactor branches

Radiofluorination of a pre-formed gallium(III) aza-macrocyclic complex: towards next-generation positron emission tomography (PET) imaging agents

As part of a study to investigate the factors influencing the development of new, more effective metal-com-plex-based positron emission tomography (PET) imaging agents, the distorted octahedral complex, [GaCl(L)]·2HO has been prepared by reaction of 1-benzyl-1,4,7-triazacyclono-nane-4,7-dicarboxylic acid hydrochloride (HL·HCl) with Ga(NO)·9HO, which is a convenient source of GaIII for reactions in water. Spectroscopic and crystallographic data for [GaCl(L)]·2HO are described, together with the crystal structure of [GaCl(L)]·MeCN. Fluorination of this complex by Cl/ F- exchange was achieved in high yield by treatment with KF in water at room temperature over 90 minutes, although the reaction was complete in approximately 30 minutes if heated to 80 °C, giving [GaF(L)]·2HO in good yield. The same complex was obtained by hydrothermal synthesis from GaF·3HO and LiL, and has been characterised by singlecrystal X-ray analysis, IR, 1H and 19F{1H} NMR spectroscopy and ESI + MS.Radiofluorination of the pre-formed [GaCl(L)]·2 HO has been demonstrated on a 210 nanomolar scale in aqueous NaOAc at pH 4 by using carrier-free F , leading to 60-70% F-incorporation after heating to 80 8C for 30 minutes. The resulting radioproduct was purified easily by using a solid-phase extraction (SPE) cartridge, leading to 98-99% radiochemical purity. The [Ga F(L)] is stable for at least 90 minutes in 10% EtOH/NaOAc solution at pH 6, but defluorinates over this time scale at pH of approximately 7.5 in phosphate buffered saline (PBS) or human serum albumin (HSA). The subtle role of the Group 13 metal ion and coligand donor set in influencing the pH dependence of this system is discussed in the context of developing potential new imaging agents for PET

Rigor of Research Methods in Studies of the Effectiveness and Safety of Cataract Extraction With Intraocular Lens Implantation

Objective: To assess the rigor of research methods reported in studies of the safety or effectiveness of contemporary cataract surgery. Design: Formal systematic identification of pertinent studies and critical appraisal of each study\u27s research methods. Subjects: From 6113 unique, potentially relevant citations that we identified, 90 original studies published between 1979 and 1991 that addressed visual acuity or complications following standard extracapsular cataract extraction with posterior chamber intraocular lens implantation, phacoemulsification with posterior chamber intraocular lens implantation, or intracapsular cataract extraction with flexible anterior chamber intraocular lens implantation. Main Outcome Measures: Strength of study design, performance, and reporting in 11 methodologic areas assessed with a standardized abstraction form by two reviewers masked to authors, their institutions, and the journal of publication. Results of reviews were tallied to produce an overall quality score (measure of rigor in research methods) for each study. Results: The mean (±SD) quality score was 43.1±20.1 out of a maximum possible score of 100. Studies received intermediate scores on description of baseline ocular disease and low scores on descriptions of other characteristics of enrolled patients, standardization of outcome assessment and follow-up duration, and handling of patient attrition. Eighty-three studies (92%) lacked a comparison group. The rigor of research methods in studies varied by the journal of publication, did not improve over time, and was no greater for studies with larger vs smaller sample sizes. Conclusions: The rigor of research methods in studies of cataract surgery can be improved if more attention is paid to fundamental principles of study design, data analysis, and reporting. © 1994, American Medical Association. All rights reserved

[GaF3(BzMe2-tacn)] – a neutral ‘metalloligand’ towards alkali metal and ammonium cations in water

The neutral complex, [GaF3(L)] (L = 1-benzyl-4,7-dimethyl-1,4,7-triazacyclononane, BzMe2-tacn), acts as a ‘metalloligand’ to Na+, K+ and [NH4]+ cations in aqueous solution, forming supramolecular assemblies containing significant Na/K–F and H3N+H⋯F coordination. κ1-[BF4]− and κ2-[PF6]− coordination is also evident to Na+ and K+, respectively

Synthesis of the Literature on Visual Acuity and Complications Following Cataract Extraction With Intraocular Lens Implantation

Objective: To better define the effectiveness and risks of modern cataract surgery. Design: Meta-analysis (formal systematic identification, selection, review, and synthesis) of published literature. Patients: Patients described in 90 studies published between 1979 and 1991 that addressed visual acuity (n=17 390 eyes) or complications (n=68 316 eyes) following standard extracapsular cataract extraction with posterior chamber intraocular lens implantation, phacoemulsification with posterior chamber intraocular lens implantation, or intracapsular cataract extraction with flexible anterior chamber intraocular lens implantation. Main Outcome Measures: The proportion of eyes with postoperative Snellen visual acuity of 20/40 or better and the proportion of eyes with each of 18 complications. Results: The pooled percentage of eyes (weighted by sample size) with postoperative visual acuity of 20/40 or better was 95.5% (95% confidence interval [CI], 95.1% to 95.9%) among eyes without preexisting ocular comorbidity and 89.7% (95% CI, 89.3% to 90.2%) for all eyes. The pooled percentage of eyes experiencing complications (weighted by sample size and, when pertinent, by quality score of the individual studies but not adjusted for variation in duration of follow-up) ranged from 0.13% for endophthalmitis to 19.7% for posterior capsule opacification. Pooled proportions of eyes with other complications were as follows: bullous keratopathy, 0.3%; intraocular lens malposition/dislocation, 1.1%; clinically apparent cystoid macular edema, 1.5%; and retinal detachment, 0.7%. Pooled results for postoperative Snellen visual acuity and most complications were similar for surgery performed via phacoemulsification vs standard extracapsular cataract extraction, although comparisons of the outcomes between these procedures should be interpreted with caution. Conclusions: The published literature indicates that modern cataract surgery yields excellent visual acuity and, although not free of complications, is a very safe procedure regardless of the extraction technique used. © 1994, American Medical Association. All rights reserved